Table of SynGAP1 Isoform α2 (UniProt Q96PV0-1) Missense Variants.
| c.dna | Variant | SGM Consensus | Domain and Structure information: based on WT protein | Annotated databases | Deep learning-based pathogenicity predictions | Folding stability-based pathogenicity predictions | Sequence/structure-based pathogenicity predictions | Phase Separation | Evolutionary/physical properties | Molecular Dynamics-based analysis | DOI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Domain | IUPred2 | ANCHOR2 | AlphaFold | MobiDB | PhosphoSitePlus | ClinVar | gnomAD | ESM1b | AlphaMissense | FoldX | Rosetta | Foldetta | PremPS | REVEL | PROVEAN | PolyPhen-2 HumDiv | PolyPhen-2 HumVar | FATHMM | SIFT | PSMutPred | PAM | Physical | SASA | Normalized B-factor backbone | Normalized B-factor sidechain | SynGAP Structural Annotation | |||||||||||||||||||||||||||||||||||||||||||||
| Score | Prediction | Score | Prediction | pLDDT | disorder | disorder | LTP | HTP | KL | PTM | Clinical Status | Review | Subm. | ID | Allele count | Allele freq. | LLR score | Prediction | Pathogenicity | Class | Optimized | Average ΔΔG | Prediction | StdDev | ΔΔG | Prediction | ΔΔG | Prediction | ΔΔG | Prediction | Score | Prediction | Score | Prediction | pph2_prob | Prediction | pph2_prob | Prediction | Nervous System Score | Prediction | Prediction | Status | Conservation | Sequences | IP RF | SP RF | Prediction | PAM250 | PAM120 | Hydropathy Δ | MW Δ | Average | Δ | Δ | StdDev | Δ | StdDev | Secondary | Tertiary bonds | Inside out | GAP-Ras interface | At membrane | No effect | MD Alert | Verdict | Description | |||||
| c.3893A>C | Q1298P 2D  AIThe SynGAP1 missense variant Q1298P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -1.819 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.196 | Likely Benign | -2.93 | Deleterious | 0.586 | Possibly Damaging | 0.105 | Benign | 2.76 | Benign | 0.03 | Affected | 0.2237 | 0.4025 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3907G>T | G1303C 2D  AIThe SynGAP1 missense variant G1303C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -5.286 | Likely Benign | 0.257 | Likely Benign | Likely Benign | 0.377 | Likely Benign | -2.49 | Neutral | 0.997 | Probably Damaging | 0.961 | Probably Damaging | 2.76 | Benign | 0.02 | Affected | 0.1319 | 0.3681 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.4009T>G | F1337V 2D  AIThe SynGAP1 missense variant F1337V is not 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 predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (two pathogenic vs two benign), and Foldetta results are unavailable. Overall, the majority of evidence (six pathogenic vs three benign) points to a pathogenic impact. The variant is most likely pathogenic, 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. | 0.823549 | Disordered | 0.979265 | Binding | 0.388 | 0.712 | 0.625 | -2.425 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.335 | Likely Benign | -3.94 | Deleterious | 0.947 | Possibly Damaging | 0.932 | Probably Damaging | 2.76 | Benign | 0.00 | Affected | 0.2470 | 0.2902 | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||||||||||||||||
| c.1778T>A | L593H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L593H is listed in ClinVar with an uncertain significance and is not present in gnomAD. In silico predictors that classify the variant as benign include only FATHMM. All other evaluated tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic effect. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized is pathogenic; 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 pathogenic. No prediction or stability result is missing or inconclusive. Overall, the variant is most likely pathogenic based on the consensus of predictions, and this assessment does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009728 | Structured | 0.110534 | Uncertain | 0.941 | 0.151 | 0.000 | Uncertain | 1 | -16.504 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.52 | Destabilizing | 0.2 | 2.32 | Destabilizing | 2.42 | Destabilizing | 2.75 | Destabilizing | 0.812 | Likely Pathogenic | -6.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.77 | Benign | 0.00 | Affected | 3.37 | 35 | 0.1101 | 0.0541 | -2 | -3 | -7.0 | 23.98 | 222.0 | 20.7 | 0.0 | 0.0 | 0.2 | 0.0 | X | X | Potentially Pathogenic | The iso-propyl side chain of Leu593, located in an α helix (res. Glu582-Met603), packs favourably with multiple hydrophobic residues in the inter-helix space (e.g., Leu598, Ile589, Phe594, Phe561).In the variant simulations, His593 retains a similar packing arrangement via its aromatic imidazole ring. However, the polar nitrogen atoms introduce hydrogen bond donors and acceptors into the previously hydrophobic space. The epsilon protonated nitrogen of His593 forms a stable hydrogen bond with the phenol group of the Tyr505 side chain in an α helix (res. Gln503-Tyr518).While the residue swap could affect the tertiary assembly and the underlying protein folding process, it is difficult to determine if the mutation would be tolerated based solely on the variant simulations. | |||||||||||||||
| c.1778T>C | L593P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L593P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic outcome. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, a conclusion that contradicts its current ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009728 | Structured | 0.110534 | Uncertain | 0.941 | 0.151 | 0.000 | Uncertain | 1 | -13.961 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.75 | Destabilizing | 0.9 | 10.77 | Destabilizing | 8.26 | Destabilizing | 2.43 | Destabilizing | 0.777 | Likely Pathogenic | -6.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.77 | Benign | 0.00 | Affected | 0.3783 | 0.1274 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||
| c.1778T>G | L593R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L593R 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 assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a destabilizing, pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009728 | Structured | 0.110534 | Uncertain | 0.941 | 0.151 | 0.000 | -16.139 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.27 | Destabilizing | 0.3 | 3.39 | Destabilizing | 3.83 | Destabilizing | 2.11 | Destabilizing | 0.740 | Likely Pathogenic | -5.87 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.77 | Benign | 0.00 | Affected | 0.1440 | 0.0615 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1892A>G | Q631R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q631R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions come from FoldX, Foldetta, and FATHMM, while pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic impact for Q631R, 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 | GAP | 0.041405 | Structured | 0.038963 | Uncertain | 0.948 | 0.230 | 0.000 | -14.881 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | -0.34 | Likely Benign | 0.1 | 0.83 | Ambiguous | 0.25 | Likely Benign | 0.77 | Ambiguous | 0.627 | Likely Pathogenic | -3.98 | Deleterious | 0.973 | Probably Damaging | 0.969 | Probably Damaging | 2.77 | Benign | 0.01 | Affected | 0.1193 | 0.0653 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.1897C>A | L633M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L633M has no ClinVar entry and is not reported in 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 and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta is also inconclusive. Overall, the majority of definitive predictions (5 pathogenic vs. 4 benign) lean toward 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. | GAP | 0.045352 | Structured | 0.045407 | Uncertain | 0.952 | 0.252 | 0.000 | -10.300 | Likely Pathogenic | 0.718 | Likely Pathogenic | Likely Benign | 0.61 | Ambiguous | 0.1 | 1.47 | Ambiguous | 1.04 | Ambiguous | 0.90 | Ambiguous | 0.355 | Likely Benign | -1.99 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.77 | Benign | 0.01 | Affected | 0.0984 | 0.2683 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.2200C>T | P734S 2D  AIThe SynGAP1 missense variant P734S is listed in ClinVar with an uncertain significance (ClinVar ID 2283225.0) and is present in the gnomAD database (gnomAD ID 6‑33441665‑C‑T). Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign effects. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this benign assessment: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign classification, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.411273 | Uncertain | 0.368 | 0.721 | 0.875 | Uncertain | 2 | 6-33441665-C-T | 2 | 1.24e-6 | -4.291 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -2.44 | Neutral | 0.344 | Benign | 0.048 | Benign | 2.77 | Benign | 0.11 | Tolerated | 3.64 | 6 | 0.3775 | 0.3650 | 1 | -1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.2209C>A | Q737K 2D  AIThe SynGAP1 missense variant Q737K 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 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. Taken together, the majority of evidence points to a benign effect for Q737K, 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 | 0.889439 | Disordered | 0.425743 | Uncertain | 0.323 | 0.803 | 0.875 | -5.841 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -1.16 | Neutral | 0.906 | Possibly Damaging | 0.551 | Possibly Damaging | 2.77 | Benign | 0.07 | Tolerated | 0.2081 | 0.4009 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2230C>G | Q744E 2D  AIThe SynGAP1 missense variant Q744E 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 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) reports “Likely Benign,” while 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 | 0.852992 | Disordered | 0.540428 | Binding | 0.316 | 0.866 | 0.875 | -4.053 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.57 | Neutral | 0.065 | Benign | 0.038 | Benign | 2.77 | Benign | 0.08 | Tolerated | 0.1453 | 0.1892 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2431C>A | P811T 2D  AIThe SynGAP1 missense variant P811T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the majority of evidence points to a benign effect for P811T, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -5.329 | Likely Benign | 0.488 | Ambiguous | Likely Benign | 0.119 | Likely Benign | -1.94 | Neutral | 0.991 | Probably Damaging | 0.864 | Possibly Damaging | 2.77 | Benign | 0.03 | Affected | 0.1679 | 0.6095 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||||
| c.2435C>G | P812R 2D  AIThe SynGAP1 P812R 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, whereas 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 of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the majority of standard predictors indicate a pathogenic impact, while the most accurate tools provide no definitive evidence. Thus, the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | -6.784 | Likely Benign | 0.799 | Likely Pathogenic | Ambiguous | 0.222 | Likely Benign | -2.70 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.77 | Benign | 0.01 | Affected | 0.1285 | 0.3525 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2494C>G | Q832E 2D AIThe SynGAP1 missense variant Q832E 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 flags it as pathogenic, but this is the sole discordant call. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.619913 | Binding | 0.290 | 0.877 | 0.375 | -3.024 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -0.37 | Neutral | 0.652 | Possibly Damaging | 0.311 | Benign | 2.77 | Benign | 0.06 | Tolerated | 0.1262 | 0.1897 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| 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 | -0.91 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.77 | Benign | 0.28 | Tolerated | 0.5351 | 0.4945 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.2621A>C | Q874P 2D AIThe SynGAP1 missense variant Q874P is reported in gnomAD (ID 6‑33443173‑A‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and 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 effect, and this conclusion does not contradict any ClinVar classification (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 | 0.490133 | Structured | 0.635258 | Binding | 0.289 | 0.873 | 0.250 | 6-33443173-A-C | 9 | 5.58e-6 | -4.622 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.219 | Likely Benign | -2.89 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.77 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2373 | 0.5911 | -1 | 0 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||
| c.2732T>C | V911A 2D  AIThe SynGAP1 missense variant V911A is not reported in ClinVar and is absent from gnomAD. All evaluated in silico predictors classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta results are unavailable. Based on the consensus of all 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 | 0.685117 | Disordered | 0.724137 | Binding | 0.327 | 0.914 | 0.375 | -3.030 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.118 | Likely Benign | 0.08 | Neutral | 0.264 | Benign | 0.102 | Benign | 2.77 | Benign | 0.41 | Tolerated | 0.3069 | 0.3336 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.2818G>A | G940S 2D  AIThe SynGAP1 missense variant G940S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443370‑G‑A). All available in silico predictors agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” High‑accuracy tools reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no reported result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign classification, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.920635 | Binding | 0.383 | 0.902 | 0.625 | Uncertain | 1 | 6-33443370-G-A | 1 | 6.20e-7 | -5.451 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.135 | Likely Benign | 0.45 | Neutral | 0.409 | Benign | 0.253 | Benign | 2.77 | Benign | 0.44 | Tolerated | 3.77 | 5 | 0.2590 | 0.4907 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2821C>A | P941T 2D AIThe SynGAP1 missense variant P941T is listed in gnomAD (ID 6‑33443373‑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, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status, as none is currently assigned. 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-A | 2 | 1.24e-6 | -6.193 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.19 | Neutral | 0.144 | Benign | 0.085 | Benign | 2.77 | Benign | 0.05 | Affected | 4.32 | 4 | 0.1612 | 0.5607 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||
| c.3005A>C | H1002P 2D  AIThe SynGAP1 missense variant H1002P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus likewise indicates Likely Benign. Foldetta results are unavailable, so they do not influence the overall assessment. Based on the majority of predictions and the high‑accuracy consensus, 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 | 0.784345 | Disordered | 0.953758 | Binding | 0.285 | 0.900 | 0.500 | -4.616 | Likely Benign | 0.242 | Likely Benign | Likely Benign | 0.213 | Likely Benign | -2.02 | Neutral | 0.989 | Probably Damaging | 0.874 | Possibly Damaging | 2.77 | Benign | 0.28 | Tolerated | 0.2015 | 0.3738 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3006T>A | H1002Q 2D  AIThe SynGAP1 missense variant H1002Q is 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.953758 | Binding | 0.285 | 0.900 | 0.500 | -5.071 | Likely Benign | 0.650 | Likely Pathogenic | Likely Benign | 0.140 | Likely Benign | -1.83 | Neutral | 0.801 | Possibly Damaging | 0.602 | Possibly Damaging | 2.77 | Benign | 0.23 | Tolerated | 0.1927 | 0.3510 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3006T>G | H1002Q 2D AIThe SynGAP1 missense variant H1002Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this conclusion, so the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.953758 | Binding | 0.285 | 0.900 | 0.500 | -5.071 | Likely Benign | 0.650 | Likely Pathogenic | Likely Benign | 0.140 | Likely Benign | -1.83 | Neutral | 0.801 | Possibly Damaging | 0.602 | Possibly Damaging | 2.77 | Benign | 0.23 | Tolerated | 0.1927 | 0.3510 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3011A>G | H1004R 2D  AIThe SynGAP1 missense variant H1004R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and no Foldetta stability data is available. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.808535 | Disordered | 0.943707 | Binding | 0.271 | 0.901 | 0.750 | -3.316 | Likely Benign | 0.813 | Likely Pathogenic | Ambiguous | 0.198 | Likely Benign | -1.88 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.77 | Benign | 0.50 | Tolerated | 0.2097 | 0.3132 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.3080A>G | N1027S 2D  AIThe SynGAP1 missense variant N1027S 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 predictions strongly suggest 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 | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -2.443 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.35 | Neutral | 0.068 | Benign | 0.039 | Benign | 2.77 | Benign | 0.50 | Tolerated | 0.3540 | 0.6874 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||||||
| c.3089A>C | H1030P 2D AIThe SynGAP1 missense variant H1030P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta results are unavailable, so they do not influence the assessment. Overall, the consensus of available predictions indicates that H1030P is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -2.185 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.154 | Likely Benign | -0.78 | Neutral | 0.812 | Possibly Damaging | 0.298 | Benign | 2.77 | Benign | 0.02 | Affected | 0.1872 | 0.4225 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.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 | -0.88 | Neutral | 0.625 | Possibly Damaging | 0.266 | Benign | 2.77 | Benign | 0.28 | Tolerated | 0.1904 | 0.5071 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3257C>A | P1086Q 2D  AIThe SynGAP1 missense variant P1086Q is not reported in ClinVar (ClinVar status: None) but is present in gnomAD (ID 6‑33443809‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs. two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. four benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.849326 | Disordered | 0.977190 | Binding | 0.393 | 0.885 | 1.000 | 6-33443809-C-A | -4.668 | Likely Benign | 0.652 | Likely Pathogenic | Likely Benign | 0.185 | Likely Benign | -2.92 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.77 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1285 | 0.4784 | -1 | 0 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||
| c.3269A>C | N1090T 2D  AIThe SynGAP1 missense variant N1090T is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of high‑accuracy predictors (AlphaMissense‑Optimized and the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also support a benign classification. In contrast, polyPhen‑2 (both HumDiv and HumVar tracks) predict a pathogenic impact, but these are the only tools in disagreement. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. Overall, the preponderance of evidence points to a benign effect for the variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -3.478 | Likely Benign | 0.542 | Ambiguous | Likely Benign | 0.129 | Likely Benign | -0.78 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.77 | Benign | 0.58 | Tolerated | 0.1451 | 0.7930 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||||||||||
| c.3283C>A | P1095T 2D AIThe SynGAP1 missense variant P1095T 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 is benign and the SGM‑Consensus is 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 | 0.922952 | Disordered | 0.979251 | Binding | 0.387 | 0.870 | 1.000 | -4.706 | Likely Benign | 0.195 | Likely Benign | Likely Benign | 0.108 | Likely Benign | -1.42 | Neutral | 0.872 | Possibly Damaging | 0.399 | Benign | 2.77 | Benign | 0.13 | Tolerated | 0.1685 | 0.6677 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3284C>G | P1095R 2D AIThe SynGAP1 missense variant P1095R is reported in ClinVar as “Not submitted” and is not present in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, all of which classify the change as benign or tolerant. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy consensus methods reinforce the benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and Foldetta data are missing. Overall, the majority of reliable predictors and consensus analyses indicate that P1095R is most likely benign, 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 | 0.922952 | Disordered | 0.979251 | Binding | 0.387 | 0.870 | 1.000 | -5.180 | Likely Benign | 0.553 | Ambiguous | Likely Benign | 0.091 | Likely Benign | -1.93 | Neutral | 0.922 | Possibly Damaging | 0.528 | Possibly Damaging | 2.77 | Benign | 0.04 | Affected | 0.1513 | 0.4576 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3287A>C | E1096A 2D  AIThe SynGAP1 missense variant E1096A is listed in ClinVar (ID 2579889.0) with an uncertain significance annotation and is not reported in gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only polyPhen‑2 HumDiv assigns a pathogenic label, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign; Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the aggregate evidence points to a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.976475 | Binding | 0.308 | 0.858 | 1.000 | Uncertain | 1 | -4.504 | Likely Benign | 0.510 | Ambiguous | Likely Benign | 0.164 | Likely Benign | -1.37 | Neutral | 0.626 | Possibly Damaging | 0.184 | Benign | 2.77 | Benign | 0.16 | Tolerated | 3.77 | 5 | 0.3805 | 0.7569 | -1 | 0 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||
| c.3310C>T | P1104S 2D AIThe SynGAP1 missense variant P1104S is listed in ClinVar (ID 2912797.0) as Benign and is present in gnomAD (variant ID 6‑33443862‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign, and AlphaMissense‑Optimized also reports Benign. Foldetta results are not available. Overall, the majority of computational evidence supports a benign classification, which is consistent with the ClinVar status. Thus, the variant is most likely benign and does not contradict the ClinVar annotation. 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 | Benign | 1 | 6-33443862-C-T | 1 | 6.54e-7 | -2.330 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.30 | Neutral | 0.770 | Possibly Damaging | 0.404 | Benign | 2.77 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.3271 | 0.5746 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| c.3344T>A | I1115N 2D  AIThe SynGAP1 missense variant I1115N 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 | 0.889439 | Disordered | 0.892339 | Binding | 0.308 | 0.912 | 0.750 | -4.018 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -0.60 | Neutral | 0.009 | Benign | 0.011 | Benign | 2.77 | Benign | 0.08 | Tolerated | 0.1299 | 0.1270 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3860C>G | P1287R 2D AIThe SynGAP1 missense variant P1287R 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 reinforce this view: 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 P1287R, 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 | 0.827927 | Disordered | 0.813701 | Binding | 0.538 | 0.777 | 0.750 | -2.180 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -1.37 | Neutral | 0.586 | Possibly Damaging | 0.172 | Benign | 2.77 | Benign | 0.01 | Affected | 0.1337 | 0.2427 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3894G>C | Q1298H 2D  AIThe SynGAP1 missense variant Q1298H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as tolerated or benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a damaging or pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect for Q1298H, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -4.109 | Likely Benign | 0.203 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -1.45 | Neutral | 0.938 | Possibly Damaging | 0.377 | Benign | 2.77 | Benign | 0.03 | Affected | 0.1083 | 0.2605 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3894G>T | Q1298H 2D AIThe SynGAP1 missense variant Q1298H is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools (polyPhen‑2 HumDiv and SIFT) predict pathogenicity, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a benign classification, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -4.109 | Likely Benign | 0.203 | Likely Benign | Likely Benign | 0.465 | Likely Benign | -1.45 | Neutral | 0.938 | Possibly Damaging | 0.377 | Benign | 2.77 | Benign | 0.03 | Affected | 0.1083 | 0.2605 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3914C>A | T1305K 2D  AIThe SynGAP1 missense variant T1305K 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 reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact for T1305K, 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 | 0.894658 | Binding | 0.390 | 0.873 | 0.875 | -4.289 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -1.33 | Neutral | 0.027 | Benign | 0.042 | Benign | 2.77 | Benign | 0.01 | Affected | 0.1290 | 0.3532 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3914C>T | T1305I 2D  AIThe SynGAP1 missense variant T1305I is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic call comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.894658 | Binding | 0.390 | 0.873 | 0.875 | -4.202 | Likely Benign | 0.221 | Likely Benign | Likely Benign | 0.154 | Likely Benign | -1.35 | Neutral | 0.027 | Benign | 0.063 | Benign | 2.77 | Benign | 0.02 | Affected | 0.0923 | 0.6149 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.4009T>A | F1337I 2D  AIThe SynGAP1 missense variant F1337I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, 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 (two pathogenic vs. two benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the majority of evaluated tools (seven pathogenic vs. three benign) indicate a pathogenic effect. This prediction 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. | 0.823549 | Disordered | 0.979265 | Binding | 0.388 | 0.712 | 0.625 | -2.761 | Likely Benign | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.252 | Likely Benign | -3.32 | Deleterious | 0.947 | Possibly Damaging | 0.950 | Probably Damaging | 2.77 | Benign | 0.00 | Affected | 0.2574 | 0.2875 | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.1460A>C | N487T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N487T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as “Likely Pathogenic.” High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No evidence from FoldX, Rosetta, or premPS is available to alter this assessment. Overall, the preponderance of computational evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -12.618 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 1.92 | Ambiguous | 0.1 | 1.94 | Ambiguous | 1.93 | Ambiguous | 0.68 | Ambiguous | 0.481 | Likely Benign | -5.97 | Deleterious | 0.987 | Probably Damaging | 0.980 | Probably Damaging | 2.78 | Benign | 0.05 | Affected | 0.1200 | 0.3441 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.1783C>G | L595V 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant L595V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, and FATHMM, while pathogenic calls are made by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions marked uncertain include FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy consensus methods give a clearer picture: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Overall, the majority of evidence points toward a pathogenic effect, 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 | 0.015344 | Structured | 0.128444 | Uncertain | 0.920 | 0.150 | 0.000 | -13.490 | Likely Pathogenic | 0.905 | Likely Pathogenic | Ambiguous | 1.29 | Ambiguous | 0.1 | 0.24 | Likely Benign | 0.77 | Ambiguous | 1.01 | Destabilizing | 0.398 | Likely Benign | -2.99 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 2.78 | Benign | 0.01 | Affected | 0.1441 | 0.3406 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1879G>T | A627S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 A627S 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, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are Rosetta, PROVEAN, and ESM1b. The remaining tools—FoldX, Foldetta, and premPS—return uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta is uncertain. Overall, the majority of available predictions lean toward a benign impact. Thus, 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 | 0.100716 | Structured | 0.037862 | Uncertain | 0.970 | 0.210 | 0.000 | -10.782 | Likely Pathogenic | 0.329 | Likely Benign | Likely Benign | 1.11 | Ambiguous | 0.2 | 2.05 | Destabilizing | 1.58 | Ambiguous | 0.71 | Ambiguous | 0.316 | Likely Benign | -2.94 | Deleterious | 0.411 | Benign | 0.387 | Benign | 2.78 | Benign | 0.11 | Tolerated | 0.2266 | 0.4224 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1891C>G | Q631E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q631E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifying it as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain result. Overall, the majority of evidence (eight pathogenic predictions versus three benign) points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, which is currently unavailable. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.038963 | Uncertain | 0.948 | 0.230 | 0.000 | -15.628 | Likely Pathogenic | 0.782 | Likely Pathogenic | Likely Benign | 0.04 | Likely Benign | 0.1 | 1.55 | Ambiguous | 0.80 | Ambiguous | 0.95 | Ambiguous | 0.532 | Likely Pathogenic | -2.99 | Deleterious | 0.997 | Probably Damaging | 0.981 | Probably Damaging | 2.78 | Benign | 0.01 | Affected | 0.1068 | 0.1264 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.2200C>A | P734T 2D AIThe SynGAP1 missense variant P734T is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus (SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as “Likely Benign,” and AlphaMissense‑Optimized also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no result available 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 is reported). 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 | -4.469 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.042 | Likely Benign | -2.08 | Neutral | 0.040 | Benign | 0.013 | Benign | 2.78 | Benign | 0.09 | Tolerated | 0.1764 | 0.4076 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| 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 | -1.22 | Neutral | 0.005 | Benign | 0.013 | Benign | 2.78 | Benign | 0.04 | Affected | 4.07 | 3 | 0.2366 | 0.4981 | -1 | 0 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||
| c.2227C>G | P743A 2D  AIThe SynGAP1 missense variant P743A 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 | 0.852992 | Disordered | 0.526809 | Binding | 0.317 | 0.862 | 0.875 | -4.253 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -1.10 | Neutral | 0.005 | Benign | 0.008 | Benign | 2.78 | Benign | 0.12 | Tolerated | 0.3158 | 0.3604 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2398G>A | G800S 2D AIThe SynGAP1 missense variant G800S is reported as “Likely Benign” by the SGM‑Consensus method and is absent from ClinVar and gnomAD. All evaluated in‑silico predictors agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. 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) also indicates a likely benign outcome. Foldetta results are unavailable. 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 | SH3-binding motif | 0.852992 | Disordered | 0.588350 | Binding | 0.303 | 0.884 | 0.625 | -3.572 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -0.69 | Neutral | 0.292 | Benign | 0.157 | Benign | 2.78 | Benign | 0.60 | Tolerated | 0.2375 | 0.4923 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||||||
| c.2399G>C | G800A 2D  AIThe SynGAP1 missense variant G800A is listed in gnomAD (6-33442951‑G‑C) but has no ClinVar entry. Across the available in‑silico predictors, every tool reports a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant. Based on the unanimous benign predictions and the absence of any pathogenic calls, the variant is most likely benign, 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 Benign | SH3-binding motif | 0.852992 | Disordered | 0.588350 | Binding | 0.303 | 0.884 | 0.625 | 6-33442951-G-C | 7 | 4.34e-6 | -3.550 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.031 | Likely Benign | -0.48 | Neutral | 0.011 | Benign | 0.006 | Benign | 2.78 | Benign | 1.00 | Tolerated | 4.32 | 2 | 0.3466 | 0.4850 | 0 | 1 | 2.2 | 14.03 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||||||||
| 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 | -2.38 | Neutral | 0.982 | Probably Damaging | 0.875 | Possibly Damaging | 2.78 | Benign | 0.01 | Affected | 0.1523 | 0.5338 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||||
| c.2494C>A | Q832K 2D AIThe SynGAP1 missense variant Q832K 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 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 unavailable. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.720929 | Disordered | 0.619913 | Binding | 0.290 | 0.877 | 0.375 | -4.964 | Likely Benign | 0.182 | Likely Benign | Likely Benign | 0.080 | Likely Benign | -0.87 | Neutral | 0.811 | Possibly Damaging | 0.348 | Benign | 2.78 | Benign | 0.10 | Tolerated | 0.1759 | 0.3568 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2504T>C | L835P 2D AIThe SynGAP1 missense variant L835P 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 result is available, so it does not influence the overall 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 | 0.608892 | Disordered | 0.642742 | Binding | 0.319 | 0.863 | 0.125 | -3.024 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.144 | Likely Benign | 0.03 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.78 | Benign | 0.04 | Affected | 0.3455 | 0.1079 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2593G>T | A865S 2D AIThe SynGAP1 missense variant A865S is reported as “Likely Benign” in SGM‑Consensus and has no ClinVar entry or gnomAD allele. 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 is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign. Foldetta results are not available. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.626222 | Binding | 0.271 | 0.788 | 0.250 | -3.102 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.050 | Likely Benign | 0.20 | Neutral | 0.009 | Benign | 0.019 | Benign | 2.78 | Benign | 0.52 | Tolerated | 0.2314 | 0.4876 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2623G>T | A875S 2D AIThe SynGAP1 missense variant A875S is not reported 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 A875S 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 | 0.545602 | Disordered | 0.632173 | Binding | 0.273 | 0.872 | 0.250 | -2.719 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -1.07 | Neutral | 0.945 | Possibly Damaging | 0.767 | Possibly Damaging | 2.78 | Benign | 0.08 | Tolerated | 0.2607 | 0.6338 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2653C>A | P885T 2D AIThe SynGAP1 missense variant P885T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status. 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 | -5.152 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -1.44 | Neutral | 0.369 | Benign | 0.171 | Benign | 2.78 | Benign | 0.00 | Affected | 0.1438 | 0.6484 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2663C>T | A888V 2D  AIThe SynGAP1 missense variant A888V is catalogued in gnomAD (ID 6‑33443215‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes, while the single pathogenic signal comes from SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign likelihood. Foldetta results are unavailable, so they do not influence the assessment. Overall, the preponderance of evidence points to a benign impact for A888V, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.575860 | Binding | 0.352 | 0.928 | 0.625 | 6-33443215-C-T | 1 | 6.20e-7 | -4.241 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.034 | Likely Benign | -0.91 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.78 | Benign | 0.00 | Affected | 4.32 | 4 | 0.1285 | 0.7056 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||
| c.2677C>A | Q893K 2D AIThe SynGAP1 missense variant Q893K 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, and FATHMM all score the substitution as benign, and AlphaMissense‑Optimized also predicts a benign outcome. No tool predicts pathogenicity; 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 corroborate this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the computational evidence strongly supports a benign classification, and this conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.447267 | Uncertain | 0.310 | 0.925 | 0.750 | -5.622 | Likely Benign | 0.496 | Ambiguous | Likely Benign | 0.053 | Likely Benign | -1.45 | Neutral | 0.451 | Benign | 0.265 | Benign | 2.78 | Benign | 0.10 | Tolerated | 0.1901 | 0.4381 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2711T>C | M904T 2D  AIThe SynGAP1 missense variant M904T is listed in ClinVar (ID 1311496.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; 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 | 0.671169 | Disordered | 0.589073 | Binding | 0.350 | 0.920 | 0.250 | Uncertain | 1 | -2.721 | Likely Benign | 0.668 | Likely Pathogenic | Likely Benign | 0.042 | Likely Benign | -1.15 | Neutral | 0.277 | Benign | 0.103 | Benign | 2.78 | Benign | 0.18 | Tolerated | 3.77 | 5 | 0.2394 | 0.2568 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||
| c.2712G>A | M904I 2D  AIThe SynGAP1 missense variant M904I is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all return benign scores, and AlphaMissense‑Optimized also predicts a benign effect. No tool predicts pathogenicity, and the only uncertain result comes from AlphaMissense‑Default, which is inconclusive. The high‑accuracy consensus methods corroborate this benign assessment: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and AlphaMissense‑Optimized explicitly labels the variant as benign. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Taken together, the evidence overwhelmingly supports a benign impact for M904I, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Thus, the variant is most likely benign, and this conclusion does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.589073 | Binding | 0.350 | 0.920 | 0.250 | -3.845 | Likely Benign | 0.385 | Ambiguous | Likely Benign | 0.023 | Likely Benign | -0.48 | Neutral | 0.039 | Benign | 0.023 | Benign | 2.78 | Benign | 0.07 | Tolerated | 0.1694 | 0.3633 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2712G>C | M904I 2D AIThe SynGAP1 missense variant M904I is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all return benign scores, and AlphaMissense‑Optimized also predicts a benign effect. No tool predicts pathogenicity, and the only uncertain result comes from AlphaMissense‑Default, which is inconclusive. The high‑accuracy consensus methods corroborate this benign assessment: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and AlphaMissense‑Optimized also indicates a benign outcome. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Taken together, the evidence overwhelmingly supports 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. | Likely Benign | 0.671169 | Disordered | 0.589073 | Binding | 0.350 | 0.920 | 0.250 | -3.845 | Likely Benign | 0.385 | Ambiguous | Likely Benign | 0.023 | Likely Benign | -0.48 | Neutral | 0.039 | Benign | 0.023 | Benign | 2.78 | Benign | 0.07 | Tolerated | 0.1694 | 0.3633 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2712G>T | M904I 2D AIThe SynGAP1 missense variant M904I is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all return benign scores, and AlphaMissense‑Optimized also predicts a benign effect. No tool predicts pathogenicity, and the only uncertain result comes from AlphaMissense‑Default, which is inconclusive. The high‑accuracy consensus methods corroborate this benign assessment: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and AlphaMissense‑Optimized also indicates a benign outcome. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Taken together, the evidence overwhelmingly supports 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. | Likely Benign | 0.671169 | Disordered | 0.589073 | Binding | 0.350 | 0.920 | 0.250 | -3.845 | Likely Benign | 0.385 | Ambiguous | Likely Benign | 0.023 | Likely Benign | -0.48 | Neutral | 0.039 | Benign | 0.023 | Benign | 2.78 | Benign | 0.07 | Tolerated | 0.1694 | 0.3633 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2729G>C | G910A 2D AIThe SynGAP1 missense variant G910A is listed in ClinVar with an “Uncertain” status (ClinVar ID 2091237.0) and is present in gnomAD (6‑33443281‑G‑C). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. The remaining predictions are uncertain: AlphaMissense‑Default is inconclusive, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.707319 | Binding | 0.264 | 0.917 | 0.250 | Uncertain | 1 | 6-33443281-G-C | 1 | 6.20e-7 | -3.587 | Likely Benign | 0.361 | Ambiguous | Likely Benign | 0.209 | Likely Benign | -1.43 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 2.78 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.3753 | 0.4544 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||
| 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 | -0.78 | Neutral | 0.058 | Benign | 0.015 | Benign | 2.78 | Benign | 0.29 | Tolerated | 3.77 | 5 | 0.2105 | 0.5108 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||
| c.2858C>G | P953R 2D AIThe SynGAP1 missense variant P953R 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 | 0.983019 | Disordered | 0.920633 | Binding | 0.403 | 0.926 | 0.750 | -6.036 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -1.50 | Neutral | 0.611 | Possibly Damaging | 0.185 | Benign | 2.78 | Benign | 0.31 | Tolerated | 0.1771 | 0.4525 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2861C>G | P954R 2D AIThe SynGAP1 missense variant P954R is not reported 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 P954R 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 | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | -6.329 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -1.19 | Neutral | 0.954 | Possibly Damaging | 0.826 | Possibly Damaging | 2.78 | Benign | 0.11 | Tolerated | 0.1548 | 0.3940 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2861C>T | P954L 2D  AIThe SynGAP1 missense variant P954L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict it to be 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 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 | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | -5.607 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.43 | Neutral | 0.977 | Probably Damaging | 0.812 | Possibly Damaging | 2.78 | Benign | 0.55 | Tolerated | 0.2346 | 0.5867 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2999T>C | I1000T 2D  AIThe SynGAP1 missense variant I1000T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign 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 status to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.745909 | Disordered | 0.957020 | Binding | 0.293 | 0.904 | 0.625 | -4.748 | Likely Benign | 0.721 | Likely Pathogenic | Likely Benign | 0.131 | Likely Benign | -0.87 | Neutral | 0.896 | Possibly Damaging | 0.596 | Possibly Damaging | 2.78 | Benign | 0.29 | Tolerated | 0.1045 | 0.1594 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3010C>G | H1004D 2D  AIThe SynGAP1 missense variant H1004D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for H1004D. 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 | 0.808535 | Disordered | 0.943707 | Binding | 0.271 | 0.901 | 0.750 | -5.275 | Likely Benign | 0.913 | Likely Pathogenic | Ambiguous | 0.148 | Likely Benign | -2.16 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.78 | Benign | 0.29 | Tolerated | 0.2695 | 0.2530 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3012C>A | H1004Q 2D AIThe SynGAP1 missense variant H1004Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 majority of evidence points to a benign impact. 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 | 0.808535 | Disordered | 0.943707 | Binding | 0.271 | 0.901 | 0.750 | -3.872 | Likely Benign | 0.853 | Likely Pathogenic | Ambiguous | 0.126 | Likely Benign | -1.55 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.78 | Benign | 0.71 | Tolerated | 3.77 | 5 | 0.1831 | 0.3832 | 0 | 3 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||
| c.3012C>G | H1004Q 2D AIThe SynGAP1 missense variant H1004Q is catalogued in gnomAD (ID 6‑33443564‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on benign impact include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while PolyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Benign,” and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Taken together, the preponderance of evidence (six benign predictions versus three pathogenic) indicates that H1004Q is most likely benign. This conclusion does not contradict ClinVar status, as the variant is not yet classified in that database. 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 | 6-33443564-C-G | 3 | 1.86e-6 | -3.872 | Likely Benign | 0.853 | Likely Pathogenic | Ambiguous | 0.126 | Likely Benign | -1.55 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.78 | Benign | 0.71 | Tolerated | 3.77 | 5 | 0.1831 | 0.3832 | 0 | 3 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||
| c.3032G>A | G1011E 2D  AIThe SynGAP1 missense variant G1011E is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those predicting a pathogenic outcome 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 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 collective predictions point to a benign effect, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.898380 | Binding | 0.332 | 0.869 | 0.625 | -3.870 | Likely Benign | 0.617 | Likely Pathogenic | Likely Benign | 0.091 | Likely Benign | -1.10 | Neutral | 0.642 | Possibly Damaging | 0.252 | Benign | 2.78 | Benign | 0.01 | Affected | 0.1692 | 0.4521 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3041G>C | G1014A 2D AIThe SynGAP1 missense variant G1014A is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess sequence conservation and functional impact (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. 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 | -3.520 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -1.06 | Neutral | 0.025 | Benign | 0.022 | Benign | 2.78 | Benign | 0.36 | Tolerated | 0.3677 | 0.4682 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3073C>A | Q1025K 2D AIThe SynGAP1 missense variant Q1025K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: benign calls come from REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas the only pathogenic call is from polyPhen‑2 HumDiv. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Thus, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which has no pathogenic annotation. 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 | -4.510 | Likely Benign | 0.529 | Ambiguous | Likely Benign | 0.041 | Likely Benign | -1.09 | Neutral | 0.649 | Possibly Damaging | 0.353 | Benign | 2.78 | Benign | 0.22 | Tolerated | 0.1690 | 0.4438 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3088C>A | H1030N 2D  AIThe SynGAP1 missense variant H1030N is not reported in ClinVar and is absent from gnomAD. Consensus prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational 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 | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -3.454 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.033 | Likely Benign | -0.88 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.78 | Benign | 0.04 | Affected | 0.1553 | 0.3195 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3088C>G | H1030D 2D AIThe SynGAP1 missense variant H1030D is reported in gnomAD (variant ID 6‑33443640‑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, and AlphaMissense‑Optimized all predict benign. Only SIFT predicts a pathogenic effect, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support this: 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 status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | 6-33443640-C-G | 1 | 6.19e-7 | -3.500 | Likely Benign | 0.424 | Ambiguous | Likely Benign | 0.189 | Likely Benign | -0.85 | Neutral | 0.126 | Benign | 0.066 | Benign | 2.78 | Benign | 0.05 | Affected | 3.77 | 5 | 0.2273 | 0.2422 | -1 | 1 | -0.3 | -22.05 | ||||||||||||||||||||||||||||||||||
| c.3094C>G | L1032V 2D AIThe SynGAP1 missense variant L1032V 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 polyPhen‑2 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 not available. Overall, the majority of evidence points to a benign impact for the variant, 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 | 0.865454 | Disordered | 0.995318 | Binding | 0.365 | 0.735 | 0.500 | -4.123 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.075 | Likely Benign | 0.16 | Neutral | 0.889 | Possibly Damaging | 0.514 | Possibly Damaging | 2.78 | Benign | 0.78 | Tolerated | 0.1637 | 0.4353 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3196C>G | P1066A 2D AIThe SynGAP1 missense variant P1066A 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 | 0.967676 | Disordered | 0.968838 | Binding | 0.403 | 0.913 | 0.875 | -4.856 | Likely Benign | 0.050 | Likely Benign | Likely Benign | 0.149 | Likely Benign | -2.35 | Neutral | 0.972 | Probably Damaging | 0.802 | Possibly Damaging | 2.78 | Benign | 0.00 | Affected | 0.3228 | 0.6042 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3200C>G | P1067R 2D AIThe SynGAP1 missense variant P1067R is not 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 interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta’s stability analysis is unavailable. Taken together, the majority of reliable predictors and the high‑accuracy tools indicate a benign impact. 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. | 0.966441 | Disordered | 0.975099 | Binding | 0.459 | 0.907 | 0.875 | -4.878 | Likely Benign | 0.376 | Ambiguous | Likely Benign | 0.167 | Likely Benign | -2.74 | Deleterious | 0.971 | Probably Damaging | 0.580 | Possibly Damaging | 2.78 | Benign | 0.01 | Affected | 0.1300 | 0.3651 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3256C>G | P1086A 2D AIThe SynGAP1 missense variant P1086A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign, and Foldetta data are unavailable. Taken together, the balance of evidence points to a benign effect for P1086A. This conclusion does not conflict with the ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.849326 | Disordered | 0.977190 | Binding | 0.393 | 0.885 | 1.000 | -4.317 | Likely Benign | 0.372 | Ambiguous | Likely Benign | 0.206 | Likely Benign | -2.98 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.78 | Benign | 0.00 | Affected | 0.3084 | 0.4463 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3256C>T | P1086S 2D AIThe SynGAP1 missense variant P1086S is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443808‑C‑T). 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 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.849326 | Disordered | 0.977190 | Binding | 0.393 | 0.885 | 1.000 | 6-33443808-C-T | -3.165 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 0.212 | Likely Benign | -3.04 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.78 | Benign | 0.00 | Affected | 3.77 | 5 | 0.3067 | 0.4894 | -1 | 1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||
| c.3277C>A | Q1093K 2D AIThe SynGAP1 missense variant Q1093K is reported in gnomAD (variant ID 6‑33443829‑C‑A) but has no ClinVar entry. Functional prediction tools uniformly favor a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify the change as benign, and AlphaMissense‑Optimized also predicts benign. No tool predicts pathogenicity; AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments corroborate 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 available predictions indicates that 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 | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | 6-33443829-C-A | -3.919 | Likely Benign | 0.558 | Ambiguous | Likely Benign | 0.061 | Likely Benign | -0.92 | Neutral | 0.224 | Benign | 0.091 | Benign | 2.78 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.1926 | 0.5861 | 1 | 1 | -0.4 | 0.04 | ||||||||||||||||||||||||||||||||||||
| c.3277C>G | Q1093E 2D AIThe SynGAP1 missense change Q1093E is not reported in ClinVar and is absent from gnomAD. In silico assessment shows unanimous benign predictions: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. No tool predicts pathogenicity. High‑accuracy consensus methods reinforce this view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” The protein‑folding stability predictor Foldetta was not available for this variant. Overall, the evidence strongly supports a benign effect, and this conclusion is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign and does not contradict existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | -3.104 | Likely Benign | 0.265 | Likely Benign | Likely Benign | 0.047 | Likely Benign | -0.59 | Neutral | 0.112 | Benign | 0.041 | Benign | 2.78 | Benign | 0.07 | Tolerated | 0.1514 | 0.3717 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3428C>A | T1143K 2D AIThe SynGAP1 missense variant T1143K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus (majority vote) supports 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 points to a benign impact for T1143K, 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 | 0.919029 | Disordered | 0.722918 | Binding | 0.275 | 0.837 | 1.000 | -3.498 | Likely Benign | 0.811 | Likely Pathogenic | Ambiguous | 0.163 | Likely Benign | -2.03 | Neutral | 0.986 | Probably Damaging | 0.895 | Possibly Damaging | 2.78 | Benign | 0.14 | Tolerated | 0.1266 | 0.2936 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3472G>C | V1158L 2D  AIThe SynGAP1 missense variant V1158L has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Tools 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 as Pathogenic, while the SGM‑Consensus remains Benign; Foldetta results are unavailable. Overall, the majority of evidence (five benign versus four pathogenic predictions, plus a benign consensus) points to a benign classification, and this does not contradict any ClinVar status because no ClinVar claim exists. Thus, the variant is most likely benign, though the AlphaMissense‑Optimized prediction introduces some uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.877504 | Binding | 0.369 | 0.847 | 0.250 | -2.345 | Likely Benign | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.187 | Likely Benign | -0.73 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.78 | Benign | 0.56 | Tolerated | 0.1066 | 0.4642 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3859C>A | P1287T 2D AIThe SynGAP1 missense variant P1287T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33447907‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.813701 | Binding | 0.538 | 0.777 | 0.750 | Uncertain | 1 | 6-33447907-C-A | -3.940 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.22 | Neutral | 0.126 | Benign | 0.041 | Benign | 2.78 | Benign | 0.04 | Affected | 3.77 | 5 | 0.1189 | 0.3995 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||
| c.3929C>G | T1310R 2D  AIThe SynGAP1 missense variant T1310R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign. Only SIFT predicts a damaging outcome, labeling it pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Consequently, the aggregate evidence indicates that T1310R is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.959076 | Binding | 0.398 | 0.904 | 0.750 | -3.632 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.231 | Likely Benign | -0.59 | Neutral | 0.001 | Benign | 0.006 | Benign | 2.78 | Benign | 0.03 | Affected | 0.0844 | 0.2501 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| c.1891C>A | Q631K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q631K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Foldetta, and FATHMM, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. Uncertain or inconclusive results are reported by Rosetta, premPS, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed picture: Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect; the SGM‑Consensus, a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome; AlphaMissense‑Optimized remains uncertain. Overall, the majority of evidence points toward a pathogenic impact, and this assessment does not conflict with the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.038963 | Uncertain | 0.948 | 0.230 | 0.000 | -15.194 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | -0.37 | Likely Benign | 0.1 | 1.13 | Ambiguous | 0.38 | Likely Benign | 0.88 | Ambiguous | 0.596 | Likely Pathogenic | -3.98 | Deleterious | 0.958 | Probably Damaging | 0.931 | Probably Damaging | 2.79 | Benign | 0.01 | Affected | 0.1288 | 0.2157 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||
| c.2230C>A | Q744K 2D AIThe SynGAP1 missense variant Q744K 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 | 0.852992 | Disordered | 0.540428 | Binding | 0.316 | 0.866 | 0.875 | -3.929 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.22 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.79 | Benign | 0.07 | Tolerated | 0.1784 | 0.3757 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.2236G>A | V746M 2D  AIThe SynGAP1 missense variant V746M 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 in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the consensus of available predictions strongly suggests that V746M 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 | 0.808535 | Disordered | 0.576597 | Binding | 0.336 | 0.867 | 0.875 | -4.194 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.010 | Likely Benign | -0.58 | Neutral | 0.065 | Benign | 0.037 | Benign | 2.79 | Benign | 0.60 | Tolerated | 0.0756 | 0.4576 | 2 | 1 | -2.3 | 32.06 | |||||||||||||||||||||||||||||||||||||||
| c.2269G>C | G757R 2D  AIThe SynGAP1 missense variant G757R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports 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 entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.830995 | Binding | 0.310 | 0.869 | 0.375 | -2.254 | Likely Benign | 0.534 | Ambiguous | Likely Benign | 0.158 | Likely Benign | -0.04 | Neutral | 0.801 | Possibly Damaging | 0.494 | Possibly Damaging | 2.79 | Benign | 0.05 | Affected | 0.0903 | 0.3481 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2431C>T | P811S 2D AIThe SynGAP1 missense variant P811S is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of high‑accuracy predictors (AlphaMissense‑Optimized and the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also support a benign classification. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact, and AlphaMissense‑Default remains uncertain. No Foldetta stability assessment is available, so it does not contribute to the evidence. Overall, the preponderance of evidence points to a benign effect for P811S, and this conclusion is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -4.733 | Likely Benign | 0.474 | Ambiguous | Likely Benign | 0.128 | Likely Benign | -1.28 | Neutral | 0.982 | Probably Damaging | 0.824 | Possibly Damaging | 2.79 | Benign | 0.78 | Tolerated | 0.3656 | 0.5960 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||||
| c.2600G>C | G867A 2D AIThe SynGAP1 missense variant G867A is not reported 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 | 0.517562 | Disordered | 0.657954 | Binding | 0.285 | 0.801 | 0.250 | -4.638 | Likely Benign | 0.172 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -1.18 | Neutral | 0.990 | Probably Damaging | 0.828 | Possibly Damaging | 2.79 | Benign | 0.94 | Tolerated | 0.3666 | 0.5534 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2659C>A | P887T 2D AIThe SynGAP1 missense variant P887T 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 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) reports “Likely Benign,” while 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 reported). 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 | -4.780 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -1.47 | Neutral | 0.292 | Benign | 0.110 | Benign | 2.79 | Benign | 0.21 | Tolerated | 0.1228 | 0.3822 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2678A>G | Q893R 2D AIThe SynGAP1 missense variant Q893R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.447267 | Uncertain | 0.310 | 0.925 | 0.750 | -3.338 | Likely Benign | 0.392 | Ambiguous | Likely Benign | 0.056 | Likely Benign | -1.43 | Neutral | 0.802 | Possibly Damaging | 0.333 | Benign | 2.79 | Benign | 0.09 | Tolerated | 0.1565 | 0.2412 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2699C>T | T900M 2D  AIThe SynGAP1 missense variant T900M is listed in ClinVar (ID 1063691.0) with an “Uncertain” clinical significance and is present in the gnomAD database (gnomAD ID 6‑33443251‑C‑T). Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign effects. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, which does not contradict the ClinVar “Uncertain” status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.465347 | Uncertain | 0.289 | 0.924 | 0.375 | Conflicting | 2 | 6-33443251-C-T | 14 | 8.68e-6 | -3.852 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.015 | Likely Benign | -0.81 | Neutral | 0.060 | Benign | 0.016 | Benign | 2.79 | Benign | 0.08 | Tolerated | 4.32 | 4 | 0.1356 | 0.6533 | -1 | -1 | 2.6 | 30.09 | ||||||||||||||||||||||||||||||||
| c.2728G>A | G910S 2D AIThe SynGAP1 missense variant G910S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, 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 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 | 0.762850 | Disordered | 0.707319 | Binding | 0.264 | 0.917 | 0.250 | -3.195 | Likely Benign | 0.331 | Likely Benign | Likely Benign | 0.234 | Likely Benign | -1.54 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.79 | Benign | 0.06 | Tolerated | 0.2671 | 0.4492 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2737A>G | T913A 2D  AIThe SynGAP1 missense variant T913A is not reported 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 likewise indicates Likely Benign. Foldetta results are unavailable, so they do not influence the overall assessment. 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 | 0.661982 | Disordered | 0.763517 | Binding | 0.339 | 0.899 | 0.375 | -2.386 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -1.41 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.79 | Benign | 0.15 | Tolerated | 0.4240 | 0.4905 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2860C>A | P954T 2D AIThe SynGAP1 missense variant P954T is not reported 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 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 | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | -5.657 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -0.77 | Neutral | 0.977 | Probably Damaging | 0.856 | Possibly Damaging | 2.79 | Benign | 0.48 | Tolerated | 0.1860 | 0.6324 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| 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 | -3.12 | Deleterious | 0.801 | Possibly Damaging | 0.602 | Possibly Damaging | 2.79 | Benign | 0.13 | Tolerated | 0.1296 | 0.5088 | -2 | -3 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.3073C>G | Q1025E 2D AIThe SynGAP1 missense variant Q1025E 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 the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta 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 any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.993410 | Binding | 0.363 | 0.746 | 0.500 | -3.010 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.60 | Neutral | 0.649 | Possibly Damaging | 0.353 | Benign | 2.79 | Benign | 1.00 | Tolerated | 0.1391 | 0.2269 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3085C>A | Q1029K 2D AIThe SynGAP1 missense variant Q1029K is not reported 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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default remains uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta data is missing. Overall, the majority of evidence points to a benign impact for Q1029K, 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 | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | -3.698 | Likely Benign | 0.516 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -1.18 | Neutral | 0.771 | Possibly Damaging | 0.482 | Possibly Damaging | 2.79 | Benign | 1.00 | Tolerated | 0.1656 | 0.4196 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3103C>T | P1035S 2D AIThe SynGAP1 missense variant P1035S is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign. Only polyPhen‑2 HumDiv flags it as pathogenic, while AlphaMissense‑Default remains uncertain. The 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. Taken together, the preponderance of evidence points to a benign impact for P1035S, 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 | 0.945666 | Disordered | 0.989572 | Binding | 0.300 | 0.756 | 0.625 | -3.678 | Likely Benign | 0.341 | Ambiguous | Likely Benign | 0.059 | Likely Benign | -0.97 | Neutral | 0.818 | Possibly Damaging | 0.355 | Benign | 2.79 | Benign | 0.28 | Tolerated | 0.3257 | 0.6253 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3110T>C | I1037T 2D AIThe SynGAP1 missense variant I1037T is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33443662‑T‑C). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the majority of predictions (seven benign vs. two pathogenic) indicate that the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.939629 | Disordered | 0.986140 | Binding | 0.309 | 0.774 | 0.625 | 6-33443662-T-C | 1 | 6.21e-7 | -2.565 | Likely Benign | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.066 | Likely Benign | 0.40 | Neutral | 0.292 | Benign | 0.110 | Benign | 2.79 | Benign | 0.34 | Tolerated | 3.77 | 5 | 0.1071 | 0.2175 | -1 | 0 | -5.2 | -12.05 | ||||||||||||||||||||||||||||||||||
| c.3199C>A | P1067T 2D AIThe SynGAP1 missense variant P1067T 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 | 0.966441 | Disordered | 0.975099 | Binding | 0.459 | 0.907 | 0.875 | -4.898 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -1.94 | Neutral | 0.827 | Possibly Damaging | 0.375 | Benign | 2.79 | Benign | 0.04 | Affected | 0.1449 | 0.6132 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3220C>G | Q1074E 2D AIThe SynGAP1 missense variant Q1074E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions strongly suggests that 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 | 0.930790 | Disordered | 0.987006 | Binding | 0.339 | 0.897 | 0.750 | -2.815 | Likely Benign | 0.419 | Ambiguous | Likely Benign | 0.096 | Likely Benign | -0.79 | Neutral | 0.264 | Benign | 0.103 | Benign | 2.79 | Benign | 0.24 | Tolerated | 0.1386 | 0.2856 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3274T>G | L1092V 2D AIThe SynGAP1 missense variant L1092V is not reported 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 high‑accuracy consensus (SGM‑Consensus) 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. 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 | 0.924947 | Disordered | 0.985431 | Binding | 0.385 | 0.890 | 1.000 | -4.906 | Likely Benign | 0.451 | Ambiguous | Likely Benign | 0.034 | Likely Benign | -0.36 | Neutral | 0.051 | Benign | 0.037 | Benign | 2.79 | Benign | 0.37 | Tolerated | 0.1658 | 0.3912 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3283C>G | P1095A 2D AIThe SynGAP1 missense variant P1095A 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 is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. 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 | 0.922952 | Disordered | 0.979251 | Binding | 0.387 | 0.870 | 1.000 | -4.555 | Likely Benign | 0.129 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.80 | Neutral | 0.580 | Possibly Damaging | 0.242 | Benign | 2.79 | Benign | 0.18 | Tolerated | 0.3122 | 0.5703 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3295T>G | Y1099D 2D  AIThe SynGAP1 missense variant Y1099D is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score the change as tolerated or benign, while only polyPhen‑2 HumDiv flags it as pathogenic. 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, SGM‑Consensus is Likely Benign, and Foldetta results are unavailable. Taken together, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar assertion, 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 | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | -4.193 | Likely Benign | 0.429 | Ambiguous | Likely Benign | 0.130 | Likely Benign | -1.08 | Neutral | 0.818 | Possibly Damaging | 0.435 | Benign | 2.79 | Benign | 0.13 | Tolerated | 0.3819 | 0.0935 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||||||||||||
| c.3697A>G | I1233V 2D  AIThe SynGAP1 missense change I1233V is not reported 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. Only AlphaMissense‑Default predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect for I1233V, 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 | Coiled-coil | 0.525368 | Disordered | 0.564054 | Binding | 0.881 | 0.531 | 0.125 | -2.826 | Likely Benign | 0.615 | Likely Pathogenic | Likely Benign | 0.036 | Likely Benign | -0.59 | Neutral | 0.437 | Benign | 0.170 | Benign | 2.79 | Benign | 0.06 | Tolerated | 0.0950 | 0.3270 | 4 | 3 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| 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 | -0.08 | Neutral | 0.042 | Benign | 0.061 | Benign | 2.79 | Benign | 0.41 | Tolerated | 0.1016 | 0.5339 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||||
| c.3791G>C | G1264A 2D AIThe SynGAP1 missense variant G1264A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus 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 preponderance of evidence points to a benign impact, and this conclusion is consistent with the lack of any ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -3.460 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.32 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.79 | Benign | 0.91 | Tolerated | 0.3504 | 0.4220 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3847C>G | P1283A 2D AIThe SynGAP1 missense variant P1283A 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 from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign. Foldetta results are unavailable, so they do not influence the overall assessment. 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 | 0.762850 | Disordered | 0.819686 | Binding | 0.484 | 0.732 | 0.875 | -3.656 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.070 | Likely Benign | 1.42 | Neutral | 0.004 | Benign | 0.004 | Benign | 2.79 | Benign | 1.00 | Tolerated | 0.2874 | 0.3370 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3893A>T | Q1298L 2D  AIThe SynGAP1 missense variant Q1298L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, PROVEAN and SIFT predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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 unavailable. Overall, the majority 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 | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -2.251 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.221 | Likely Benign | -3.04 | Deleterious | 0.224 | Benign | 0.078 | Benign | 2.79 | Benign | 0.04 | Affected | 0.0667 | 0.4164 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3902C>A | P1301H 2D  AIThe SynGAP1 missense variant P1301H is listed in ClinVar (ID 212356.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451776‑C‑A). 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 high‑accuracy consensus methods report a benign outcome: AlphaMissense‑Optimized predicts 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 predictions, including the high‑accuracy consensus, support a benign classification, which does not contradict the ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | Conflicting | 2 | 6-33451776-C-A | 5 | 3.10e-6 | -5.756 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.232 | Likely Benign | -1.13 | Neutral | 0.642 | Possibly Damaging | 0.378 | Benign | 2.79 | Benign | 0.04 | Affected | 3.77 | 5 | 0.1305 | 0.2965 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||
| c.3908G>T | G1303V 2D  AIThe SynGAP1 missense variant G1303V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -3.513 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.147 | Likely Benign | -2.44 | Neutral | 0.990 | Probably Damaging | 0.846 | Possibly Damaging | 2.79 | Benign | 0.02 | Affected | 0.1511 | 0.3508 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.2157C>A | N719K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, ESM1b, and Foldetta) 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 reliable predictions indicate a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | -7.454 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | -0.64 | Ambiguous | 0.0 | -0.62 | Ambiguous | -0.63 | Ambiguous | 0.42 | Likely Benign | 0.250 | Likely Benign | -1.84 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.80 | Benign | 0.55 | Tolerated | 0.1424 | 0.3112 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.2157C>G | N719K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719K is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors shows a predominance of benign calls: REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized all predict a neutral effect, whereas polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict pathogenicity. FoldX, Rosetta, ESM1b, and Foldetta are inconclusive. High‑accuracy assessment further supports a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign outcome; Foldetta remains uncertain. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | -7.454 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | -0.64 | Ambiguous | 0.0 | -0.62 | Ambiguous | -0.63 | Ambiguous | 0.42 | Likely Benign | 0.244 | Likely Benign | -1.84 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.80 | Benign | 0.55 | Tolerated | 0.1424 | 0.3112 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.2210A>T | Q737L 2D AIThe SynGAP1 missense variant Q737L is not reported 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 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 | 0.889439 | Disordered | 0.425743 | Uncertain | 0.323 | 0.803 | 0.875 | -2.789 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -2.44 | Neutral | 0.959 | Probably Damaging | 0.721 | Possibly Damaging | 2.80 | Benign | 1.00 | Tolerated | 0.0958 | 0.5494 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2231A>G | Q744R 2D AIThe SynGAP1 missense variant Q744R is not reported 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 further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign. Foldetta results are unavailable. Overall, the majority 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. | Likely Benign | 0.852992 | Disordered | 0.540428 | Binding | 0.316 | 0.866 | 0.875 | -2.207 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.43 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.80 | Benign | 0.05 | Affected | 0.1437 | 0.1588 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.2237T>C | V746A 2D AIThe SynGAP1 missense variant V746A 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 | 0.808535 | Disordered | 0.576597 | Binding | 0.336 | 0.867 | 0.875 | -2.875 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -0.29 | Neutral | 0.010 | Benign | 0.005 | Benign | 2.80 | Benign | 0.21 | Tolerated | 0.2566 | 0.2531 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.2459A>C | Y820S 2D  AIThe SynGAP1 missense variant Y820S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign (2 benign vs. 1 pathogenic). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for Y820S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.733139 | Disordered | 0.695550 | Binding | 0.293 | 0.883 | 0.625 | -7.094 | In-Between | 0.723 | Likely Pathogenic | Likely Benign | 0.101 | Likely Benign | -1.79 | Neutral | 0.999 | Probably Damaging | 0.951 | Probably Damaging | 2.80 | Benign | 0.22 | Tolerated | 0.5166 | 0.2291 | Weaken | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2611C>G | H871D 2D AIThe SynGAP1 missense variant H871D is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.480142 | Structured | 0.679301 | Binding | 0.279 | 0.858 | 0.250 | -3.263 | Likely Benign | 0.257 | Likely Benign | Likely Benign | 0.245 | Likely Benign | -0.51 | Neutral | 0.016 | Benign | 0.026 | Benign | 2.80 | Benign | 0.31 | Tolerated | 0.2271 | 0.1617 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.2653C>G | P885A 2D AIThe SynGAP1 missense variant P885A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, 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 | 0.690604 | Disordered | 0.636133 | Binding | 0.344 | 0.917 | 0.250 | -3.908 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -1.29 | Neutral | 0.112 | Benign | 0.084 | Benign | 2.80 | Benign | 0.00 | Affected | 0.3425 | 0.5481 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2710A>G | M904V 2D  AIThe SynGAP1 missense variant M904V is reported in ClinVar (ID 833650.0) as benign and is present in gnomAD (variant ID 6‑33443262‑A‑G). 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 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 method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the computational evidence strongly supports a benign classification, which aligns with the ClinVar status and shows no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.589073 | Binding | 0.350 | 0.920 | 0.250 | Likely Benign | 2 | 6-33443262-A-G | 77 | 4.78e-5 | -2.907 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.33 | Neutral | 0.039 | Benign | 0.023 | Benign | 2.80 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.3724 | 0.3948 | 2 | 1 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||||
| c.2711T>A | M904K 2D  AIThe SynGAP1 missense variant M904K is not reported 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, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available 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 | 0.671169 | Disordered | 0.589073 | Binding | 0.350 | 0.920 | 0.250 | -2.333 | Likely Benign | 0.744 | Likely Pathogenic | Likely Benign | 0.033 | Likely Benign | -1.08 | Neutral | 0.277 | Benign | 0.137 | Benign | 2.80 | Benign | 1.00 | Tolerated | 0.1696 | 0.0871 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| 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 | -0.74 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.80 | Benign | 0.74 | Tolerated | 0.3541 | 0.5147 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| 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 | -0.41 | Neutral | 0.979 | Probably Damaging | 0.821 | Possibly Damaging | 2.80 | Benign | 0.82 | Tolerated | 0.3462 | 0.4948 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| 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 | 0.10 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.80 | Benign | 0.10 | Tolerated | 4.32 | 4 | 0.2844 | 0.5190 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.2999T>G | I1000S 2D  AIThe SynGAP1 missense variant I1000S is 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 (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) 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 (seven benign vs. three pathogenic predictions) supports a benign classification. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.745909 | Disordered | 0.957020 | Binding | 0.293 | 0.904 | 0.625 | -3.694 | Likely Benign | 0.587 | Likely Pathogenic | Likely Benign | 0.151 | Likely Benign | -0.38 | Neutral | 0.946 | Possibly Damaging | 0.673 | Possibly Damaging | 2.80 | Benign | 0.19 | Tolerated | 0.2501 | 0.1270 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3040G>C | G1014R 2D AIThe SynGAP1 missense variant G1014R 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‑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; however, the Foldetta protein‑folding stability assessment is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely benign. 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 | -3.234 | Likely Benign | 0.562 | Ambiguous | Likely Benign | 0.067 | Likely Benign | -1.47 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.80 | Benign | 0.12 | Tolerated | 0.1044 | 0.4714 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3083T>A | L1028Q 2D  AIThe SynGAP1 missense variant L1028Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.995137 | Binding | 0.364 | 0.730 | 0.500 | -2.718 | Likely Benign | 0.612 | Likely Pathogenic | Likely Benign | 0.179 | Likely Benign | -0.19 | Neutral | 0.986 | Probably Damaging | 0.825 | Possibly Damaging | 2.80 | Benign | 0.38 | Tolerated | 0.1110 | 0.1403 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3283C>T | P1095S 2D AIThe SynGAP1 missense variant P1095S is reported in gnomAD (ID 6‑33443835‑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 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, was not available for this variant. Based on the unanimous benign predictions and the absence of any pathogenic signal, 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 | 0.922952 | Disordered | 0.979251 | Binding | 0.387 | 0.870 | 1.000 | 6-33443835-C-T | 7 | 4.51e-6 | -3.819 | Likely Benign | 0.182 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -0.64 | Neutral | 0.207 | Benign | 0.072 | Benign | 2.80 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.3150 | 0.5963 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3427A>G | T1143A 2D AIThe SynGAP1 missense variant T1143A is not reported 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. Based on the preponderance of benign predictions and the consensus from high‑accuracy methods, 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 | 0.722918 | Binding | 0.275 | 0.837 | 1.000 | -3.340 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -1.19 | Neutral | 0.877 | Possibly Damaging | 0.675 | Possibly Damaging | 2.80 | Benign | 0.43 | Tolerated | 0.3252 | 0.3546 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3775A>C | I1259L 2D  AIThe SynGAP1 missense variant I1259L is not reported in ClinVar and has no entries in 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 also indicates Likely Benign. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for I1259L, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.494003 | Structured | 0.576405 | Binding | 0.885 | 0.574 | 0.250 | -5.822 | Likely Benign | 0.770 | Likely Pathogenic | Likely Benign | 0.152 | Likely Benign | -0.01 | Neutral | 0.981 | Probably Damaging | 0.970 | Probably Damaging | 2.80 | Benign | 0.18 | Tolerated | 0.0639 | 0.3078 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||||
| c.3860C>A | P1287H 2D AIThe SynGAP1 missense variant P1287H is recorded in gnomAD (6‑33447908‑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. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is not available for this variant. Based on the aggregate predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.813701 | Binding | 0.538 | 0.777 | 0.750 | 6-33447908-C-A | -3.606 | Likely Benign | 0.135 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -1.36 | Neutral | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 2.80 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1306 | 0.3448 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||
| c.3890G>A | R1297K 2D  AIThe SynGAP1 missense variant R1297K is catalogued in gnomAD (ID 6‑33451764‑G‑A) 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 tolerated or benign. Grouping by consensus, all listed predictors fall into the benign category, with no tool reporting a pathogenic outcome. 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 classification. Foldetta stability analysis is unavailable for this variant. Consequently, the aggregate evidence strongly supports a benign interpretation, and this assessment does not conflict with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | 6-33451764-G-A | 1 | 6.20e-7 | -3.780 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.074 | Likely Benign | 0.55 | Neutral | 0.000 | Benign | 0.004 | Benign | 2.80 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.4109 | 0.2801 | 2 | 3 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||||||
| c.3899C>A | P1300H 2D AIThe SynGAP1 missense variant P1300H 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 | 0.788093 | Disordered | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | -5.062 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.48 | Neutral | 0.990 | Probably Damaging | 0.840 | Possibly Damaging | 2.80 | Benign | 0.01 | Affected | 0.1757 | 0.3802 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3928A>T | T1310S 2D AIThe SynGAP1 missense variant T1310S 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 for this variant. 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 | -2.809 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.23 | Neutral | 0.089 | Benign | 0.120 | Benign | 2.80 | Benign | 0.17 | Tolerated | 0.2629 | 0.3418 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3929C>A | T1310K 2D AIThe SynGAP1 missense variant T1310K is not reported 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 | 0.812494 | Disordered | 0.959076 | Binding | 0.398 | 0.904 | 0.750 | -4.388 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -0.64 | Neutral | 0.111 | Benign | 0.116 | Benign | 2.80 | Benign | 0.04 | Affected | 0.0992 | 0.2978 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||||
| c.1459A>G | N487D 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant N487D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, Foldetta, and FATHMM, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX and premPS are inconclusive. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, while Foldetta indicates a benign folding stability change. Overall, the preponderance of evidence points to a pathogenic effect for this variant, 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 | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -13.330 | Likely Pathogenic | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.80 | Ambiguous | 0.2 | -0.21 | Likely Benign | 0.30 | Likely Benign | 0.84 | Ambiguous | 0.513 | Likely Pathogenic | -4.97 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.81 | Benign | 0.01 | Affected | 0.1728 | 0.1815 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.1862G>C | R621P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R621P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, whereas the remaining eleven tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. The high‑accuracy subset further supports this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. No prediction is inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently contains no entry for R621P. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.084420 | Uncertain | 0.945 | 0.216 | 0.000 | -17.022 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.94 | Destabilizing | 0.4 | 9.39 | Destabilizing | 7.17 | Destabilizing | 0.96 | Ambiguous | 0.745 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.81 | Benign | 0.01 | Affected | 0.2143 | 0.3692 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1925A>T | K642M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K642M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess the variant’s effect fall into two broad groups: benign predictions come from FoldX, premPS, and FATHMM; pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 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, classifies the variant as likely pathogenic. High‑accuracy assessments are as follows: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus also predicts pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence from multiple independent predictors indicates that K642M 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 | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | -13.557 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.43 | Likely Benign | 0.1 | 0.62 | Ambiguous | 0.53 | Ambiguous | 0.21 | Likely Benign | 0.510 | Likely Pathogenic | -5.88 | Deleterious | 1.000 | Probably Damaging | 0.941 | Probably Damaging | 2.81 | Benign | 0.00 | Affected | 0.1256 | 0.3589 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.2222C>A | P741H 2D AIThe SynGAP1 missense variant P741H is not reported 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 | 0.885302 | Disordered | 0.493550 | Uncertain | 0.354 | 0.859 | 0.875 | -5.592 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -0.99 | Neutral | 0.006 | Benign | 0.007 | Benign | 2.81 | Benign | 0.01 | Affected | 0.1372 | 0.3831 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2265G>A | M755I 2D AIThe SynGAP1 missense variant M755I 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 | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -3.856 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -0.55 | Neutral | 0.039 | Benign | 0.014 | Benign | 2.81 | Benign | 0.14 | Tolerated | 0.1059 | 0.2403 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2265G>C | M755I 2D AIThe SynGAP1 missense variant M755I 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 | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -3.856 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.031 | Likely Benign | -0.55 | Neutral | 0.039 | Benign | 0.014 | Benign | 2.81 | Benign | 0.14 | Tolerated | 0.1059 | 0.2403 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2265G>T | M755I 2D AIThe SynGAP1 missense variant M755I 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 | 0.490133 | Structured | 0.783855 | Binding | 0.336 | 0.873 | 0.375 | -3.856 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -0.55 | Neutral | 0.039 | Benign | 0.014 | Benign | 2.81 | Benign | 0.14 | Tolerated | 0.1059 | 0.2403 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2659C>G | P887A 2D AIThe SynGAP1 missense variant P887A 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 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) reports “Likely Benign,” while 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 | 0.716283 | Disordered | 0.602269 | Binding | 0.348 | 0.925 | 0.500 | -2.986 | Likely Benign | 0.047 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -1.64 | Neutral | 0.011 | Benign | 0.004 | Benign | 2.81 | Benign | 0.36 | Tolerated | 0.2744 | 0.3597 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| 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 | -1.72 | Neutral | 0.152 | Benign | 0.070 | Benign | 2.81 | Benign | 0.18 | Tolerated | 0.1800 | 0.5164 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| 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 | -0.98 | Neutral | 0.124 | Benign | 0.061 | Benign | 2.81 | Benign | 0.41 | Tolerated | 0.3476 | 0.5203 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3034C>G | P1012A 2D AIThe SynGAP1 missense variant P1012A 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 | 0.834292 | Disordered | 0.894674 | Binding | 0.319 | 0.866 | 0.625 | -4.038 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -0.55 | Neutral | 0.112 | Benign | 0.084 | Benign | 2.81 | Benign | 0.26 | Tolerated | 0.3272 | 0.4900 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| 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 | -0.23 | Neutral | 0.224 | Benign | 0.131 | Benign | 2.81 | Benign | 0.22 | Tolerated | 3.77 | 5 | 0.3217 | 0.5300 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3081C>A | N1027K 2D AIThe SynGAP1 missense variant N1027K is not reported 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, while those that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and the SGM‑Consensus result is benign; Foldetta predictions 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 | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -3.177 | Likely Benign | 0.841 | Likely Pathogenic | Ambiguous | 0.063 | Likely Benign | -0.64 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 2.81 | Benign | 0.65 | Tolerated | 0.1808 | 0.6079 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3081C>G | N1027K 2D AIThe SynGAP1 missense variant N1027K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and AlphaMissense‑Optimized is uncertain. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. 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 | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -3.177 | Likely Benign | 0.841 | Likely Pathogenic | Ambiguous | 0.063 | Likely Benign | -0.64 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 2.81 | Benign | 0.65 | Tolerated | 0.1808 | 0.6079 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| 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 | 0.06 | Neutral | 0.220 | Benign | 0.085 | Benign | 2.81 | Benign | 1.00 | Tolerated | 0.4387 | 0.5282 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3110T>A | I1037N 2D AIThe SynGAP1 missense variant I1037N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a Likely Benign classification, while AlphaMissense‑Optimized remains uncertain. Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.939629 | Disordered | 0.986140 | Binding | 0.309 | 0.774 | 0.625 | -3.955 | Likely Benign | 0.832 | Likely Pathogenic | Ambiguous | 0.131 | Likely Benign | 1.56 | Neutral | 0.666 | Possibly Damaging | 0.211 | Benign | 2.81 | Benign | 0.34 | Tolerated | 0.1022 | 0.1140 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3112A>G | T1038A 2D AIThe SynGAP1 missense variant T1038A 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, whereas 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 the available predictions points to a benign impact, and this is consistent with the lack of ClinVar evidence, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.938133 | Disordered | 0.982911 | Binding | 0.279 | 0.794 | 0.625 | -3.544 | Likely Benign | 0.265 | Likely Benign | Likely Benign | 0.047 | Likely Benign | -0.79 | Neutral | 0.649 | Possibly Damaging | 0.209 | Benign | 2.81 | Benign | 0.15 | Tolerated | 0.3429 | 0.3983 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3145C>G | P1049A 2D AIThe SynGAP1 missense variant P1049A 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 | 0.978316 | Disordered | 0.917915 | Binding | 0.428 | 0.920 | 0.750 | -3.870 | Likely Benign | 0.049 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -1.43 | Neutral | 0.180 | Benign | 0.171 | Benign | 2.81 | Benign | 0.06 | Tolerated | 0.3306 | 0.4897 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3287A>T | E1096V 2D  AIThe SynGAP1 missense variant E1096V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence indicates the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.976475 | Binding | 0.308 | 0.858 | 1.000 | -3.588 | Likely Benign | 0.650 | Likely Pathogenic | Likely Benign | 0.138 | Likely Benign | -1.06 | Neutral | 0.043 | Benign | 0.017 | Benign | 2.81 | Benign | 0.03 | Affected | 0.1082 | 0.7596 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3311C>T | P1104L 2D AIThe SynGAP1 missense variant P1104L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also predicts Likely Benign; Foldetta results are unavailable. Overall, the consensus of the majority of tools, including the high‑accuracy predictors, points to a benign impact. This conclusion is consistent with the lack of ClinVar evidence and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.936162 | Disordered | 0.954801 | Binding | 0.440 | 0.863 | 0.875 | -3.846 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -0.33 | Neutral | 0.626 | Possibly Damaging | 0.168 | Benign | 2.81 | Benign | 1.00 | Tolerated | 0.2264 | 0.6795 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3748C>A | Q1250K 2D AIThe SynGAP1 missense variant Q1250K 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, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the 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 | Coiled-coil | 0.759478 | Disordered | 0.360484 | Uncertain | 0.881 | 0.554 | 0.750 | -6.804 | Likely Benign | 0.258 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -0.60 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 2.81 | Benign | 0.13 | Tolerated | 0.1464 | 0.2484 | 1 | 1 | -0.4 | 0.04 | ||||||||||||||||||||||||||||||||||||||
| c.3757G>T | A1253S 2D AIThe SynGAP1 missense variant A1253S 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 predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign status. Foldetta results are unavailable. Based on the consensus of all available predictions, 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 | Coiled-coil | 0.661982 | Disordered | 0.391377 | Uncertain | 0.881 | 0.550 | 0.750 | -3.639 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.041 | Likely Benign | 0.05 | Neutral | 0.081 | Benign | 0.111 | Benign | 2.81 | Benign | 0.33 | Tolerated | 0.2003 | 0.4159 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3902C>G | P1301R 2D AIThe SynGAP1 missense variant P1301R is listed in ClinVar with an uncertain significance (ClinVar ID 2092739.0) and is present in gnomAD (ID 6‑33451776‑C‑G). Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign effects. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. In summary, all available predictions agree on a benign impact, and this consensus does not contradict the ClinVar uncertain status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | Uncertain | 1 | 6-33451776-C-G | 15 | 9.30e-6 | -4.753 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -1.13 | Neutral | 0.077 | Benign | 0.059 | Benign | 2.81 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.1352 | 0.1929 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||
| c.3907G>C | G1303R 2D AIThe SynGAP1 missense variant G1303R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic effect, whereas REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a benign outcome. Grouping by consensus, the benign‑predicating tools outnumber the pathogenic ones. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized classifies the variant as benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b, FATHMM, and PROVEAN—also reports a likely benign status. No Foldetta stability analysis is available for this residue. Overall, the preponderance of evidence points to a benign effect for G1303R, 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 | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -3.093 | Likely Benign | 0.536 | Ambiguous | Likely Benign | 0.364 | Likely Benign | -1.84 | Neutral | 0.970 | Probably Damaging | 0.787 | Possibly Damaging | 2.81 | Benign | 0.05 | Affected | 0.1024 | 0.3596 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3998A>T | E1333V 2D AIThe SynGAP1 E1333V 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 are REVEL, ESM1b, and FATHMM. Tools 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 (two pathogenic vs two benign votes), and Foldetta results are unavailable. Overall, the majority of evidence (six pathogenic vs three benign) points to a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.953319 | Binding | 0.347 | 0.746 | 0.750 | -4.322 | Likely Benign | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.289 | Likely Benign | -4.30 | Deleterious | 0.994 | Probably Damaging | 0.981 | Probably Damaging | 2.81 | Benign | 0.00 | Affected | 0.0994 | 0.7615 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||||
| c.4009T>C | F1337L 2D  AIThe SynGAP1 missense variant F1337L 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 FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, the majority of evaluated predictors (six pathogenic vs. three benign) indicate a likely pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.823549 | Disordered | 0.979265 | Binding | 0.388 | 0.712 | 0.625 | -2.396 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.186 | Likely Benign | -3.17 | Deleterious | 0.880 | Possibly Damaging | 0.899 | Possibly Damaging | 2.81 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2765 | 0.3543 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||||
| c.4011C>A | F1337L 2D AIThe SynGAP1 missense variant F1337L is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33451885‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of evaluated tools predict a pathogenic impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.823549 | Disordered | 0.979265 | Binding | 0.388 | 0.712 | 0.625 | 6-33451885-C-A | -2.396 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.111 | Likely Benign | -3.17 | Deleterious | 0.880 | Possibly Damaging | 0.899 | Possibly Damaging | 2.81 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2765 | 0.3543 | 0 | 2 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||
| c.4011C>G | F1337L 2D AIThe SynGAP1 missense variant F1337L is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic versus two benign votes), and Foldetta data are unavailable. With a predominance of pathogenic calls and a single high‑confidence pathogenic prediction, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar entry exists for F1337L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.823549 | Disordered | 0.979265 | Binding | 0.388 | 0.712 | 0.625 | -2.396 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.122 | Likely Benign | -3.17 | Deleterious | 0.880 | Possibly Damaging | 0.899 | Possibly Damaging | 2.81 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2765 | 0.3543 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||||
| c.1541T>A | I514N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the overwhelming consensus of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | -13.869 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.41 | Destabilizing | 0.3 | 2.41 | Destabilizing | 2.91 | Destabilizing | 2.61 | Destabilizing | 0.582 | Likely Pathogenic | -6.86 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.82 | Benign | 0.00 | Affected | 0.0770 | 0.0142 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.1541T>C | I514T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514T has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the majority of algorithms—SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. Rosetta reports an uncertain outcome and is not included in the consensus groups. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Taken together, the evidence overwhelmingly points to a pathogenic effect, and this conclusion is not contradicted by the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | -8.820 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 2.92 | Destabilizing | 0.1 | 1.88 | Ambiguous | 2.40 | Destabilizing | 1.94 | Destabilizing | 0.617 | Likely Pathogenic | -4.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.82 | Benign | 0.00 | Affected | 0.0962 | 0.0480 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.1541T>G | I514S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) 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 because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | -12.512 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 4.03 | Destabilizing | 0.2 | 3.70 | Destabilizing | 3.87 | Destabilizing | 2.11 | Destabilizing | 0.625 | Likely Pathogenic | -5.86 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.82 | Benign | 0.00 | Affected | 0.2296 | 0.0530 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1862G>A | R621Q 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R621Q is listed in ClinVar (ID 578137.0) as benign and is present in gnomAD (variant ID 6‑33440914‑G‑A). Functional prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. 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. No evidence from FoldX, Rosetta, or Foldetta supports a benign outcome. Overall, the preponderance of predictions indicates a likely pathogenic effect, which contradicts the benign classification reported in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.084420 | Uncertain | 0.945 | 0.216 | 0.000 | Likely Benign | 1 | 6-33440914-G-A | 19 | 1.18e-5 | -14.682 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 0.81 | Ambiguous | 0.1 | 1.13 | Ambiguous | 0.97 | Ambiguous | 1.35 | Destabilizing | 0.621 | Likely Pathogenic | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.82 | Benign | 0.01 | Affected | 3.37 | 35 | 0.2590 | 0.1963 | 1 | 1 | 1.0 | -28.06 | 243.7 | 54.3 | 0.0 | 0.0 | -0.4 | 0.2 | X | X | Potentially Pathogenic | The guanidinium group of Arg621, located in an α helix (res. Glu617-Asn635), forms a salt bridge with Glu525 in a nearby loop and stacks with Leu635. In the variant simulations, the carboxamide side chain of Gln621, which can act as both a hydrogen bond acceptor and donor, also stacks with Leu635 but can only sporadically hydrogen bond with Glu525.Accordingly, the residue swap could affect the tertiary structure integrity by disrupting the salt bridge formation. Additionally, due to its location at the GAP-Ras interface, the residue swap could impact the complex formation with the GTPase, but this cannot be investigated using solvent-only simulations. | ||||||||||||
| c.2231A>C | Q744P 2D AIThe SynGAP1 missense variant Q744P 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 Q744P, 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 | 0.852992 | Disordered | 0.540428 | Binding | 0.316 | 0.866 | 0.875 | -2.062 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.080 | Likely Benign | -0.46 | Neutral | 0.784 | Possibly Damaging | 0.206 | Benign | 2.82 | Benign | 0.12 | Tolerated | 0.2584 | 0.4397 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| 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 | -0.68 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.82 | Benign | 0.08 | Tolerated | 4.32 | 2 | 0.0896 | 0.5065 | 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 | -0.68 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.82 | Benign | 0.08 | Tolerated | 4.32 | 2 | 0.0896 | 0.5065 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||
| 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 | -3.63 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.82 | Benign | 0.04 | Affected | 0.3534 | 0.5050 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2632A>T | T878S 2D AIThe SynGAP1 missense variant T878S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.628767 | Binding | 0.288 | 0.878 | 0.250 | -2.493 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.073 | Likely Benign | -0.06 | Neutral | 0.009 | Benign | 0.012 | Benign | 2.82 | Benign | 0.03 | Affected | 0.3557 | 0.4867 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2678A>T | Q893L 2D AIThe SynGAP1 missense variant Q893L 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 | 0.754692 | Disordered | 0.447267 | Uncertain | 0.310 | 0.925 | 0.750 | -1.964 | Likely Benign | 0.204 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.92 | Neutral | 0.451 | Benign | 0.209 | Benign | 2.82 | Benign | 1.00 | Tolerated | 0.0904 | 0.5643 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2725A>C | M909L 2D  AIThe SynGAP1 missense variant M909L 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. Overall, the consensus of all available predictions points to a benign effect, and this is consistent with the lack of a ClinVar classification—there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | -1.417 | Likely Benign | 0.152 | Likely Benign | Likely Benign | 0.184 | Likely Benign | -0.85 | Neutral | 0.002 | Benign | 0.006 | Benign | 2.82 | Benign | 0.32 | Tolerated | 3.77 | 5 | 0.1591 | 0.4352 | 2 | 4 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2725A>T | M909L 2D AIThe SynGAP1 missense variant M909L is catalogued in gnomAD (ID 6‑33443277‑A‑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 variant 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 not available. 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 | 0.642678 | Disordered | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | 6-33443277-A-T | 4 | 2.48e-6 | -1.417 | Likely Benign | 0.152 | Likely Benign | Likely Benign | 0.184 | Likely Benign | -0.85 | Neutral | 0.002 | Benign | 0.006 | Benign | 2.82 | Benign | 0.32 | Tolerated | 3.77 | 5 | 0.1591 | 0.4352 | 2 | 4 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||
| c.2727G>A | M909I 2D AIThe SynGAP1 missense variant M909I is not reported 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. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | -3.636 | Likely Benign | 0.703 | Likely Pathogenic | Likely Benign | 0.097 | Likely Benign | -1.15 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 2.82 | Benign | 0.25 | Tolerated | 0.1392 | 0.3298 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2727G>C | M909I 2D AIThe SynGAP1 missense variant M909I is not reported 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. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta 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 | 0.642678 | Disordered | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | -3.636 | Likely Benign | 0.703 | Likely Pathogenic | Likely Benign | 0.097 | Likely Benign | -1.15 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 2.82 | Benign | 0.25 | Tolerated | 0.1392 | 0.3298 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2727G>T | M909I 2D AIThe SynGAP1 missense variant M909I is not reported 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. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta 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 | 0.642678 | Disordered | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | -3.636 | Likely Benign | 0.703 | Likely Pathogenic | Likely Benign | 0.097 | Likely Benign | -1.15 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 2.82 | Benign | 0.25 | Tolerated | 0.1392 | 0.3298 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2767A>C | I923L 2D AIThe SynGAP1 missense variant I923L is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors—including REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) 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 | 0.562014 | Disordered | 0.964857 | Binding | 0.292 | 0.852 | 0.250 | -1.637 | Likely Benign | 0.157 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.03 | Neutral | 0.166 | Benign | 0.101 | Benign | 2.82 | Benign | 0.56 | Tolerated | 0.1133 | 0.4528 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.2810A>G | D937G 2D  AIThe SynGAP1 missense variant D937G is not reported 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 prediction is available, so it does not influence the assessment. Overall, the majority of evidence indicates that D937G is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.819762 | Disordered | 0.963385 | Binding | 0.348 | 0.883 | 0.625 | -0.770 | Likely Benign | 0.301 | Likely Benign | Likely Benign | 0.155 | Likely Benign | -0.93 | Neutral | 0.990 | Probably Damaging | 0.817 | Possibly Damaging | 2.82 | Benign | 0.72 | Tolerated | 0.4313 | 0.7006 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3109A>C | I1037L 2D AIThe SynGAP1 missense variant I1037L is not reported in ClinVar and is absent from gnomAD, indicating no known clinical or population evidence. Functional prediction tools uniformly favor a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity, and the only uncertain call comes from AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as “Likely Benign.” High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise 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 consensus of available predictions indicates that I1037L 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 | 0.939629 | Disordered | 0.986140 | Binding | 0.309 | 0.774 | 0.625 | -2.563 | Likely Benign | 0.448 | Ambiguous | Likely Benign | 0.074 | Likely Benign | -0.46 | Neutral | 0.421 | Benign | 0.128 | Benign | 2.82 | Benign | 0.81 | Tolerated | 0.0939 | 0.4302 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3115A>C | I1039L 2D AIThe SynGAP1 missense variant I1039L 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 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, is not available for this variant. Overall, the consensus of all available predictions strongly supports a benign classification, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.969315 | Disordered | 0.979204 | Binding | 0.292 | 0.806 | 0.625 | -2.035 | Likely Benign | 0.269 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -0.14 | Neutral | 0.264 | Benign | 0.048 | Benign | 2.82 | Benign | 0.98 | Tolerated | 0.1057 | 0.4605 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3334G>A | E1112K 2D  AIThe SynGAP1 missense variant E1112K is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. Only two tools predict pathogenicity: SIFT and AlphaMissense‑Default. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the majority of predictions, including the high‑accuracy tools, suggest the variant is most likely benign, and this is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.909381 | Binding | 0.335 | 0.902 | 0.875 | -3.772 | Likely Benign | 0.684 | Likely Pathogenic | Likely Benign | 0.210 | Likely Benign | 0.15 | Neutral | 0.245 | Benign | 0.096 | Benign | 2.82 | Benign | 0.02 | Affected | 0.3002 | 0.7704 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3343A>C | I1115L 2D AIThe SynGAP1 missense variant I1115L is listed in ClinVar (ID 4178654) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443895‑A‑C). 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 effect, so the pathogenic‑prediction group is empty. High‑accuracy assessments reinforce this benign consensus: 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 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 | 0.889439 | Disordered | 0.892339 | Binding | 0.308 | 0.912 | 0.750 | Uncertain | 1 | 6-33443895-A-C | 1 | 7.56e-7 | -2.308 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.120 | Likely Benign | -0.46 | Neutral | 0.004 | Benign | 0.007 | Benign | 2.82 | Benign | 1.00 | Tolerated | 4.32 | 2 | 0.1154 | 0.4575 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||||
| c.3638A>G | N1213S 2D AIThe SynGAP1 missense variant N1213S is listed in ClinVar as Benign (ClinVar ID 708250.0) and is present in the gnomAD database (gnomAD ID 6‑33446630‑A‑G). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, PolyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar classification and indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.580690 | Disordered | 0.521638 | Binding | 0.888 | 0.561 | 0.500 | Benign | 1 | 6-33446630-A-G | 13 | 8.05e-6 | -4.086 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -0.56 | Neutral | 0.906 | Possibly Damaging | 0.551 | Possibly Damaging | 2.82 | Benign | 0.68 | Tolerated | 3.77 | 5 | 0.2607 | 0.4591 | 1 | 1 | 2.7 | -27.03 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||||||
| c.374C>A | P125H 2D AIThe SynGAP1 missense variant P125H is not 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 and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2). Foldetta results are unavailable. Overall, the majority of conventional predictors (five pathogenic vs four benign) lean toward a pathogenic interpretation, but the single high‑accuracy benign prediction and the inconclusive SGM Consensus temper this view. No ClinVar annotation is present, so there is no reported status to contradict the computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.704227 | Binding | 0.373 | 0.878 | 0.625 | -5.177 | Likely Benign | 0.583 | Likely Pathogenic | Likely Benign | 0.235 | Likely Benign | -4.18 | Deleterious | 0.996 | Probably Damaging | 0.750 | Possibly Damaging | 2.82 | Benign | 0.01 | Affected | 0.1598 | 0.4263 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||||||
| c.3899C>G | P1300R 2D AIThe SynGAP1 missense variant P1300R 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 analysis is available, so it does not influence the conclusion. Overall, the majority of evidence points to a benign effect for P1300R, 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 | 0.788093 | Disordered | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | -3.930 | Likely Benign | 0.195 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -1.27 | Neutral | 0.901 | Possibly Damaging | 0.516 | Possibly Damaging | 2.82 | Benign | 0.05 | Affected | 0.1516 | 0.2733 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3920C>A | P1307Q 2D AIThe SynGAP1 missense variant P1307Q is listed in ClinVar (ID 982827.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451794‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | Uncertain | 1 | 6-33451794-C-A | -4.227 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.192 | Likely Benign | -0.88 | Neutral | 0.988 | Probably Damaging | 0.765 | Possibly Damaging | 2.82 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1629 | 0.4464 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||
| c.3920C>G | P1307R 2D AIThe SynGAP1 missense variant P1307R 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 a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the available predictions indicates that P1307R 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 | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | -4.022 | Likely Benign | 0.183 | Likely Benign | Likely Benign | 0.225 | Likely Benign | -1.17 | Neutral | 0.887 | Possibly Damaging | 0.664 | Possibly Damaging | 2.82 | Benign | 0.06 | Tolerated | 0.1552 | 0.2763 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3920C>T | P1307L 2D AIThe SynGAP1 missense variant P1307L is listed in ClinVar (ID 1991214.0) as benign and is present in gnomAD (variant ID 6‑33451794‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign,” and AlphaMissense‑Optimized also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions, including the high‑accuracy consensus, indicate a benign impact. This conclusion aligns with the ClinVar benign classification and does not contradict the reported clinical status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | Benign | 1 | 6-33451794-C-T | 11 | 6.82e-6 | -4.044 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.292 | Likely Benign | -1.49 | Neutral | 0.779 | Possibly Damaging | 0.220 | Benign | 2.82 | Benign | 0.04 | Affected | 3.77 | 5 | 0.2546 | 0.6387 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||
| c.4010T>A | F1337Y 2D  AIThe SynGAP1 missense variant F1337Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the balance of evidence, including the SGM‑Consensus and the majority of individual predictors, leans toward a benign interpretation. 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 | 0.823549 | Disordered | 0.979265 | Binding | 0.388 | 0.712 | 0.625 | -3.481 | Likely Benign | 0.855 | Likely Pathogenic | Ambiguous | 0.202 | Likely Benign | -1.80 | Neutral | 0.947 | Possibly Damaging | 0.899 | Possibly Damaging | 2.82 | Benign | 0.00 | Affected | 0.1722 | 0.2754 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.1862G>T | R621L 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R621L has no ClinVar entry and is absent from gnomAD. Prediction tools that classify it as benign include Rosetta, premPS, and FATHMM, whereas the majority—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—label it pathogenic or likely pathogenic. FoldX and Foldetta return uncertain results and are not considered evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, and Foldetta remains inconclusive. Overall, the consensus of the available predictions points to a pathogenic effect for R621L, 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 | 0.222385 | Structured | 0.084420 | Uncertain | 0.945 | 0.216 | 0.000 | -16.055 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 1.70 | Ambiguous | 0.3 | -0.22 | Likely Benign | 0.74 | Ambiguous | 0.34 | Likely Benign | 0.718 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.83 | Benign | 0.00 | Affected | 0.1424 | 0.3568 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.2277G>A | M759I 2D AIThe SynGAP1 missense variant M759I is listed in ClinVar (ID 3686687.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33441742‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | Uncertain | 1 | 6-33441742-G-A | 1 | 6.20e-7 | -4.058 | Likely Benign | 0.393 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -0.88 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.83 | Benign | 0.34 | Tolerated | 3.99 | 5 | 0.1235 | 0.3129 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||
| c.2277G>C | M759I 2D AIThe SynGAP1 missense variant M759I is catalogued in gnomAD (6‑33441742‑G‑C) and has no ClinVar entry. Consensus from multiple in‑silico predictors points to a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score the variant as benign, while only polyPhen‑2 HumDiv flags it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy tools reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are not available, so they do not influence the assessment. Overall, the computational evidence overwhelmingly supports a benign classification, and this is consistent with the absence of a pathogenic ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | 6-33441742-G-C | -4.058 | Likely Benign | 0.393 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -0.88 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.83 | Benign | 0.34 | Tolerated | 3.99 | 5 | 0.1235 | 0.3129 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||
| c.2277G>T | M759I 2D AIThe SynGAP1 missense variant M759I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. 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 preponderance of evidence from multiple prediction algorithms and high‑accuracy tools points to a benign impact for M759I, 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 | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | -4.058 | Likely Benign | 0.393 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -0.88 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.83 | Benign | 0.34 | Tolerated | 3.99 | 5 | 0.1235 | 0.3129 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2341A>C | M781L 2D AIThe SynGAP1 missense variant M781L 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 | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | -2.334 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -0.41 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.83 | Benign | 0.88 | Tolerated | 0.1530 | 0.3669 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2341A>T | M781L 2D AIThe SynGAP1 missense variant M781L 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 predicts pathogenicity. High‑accuracy assessments corroborate this benign classification: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign status. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this prediction 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 | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | -2.334 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -0.41 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.83 | Benign | 0.88 | Tolerated | 0.1530 | 0.3669 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2402G>C | G801A 2D AIThe SynGAP1 missense variant G801A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool 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 not available, so they do not influence the assessment. **Overall, 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 | SH3-binding motif | 0.874069 | Disordered | 0.636323 | Binding | 0.320 | 0.892 | 0.625 | -3.747 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.025 | Likely Benign | -0.61 | Neutral | 0.025 | Benign | 0.034 | Benign | 2.83 | Benign | 0.50 | Tolerated | 0.3458 | 0.4681 | 1 | 0 | 2.2 | 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 | 0.32 | Neutral | 0.001 | Benign | 0.006 | Benign | 2.83 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.2682 | 0.5208 | 0 | 1 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||
| c.2513A>G | N838S 2D AIThe SynGAP1 missense variant at residue N838S is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only the two polyPhen‑2 classifiers (HumDiv and HumVar) predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence supports a benign classification, and this is not in conflict with ClinVar, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.613320 | Binding | 0.276 | 0.861 | 0.250 | -3.748 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -1.24 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.83 | Benign | 0.50 | Tolerated | 0.3552 | 0.5485 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||||||
| c.2813G>T | G938V 2D AIThe SynGAP1 missense variant G938V is not reported 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 benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that G938V 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 | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | -6.112 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -0.81 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.83 | Benign | 0.31 | Tolerated | 0.1230 | 0.3811 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3017A>C | Y1006S 2D AIThe SynGAP1 missense variant Y1006S has no ClinVar record and is not listed in gnomAD. 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, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, 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 majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no entry for Y1006S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.930554 | Binding | 0.264 | 0.896 | 0.750 | -2.522 | Likely Benign | 0.582 | Likely Pathogenic | Likely Benign | 0.170 | Likely Benign | -0.58 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.83 | Benign | 0.90 | Tolerated | 0.4426 | 0.2274 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3085C>G | Q1029E 2D AIThe SynGAP1 missense variant Q1029E is reported in gnomAD (ID 6‑33443637‑C‑G) 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, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates 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 | 0.852992 | Disordered | 0.995643 | Binding | 0.375 | 0.734 | 0.500 | 6-33443637-C-G | 17 | 1.05e-5 | -3.660 | Likely Benign | 0.281 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -0.92 | Neutral | 0.625 | Possibly Damaging | 0.258 | Benign | 2.83 | Benign | 0.26 | Tolerated | 3.77 | 5 | 0.1327 | 0.2433 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||
| c.3110T>G | I1037S 2D AIThe SynGAP1 missense variant I1037S is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which classifies the variant as Likely Benign. Only AlphaMissense‑Default predicts a pathogenic outcome, while AlphaMissense‑Optimized is uncertain and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Based on the overall consensus of the majority of tools, 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 | 0.939629 | Disordered | 0.986140 | Binding | 0.309 | 0.774 | 0.625 | -2.247 | Likely Benign | 0.935 | Likely Pathogenic | Ambiguous | 0.120 | Likely Benign | 0.43 | Neutral | 0.032 | Benign | 0.017 | Benign | 2.83 | Benign | 0.27 | Tolerated | 0.2634 | 0.1110 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3206A>T | Q1069L 2D AIThe SynGAP1 missense variant Q1069L 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 | 0.943310 | Disordered | 0.981477 | Binding | 0.333 | 0.906 | 0.875 | -4.278 | Likely Benign | 0.141 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -0.96 | Neutral | 0.003 | Benign | 0.008 | Benign | 2.83 | Benign | 0.10 | Tolerated | 0.0936 | 0.6624 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3295T>A | Y1099N 2D  AIThe SynGAP1 missense variant Y1099N 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 is benign and the SGM‑Consensus is 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 | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | -4.329 | Likely Benign | 0.269 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -1.01 | Neutral | 0.818 | Possibly Damaging | 0.360 | Benign | 2.83 | Benign | 0.16 | Tolerated | 0.2121 | 0.0935 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||||||||||||
| c.3547T>G | Y1183D 2D AISynGAP1 missense variant Y1183D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools show mixed results: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, a majority‑vote model of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts the variant as likely benign. High‑accuracy assessments further indicate AlphaMissense‑Optimized as pathogenic, whereas Foldetta (FoldX‑MD/Rosetta stability analysis) is not available for this residue. Overall, the balance of evidence leans toward a benign effect, and this assessment does not conflict with ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.527818 | Binding | 0.523 | 0.652 | 0.500 | -2.718 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.097 | Likely Benign | -1.10 | Neutral | 0.986 | Probably Damaging | 0.787 | Possibly Damaging | 2.83 | Benign | 0.61 | Tolerated | 0.4602 | 0.0243 | -4 | -3 | -2.2 | -48.09 | ||||||||||||||||||||||||||||||||||||||
| c.374C>G | P125R 2D AIThe SynGAP1 missense variant P125R is not 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 those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta data are unavailable. Consequently, the overall computational evidence is split evenly between benign and pathogenic predictions, with no decisive support from the most accurate methods. Based on these predictions, the variant’s impact remains inconclusive; it is neither clearly benign nor pathogenic, 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. | 0.505461 | Disordered | 0.704227 | Binding | 0.373 | 0.878 | 0.625 | -5.658 | Likely Benign | 0.792 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | -4.33 | Deleterious | 0.952 | Possibly Damaging | 0.521 | Possibly Damaging | 2.83 | Benign | 0.09 | Tolerated | 0.1461 | 0.2913 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.374C>T | P125L 2D AIThe SynGAP1 missense variant P125L is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta results are unavailable. Overall, the majority of evidence (5 benign vs 3 pathogenic, with one uncertain) 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. | 0.505461 | Disordered | 0.704227 | Binding | 0.373 | 0.878 | 0.625 | -4.565 | Likely Benign | 0.550 | Ambiguous | Likely Benign | 0.147 | Likely Benign | -4.82 | Deleterious | 0.906 | Possibly Damaging | 0.272 | Benign | 2.83 | Benign | 0.01 | Affected | 0.2189 | 0.6478 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3892C>G | Q1298E 2D AIThe SynGAP1 missense variant Q1298E 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 | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -3.530 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -1.14 | Neutral | 0.026 | Benign | 0.018 | Benign | 2.83 | Benign | 0.06 | Tolerated | 0.1235 | 0.1330 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3902C>T | P1301L 2D AIThe SynGAP1 missense variant P1301L is reported in gnomAD (ID 6‑33451776‑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 pathogenic annotation, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | 6-33451776-C-T | 3 | 1.86e-6 | -4.152 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -1.63 | Neutral | 0.017 | Benign | 0.028 | Benign | 2.83 | Benign | 0.11 | Tolerated | 3.77 | 5 | 0.1886 | 0.4655 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.3908G>C | G1303A 2D AIThe SynGAP1 missense variant G1303A 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 is benign and the SGM‑Consensus is 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 | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -2.637 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.29 | Neutral | 0.790 | Possibly Damaging | 0.433 | Benign | 2.83 | Benign | 0.11 | Tolerated | 0.3822 | 0.4092 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3911C>T | P1304L 2D AIThe SynGAP1 missense variant P1304L is reported in gnomAD (ID 6‑33451785‑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. The high‑accuracy consensus (SGM‑Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome, while AlphaMissense‑Optimized independently scores it 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 any ClinVar pathogenic classification, the variant is most likely benign and does not contradict existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | 6-33451785-C-T | 1 | 6.20e-7 | -4.080 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -1.33 | Neutral | 0.126 | Benign | 0.066 | Benign | 2.83 | Benign | 0.06 | Tolerated | 0.2200 | 0.5478 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||
| 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 | 0.20 | Neutral | 0.003 | Benign | 0.026 | Benign | 2.83 | Benign | 0.08 | Tolerated | 0.3683 | 0.4988 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3928A>G | T1310A 2D AIThe SynGAP1 missense variant T1310A 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. 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) is “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 | 0.812494 | Disordered | 0.959076 | Binding | 0.398 | 0.904 | 0.750 | -2.883 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.084 | Likely Benign | -0.21 | Neutral | 0.041 | Benign | 0.039 | Benign | 2.83 | Benign | 0.13 | Tolerated | 0.3238 | 0.3177 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3997G>C | E1333Q 2D  AIThe SynGAP1 missense variant E1333Q 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 impact are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (3 benign vs. 1 pathogenic votes) also indicates benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the preponderance of evidence points to a benign effect for E1333Q, 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 | 0.930790 | Disordered | 0.953319 | Binding | 0.347 | 0.746 | 0.750 | -4.034 | Likely Benign | 0.746 | Likely Pathogenic | Likely Benign | 0.217 | Likely Benign | -1.84 | Neutral | 0.980 | Probably Damaging | 0.968 | Probably Damaging | 2.83 | Benign | 0.00 | Affected | 0.1548 | 0.7617 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3998A>C | E1333A 2D AIThe SynGAP1 missense variant E1333A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returned an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2). Foldetta, which would assess protein‑folding stability, has no available output for this variant. Overall, more tools predict pathogenicity than benignity, and no ClinVar entry contradicts this assessment. Thus, the variant is most likely pathogenic based on the current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.953319 | Binding | 0.347 | 0.746 | 0.750 | -3.636 | Likely Benign | 0.834 | Likely Pathogenic | Ambiguous | 0.254 | Likely Benign | -3.76 | Deleterious | 0.980 | Probably Damaging | 0.956 | Probably Damaging | 2.83 | Benign | 0.00 | Affected | 0.4177 | 0.7382 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3998A>G | E1333G 2D  AIThe SynGAP1 missense variant E1333G is not 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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie and therefore unavailable; Foldetta, which would evaluate protein‑folding stability, has no result for this variant. Overall, more tools predict pathogenicity than benignity, and no ClinVar entry contradicts this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.953319 | Binding | 0.347 | 0.746 | 0.750 | -4.504 | Likely Benign | 0.801 | Likely Pathogenic | Ambiguous | 0.260 | Likely Benign | -4.31 | Deleterious | 0.994 | Probably Damaging | 0.968 | Probably Damaging | 2.83 | Benign | 0.00 | Affected | 0.3101 | 0.6217 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.1861C>G | R621G 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R621G is reported in gnomAD (ID 6‑33440913‑C‑G) but has no ClinVar entry. In silico predictors largely agree on a deleterious effect: pathogenic calls come from REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only benign prediction is from FATHMM; FoldX and Foldetta give uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.084420 | Uncertain | 0.945 | 0.216 | 0.000 | 6-33440913-C-G | 1 | 6.20e-7 | -16.611 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 1.18 | Ambiguous | 0.3 | 2.07 | Destabilizing | 1.63 | Ambiguous | 1.17 | Destabilizing | 0.558 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.84 | Benign | 0.01 | Affected | 3.37 | 35 | 0.3109 | 0.2651 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||
| c.1991T>G | L664W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: benign calls are made only by REVEL and FATHMM, whereas the remaining 13 predictors—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.089318 | Uncertain | 0.937 | 0.339 | 0.000 | -17.438 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 7.81 | Destabilizing | 0.5 | 3.17 | Destabilizing | 5.49 | Destabilizing | 1.57 | Destabilizing | 0.479 | Likely Benign | -5.99 | Deleterious | 1.000 | Probably Damaging | 0.984 | Probably Damaging | 2.84 | Benign | 0.00 | Affected | 0.0543 | 0.2272 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||
| c.2222C>T | P741L 2D AIThe SynGAP1 missense variant P741L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.493550 | Uncertain | 0.354 | 0.859 | 0.875 | -4.850 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -0.63 | Neutral | 0.001 | Benign | 0.003 | Benign | 2.84 | Benign | 0.03 | Affected | 0.1978 | 0.5780 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2225G>C | R742P 2D AIThe SynGAP1 missense variant R742P is catalogued in gnomAD (6-33441690‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign or likely benign outcome. Only SIFT classifies the change as pathogenic, representing the sole discordant prediction. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise reports likely benign. The Foldetta protein‑folding stability analysis is not available for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.509587 | Binding | 0.309 | 0.856 | 0.875 | 6-33441690-G-C | 1 | 6.20e-7 | -2.920 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -0.51 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.84 | Benign | 0.03 | Affected | 4.32 | 2 | 0.2598 | 0.3637 | -2 | 0 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||
| c.2275A>C | M759L 2D AIThe SynGAP1 missense variant M759L is listed in ClinVar with an uncertain significance (ClinVar ID 942432.0) and is present in gnomAD (gnomAD ID 6‑33441740‑A‑C). 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 classifications. 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, has no available result for this variant. Overall, the computational evidence strongly supports a benign impact, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | Uncertain | 1 | 6-33441740-A-C | 2 | 1.24e-6 | -2.431 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.53 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.84 | Benign | 1.00 | Tolerated | 3.99 | 5 | 0.1308 | 0.4005 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||
| c.2275A>T | M759L 2D AIThe SynGAP1 missense variant M759L 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 classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.879389 | Binding | 0.299 | 0.864 | 0.375 | -2.431 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.53 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.84 | Benign | 1.00 | Tolerated | 3.99 | 5 | 0.1308 | 0.4005 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2398G>C | G800R 2D AIThe SynGAP1 missense variant G800R is not reported 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 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. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.852992 | Disordered | 0.588350 | Binding | 0.303 | 0.884 | 0.625 | -3.613 | Likely Benign | 0.405 | Ambiguous | Likely Benign | 0.147 | Likely Benign | -0.27 | Neutral | 0.003 | Benign | 0.004 | Benign | 2.84 | Benign | 0.17 | Tolerated | 0.0868 | 0.3835 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2402G>A | G801D 2D  AIThe SynGAP1 missense variant G801D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic call comes from polyPhen‑2 HumDiv. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments reinforce this view: 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 evidence points to a benign effect, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.874069 | Disordered | 0.636323 | Binding | 0.320 | 0.892 | 0.625 | -5.312 | Likely Benign | 0.414 | Ambiguous | Likely Benign | 0.066 | Likely Benign | -0.69 | Neutral | 0.611 | Possibly Damaging | 0.346 | Benign | 2.84 | Benign | 0.25 | Tolerated | 0.1631 | 0.1835 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||
| c.2495A>T | Q832L 2D AIThe SynGAP1 missense variant Q832L 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 variant as benign. 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 further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta results are unavailable. Overall, the preponderance of evidence indicates that 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 | 0.720929 | Disordered | 0.619913 | Binding | 0.290 | 0.877 | 0.375 | -2.299 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.090 | Likely Benign | -0.58 | Neutral | 0.811 | Possibly Damaging | 0.424 | Benign | 2.84 | Benign | 1.00 | Tolerated | 0.0676 | 0.4852 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2654C>G | P885R 2D AIThe SynGAP1 missense variant P885R is reported in gnomAD (ID 6‑33443206‑C‑G) 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 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 impact, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.636133 | Binding | 0.344 | 0.917 | 0.250 | 6-33443206-C-G | 1 | 6.20e-7 | -4.166 | Likely Benign | 0.308 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -1.99 | Neutral | 0.586 | Possibly Damaging | 0.377 | Benign | 2.84 | Benign | 0.00 | Affected | 4.32 | 4 | 0.1311 | 0.3505 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||
| c.2729G>A | G910D 2D AIThe SynGAP1 missense variant G910D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.707319 | Binding | 0.264 | 0.917 | 0.250 | -4.190 | Likely Benign | 0.856 | Likely Pathogenic | Ambiguous | 0.214 | Likely Benign | -1.87 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.84 | Benign | 0.05 | Affected | 0.1642 | 0.1477 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2827G>T | G943C 2D AIThe SynGAP1 missense variant G943C is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which itself is “Likely Benign”). In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b all predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence—including the consensus and high‑accuracy tools—points to a benign impact. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.973328 | Disordered | 0.860437 | Binding | 0.372 | 0.910 | 0.750 | -9.822 | Likely Pathogenic | 0.108 | Likely Benign | Likely Benign | 0.356 | Likely Benign | -0.94 | Neutral | 0.938 | Possibly Damaging | 0.649 | Possibly Damaging | 2.84 | Benign | 0.10 | Tolerated | 0.1425 | 0.4439 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3034C>A | P1012T 2D AIThe SynGAP1 missense variant P1012T 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, 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 | 0.834292 | Disordered | 0.894674 | Binding | 0.319 | 0.866 | 0.625 | -4.788 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -0.56 | Neutral | 0.369 | Benign | 0.171 | Benign | 2.84 | Benign | 0.14 | Tolerated | 0.1399 | 0.5730 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3091A>C | M1031L 2D AIThe SynGAP1 missense variant M1031L 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, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | -2.213 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -0.82 | Neutral | 0.044 | Benign | 0.018 | Benign | 2.84 | Benign | 0.33 | Tolerated | 0.1220 | 0.4050 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3091A>T | M1031L 2D AIThe SynGAP1 missense variant M1031L 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, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.995959 | Binding | 0.340 | 0.736 | 0.500 | -2.213 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -0.82 | Neutral | 0.044 | Benign | 0.018 | Benign | 2.84 | Benign | 0.33 | Tolerated | 0.1220 | 0.4050 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| 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 | -2.39 | Neutral | 0.463 | Possibly Damaging | 0.087 | Benign | 2.84 | Benign | 0.01 | Affected | 0.1369 | 0.5415 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3598G>C | E1200Q 2D AIThe SynGAP1 missense variant E1200Q 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, so these do not influence the overall interpretation. High‑accuracy assessments—AlphaMissense‑Optimized (benign) and SGM‑Consensus (likely benign)—support a benign classification. 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 | Coiled-coil | 0.545602 | Disordered | 0.458056 | Uncertain | 0.889 | 0.596 | 0.250 | -4.411 | Likely Benign | 0.464 | Ambiguous | Likely Benign | 0.183 | Likely Benign | 0.14 | Neutral | 0.994 | Probably Damaging | 0.946 | Probably Damaging | 2.84 | Benign | 0.30 | Tolerated | 0.0767 | 0.4012 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||
| c.3899C>T | P1300L 2D AIThe SynGAP1 missense variant P1300L is reported in gnomAD (variant ID 6‑33451773‑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 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, also indicates a likely benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of tools, including the high‑accuracy methods, supports a benign interpretation. This prediction 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 | 0.788093 | Disordered | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | 6-33451773-C-T | 1 | 6.20e-7 | -3.562 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -1.35 | Neutral | 0.649 | Possibly Damaging | 0.209 | Benign | 2.84 | Benign | 0.19 | Tolerated | 3.77 | 5 | 0.2348 | 0.5680 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.3907G>A | G1303S 2D AIThe SynGAP1 missense variant G1303S is listed in ClinVar (ID 1736068.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only polyPhen‑2 HumDiv predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this is 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 | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | Uncertain | 1 | -2.271 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.155 | Likely Benign | -0.19 | Neutral | 0.649 | Possibly Damaging | 0.433 | Benign | 2.84 | Benign | 0.18 | Tolerated | 0.2605 | 0.4197 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||
| c.3911C>A | P1304Q 2D AIThe SynGAP1 missense variant P1304Q is not reported in ClinVar and has no entry in gnomAD. 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, is classified as Likely Benign. High‑accuracy predictions are consistent: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | -4.890 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -0.84 | Neutral | 0.586 | Possibly Damaging | 0.287 | Benign | 2.84 | Benign | 0.04 | Affected | 0.1512 | 0.4149 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3997G>A | E1333K 2D AISynGAP1 missense variant E1333K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic impact are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, 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 Uncertain, and Foldetta results are unavailable. Overall, the consensus of multiple benign‑predicting tools and the SGM‑Consensus suggests a benign outcome, whereas a subset of tools indicates pathogenicity. Thus, the variant is most likely benign based on the current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.953319 | Binding | 0.347 | 0.746 | 0.750 | -5.038 | Likely Benign | 0.942 | Likely Pathogenic | Ambiguous | 0.244 | Likely Benign | -2.49 | Neutral | 0.980 | Probably Damaging | 0.956 | Probably Damaging | 2.84 | Benign | 0.00 | Affected | 0.2728 | 0.7491 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.1892A>T | Q631L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q631L is not reported in ClinVar (ClinVar status: None) and has no entry in gnomAD (gnomAD status: None). Prediction tools that agree on a benign effect include FATHMM and Foldetta, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (likely pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as benign; these results are reported but not used as definitive evidence when inconclusive. Overall, the preponderance of evidence from consensus and individual predictors indicates a pathogenic effect for Q631L. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.038963 | Uncertain | 0.948 | 0.230 | 0.000 | -14.727 | Likely Pathogenic | 0.901 | Likely Pathogenic | Ambiguous | -1.23 | Ambiguous | 0.0 | 0.95 | Ambiguous | -0.14 | Likely Benign | 0.51 | Ambiguous | 0.619 | Likely Pathogenic | -6.97 | Deleterious | 0.982 | Probably Damaging | 0.954 | Probably Damaging | 2.85 | Benign | 0.05 | Affected | 0.0627 | 0.3150 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||
| c.1991T>C | L664S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664S is listed in ClinVar as Benign (ClinVar ID 2429773.0) and is present in gnomAD (ID 6‑33441250‑T‑C). Prediction tools that report a benign effect include only FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact, and the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Based on the overwhelming majority of pathogenic predictions—including the high‑accuracy tools—the variant is most likely pathogenic, which contradicts its ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.089318 | Uncertain | 0.937 | 0.339 | 0.000 | Likely Benign | 1 | 6-33441250-T-C | 1 | 6.20e-7 | -16.498 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.75 | Destabilizing | 0.2 | 3.63 | Destabilizing | 3.69 | Destabilizing | 2.77 | Destabilizing | 0.543 | Likely Pathogenic | -5.99 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.85 | Benign | 0.00 | Affected | 3.38 | 28 | 0.2091 | 0.0896 | -3 | -2 | -4.6 | -26.08 | 215.5 | 50.1 | 0.0 | 0.0 | -0.2 | 0.2 | X | Potentially Benign | The iso-butyl side chain of L664, located on an α-helix (res. Ser641-Glu666), hydrophobically interacts with residues in the inter-helix space between three helices (res. Glu617-Asn635, res. Glu582-Met603, and res. Ser641-Glu666), such as Ile589, Phe663, and Met660. In the variant simulations, the hydroxyl group of Ser664 forms hydrogen bonds with the backbone carbonyl oxygen of another helix residue, such as Met660 or Gln661. This interaction is known to destabilize hydrogen bonding in the α-helix, but this effect was not observed in the simulations. Additionally, Ser664 occasionally forms hydrogen bonds with the carboxylate group of Asp586 on another α-helix (res. Glu582-Met603), which could minimally influence the tertiary structure assembly. Despite these interactions, no major negative effects on the protein structure were observed during the simulations. | |||||||||||||
| c.2156A>G | N719S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719S is reported in gnomAD (variant ID 6‑33441621‑A‑G) but has no ClinVar entry. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, 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 status: AlphaMissense‑Optimized predicts Benign; the SGM‑Consensus itself is Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts Benign. Overall, the preponderance of evidence indicates that 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 | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | 6-33441621-A-G | 2 | 1.24e-6 | -5.190 | Likely Benign | 0.072 | Likely Benign | Likely Benign | -0.06 | Likely Benign | 0.0 | -0.29 | Likely Benign | -0.18 | Likely Benign | 0.46 | Likely Benign | 0.087 | Likely Benign | -1.83 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.85 | Benign | 0.40 | Tolerated | 3.50 | 9 | 0.2611 | 0.4653 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||
| c.2222C>G | P741R 2D AIThe SynGAP1 missense variant P741R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.493550 | Uncertain | 0.354 | 0.859 | 0.875 | -4.434 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.070 | Likely Benign | -1.19 | Neutral | 0.642 | Possibly Damaging | 0.393 | Benign | 2.85 | Benign | 0.02 | Affected | 0.1303 | 0.2712 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2237T>A | V746E 2D  AIThe SynGAP1 missense variant V746E 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 predicts benign. 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 | 0.808535 | Disordered | 0.576597 | Binding | 0.336 | 0.867 | 0.875 | -4.136 | Likely Benign | 0.315 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.94 | Neutral | 0.642 | Possibly Damaging | 0.316 | Benign | 2.85 | Benign | 0.05 | Affected | 0.0928 | 0.1813 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||||||||||||
| c.2290A>G | N764D 2D AIThe SynGAP1 missense variant N764D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, SGM‑Consensus also predicts benign, and Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | -6.012 | Likely Benign | 0.572 | Likely Pathogenic | Likely Benign | 0.057 | Likely Benign | -1.00 | Neutral | 0.992 | Probably Damaging | 0.893 | Possibly Damaging | 2.85 | Benign | 0.07 | Tolerated | 0.1769 | 0.2921 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.2347A>G | M783V 2D AIThe SynGAP1 missense variant M783V is catalogued in gnomAD (ID 6‑33442899‑A‑G) 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 reports a pathogenic outcome. 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. Consequently, the variant is most likely benign, and this prediction 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 | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | 6-33442899-A-G | 1 | 6.21e-7 | -3.453 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -0.96 | Neutral | 0.072 | Benign | 0.026 | Benign | 2.85 | Benign | 0.12 | Tolerated | 3.64 | 6 | 0.3444 | 0.3710 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||||||
| c.2521G>C | V841L 2D AIThe SynGAP1 missense variant V841L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Two tools—ESM1b and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.622677 | Disordered | 0.616495 | Binding | 0.261 | 0.873 | 0.125 | -7.924 | In-Between | 0.514 | Ambiguous | Likely Benign | 0.157 | Likely Benign | -0.01 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.85 | Benign | 0.56 | Tolerated | 0.0850 | 0.4233 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2521G>T | V841L 2D AIThe SynGAP1 missense variant V841L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Two tools—ESM1b and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta results are unavailable. Overall, the balance of evidence favors a benign classification, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.622677 | Disordered | 0.616495 | Binding | 0.261 | 0.873 | 0.125 | -7.924 | In-Between | 0.514 | Ambiguous | Likely Benign | 0.157 | Likely Benign | -0.01 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.85 | Benign | 0.56 | Tolerated | 0.0850 | 0.4233 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2659C>T | P887S 2D AIThe SynGAP1 missense variant P887S 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 view: 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 predictions strongly suggest that P887S 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 | 0.716283 | Disordered | 0.602269 | Binding | 0.348 | 0.925 | 0.500 | -3.462 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -1.26 | Neutral | 0.032 | Benign | 0.017 | Benign | 2.85 | Benign | 0.25 | Tolerated | 0.2770 | 0.3946 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2819G>C | G940A 2D AIThe SynGAP1 missense variant G940A 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 any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.920635 | Binding | 0.383 | 0.902 | 0.625 | -5.356 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.163 | Likely Benign | 0.64 | Neutral | 0.004 | Benign | 0.012 | Benign | 2.85 | Benign | 0.89 | Tolerated | 0.3627 | 0.4831 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2828G>A | G943D 2D AIThe SynGAP1 missense variant G943D is not reported in ClinVar and is absent from gnomAD. In silico predictors 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) reports “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Taken together, the overwhelming majority of predictions indicate a benign effect, and this conclusion does not contradict any ClinVar status (none is assigned). Thus, the variant is most likely benign. 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 | -7.951 | In-Between | 0.304 | Likely Benign | Likely Benign | 0.296 | Likely Benign | -0.28 | Neutral | 0.224 | Benign | 0.113 | Benign | 2.85 | Benign | 0.11 | Tolerated | 0.1904 | 0.2826 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2828G>T | G943V 2D AIThe SynGAP1 missense variant G943V 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. The only tool with an uncertain outcome is ESM1b, which does not alter the overall consensus. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign classification. High‑accuracy predictors corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are not available. Taken together, the evidence overwhelmingly supports a benign interpretation, and there is no conflict with 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 | -7.658 | In-Between | 0.092 | Likely Benign | Likely Benign | 0.265 | Likely Benign | -0.43 | Neutral | 0.224 | Benign | 0.062 | Benign | 2.85 | Benign | 0.16 | Tolerated | 0.1399 | 0.3507 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3089A>G | H1030R 2D AIThe SynGAP1 missense variant H1030R is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. 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) is “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 | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -2.312 | Likely Benign | 0.340 | Likely Benign | Likely Benign | 0.031 | Likely Benign | -1.08 | Neutral | 0.224 | Benign | 0.066 | Benign | 2.85 | Benign | 0.06 | Tolerated | 0.1872 | 0.2955 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.3284C>A | P1095Q 2D AIThe SynGAP1 missense variant P1095Q 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 flags it as pathogenic, but this is the sole 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 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 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 | 0.922952 | Disordered | 0.979251 | Binding | 0.387 | 0.870 | 1.000 | -4.171 | Likely Benign | 0.295 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -1.64 | Neutral | 0.922 | Possibly Damaging | 0.441 | Benign | 2.85 | Benign | 0.45 | Tolerated | 0.1573 | 0.5519 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3644A>G | K1215R 2D  AIThe SynGAP1 missense variant K1215R 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, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates 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 reinforce the benign prediction: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign, with no Foldetta data to contradict. Overall, the majority of evidence points to a benign effect, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.497853 | Structured | 0.503613 | Binding | 0.888 | 0.568 | 0.375 | -5.652 | Likely Benign | 0.360 | Ambiguous | Likely Benign | 0.106 | Likely Benign | -0.57 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.85 | Benign | 0.28 | Tolerated | 0.4051 | 0.0582 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||||||
| 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 | -3.78 | Deleterious | 0.036 | Benign | 0.014 | Benign | 2.85 | Benign | 0.01 | Affected | 0.1502 | 0.4995 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3758C>T | A1253V 2D AIThe SynGAP1 missense variant A1253V 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. High‑accuracy assessments confirm this: AlphaMissense‑Optimized classifies the variant as 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, was not available for this variant. ClinVar contains no entry for A1253V, and the variant is absent from gnomAD. Based on the unanimous benign predictions and lack of conflicting 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 | Coiled-coil | 0.661982 | Disordered | 0.391377 | Uncertain | 0.881 | 0.550 | 0.750 | -4.706 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.057 | Likely Benign | 0.20 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.85 | Benign | 1.00 | Tolerated | 0.0784 | 0.4473 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||||
| c.1693C>A | L565M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L565M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools, Rosetta and premPS, give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it is a 2‑vs‑2 split. No prediction or folding stability result is missing; the only unavailable result is the SGM Consensus. Overall, the balance of evidence (five benign vs four pathogenic predictions, with two high‑accuracy tools supporting benign) indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.034884 | Structured | 0.045819 | Uncertain | 0.922 | 0.205 | 0.000 | -10.346 | Likely Pathogenic | 0.666 | Likely Pathogenic | Likely Benign | 0.24 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.38 | Likely Benign | 0.69 | Ambiguous | 0.255 | Likely Benign | -1.99 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.86 | Benign | 0.08 | Tolerated | 0.0934 | 0.2613 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.1897C>G | L633V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L633V is not reported in ClinVar and is present in the gnomAD database (ID 6‑33440949‑C‑G). Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, SGM‑Consensus, and Foldetta; the Rosetta score is uncertain and therefore not considered. High‑accuracy methods give a pathogenic consensus: AlphaMissense‑Optimized predicts benign, but the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta both predict pathogenic. Overall, the majority of evidence supports a pathogenic impact for L633V, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.045407 | Uncertain | 0.952 | 0.252 | 0.000 | 6-33440949-C-G | 1 | 6.20e-7 | -9.992 | Likely Pathogenic | 0.760 | Likely Pathogenic | Likely Benign | 2.32 | Destabilizing | 0.2 | 1.71 | Ambiguous | 2.02 | Destabilizing | 1.32 | Destabilizing | 0.327 | Likely Benign | -2.99 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.86 | Benign | 0.03 | Affected | 3.37 | 34 | 0.1517 | 0.2766 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||
| c.1925A>C | K642T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K642T is listed in ClinVar (ID 437411.0) as Pathogenic and is not reported in gnomAD. Functional prediction tools split in a 7‑to‑5 ratio: pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default, while benign calls come from REVEL, Rosetta, Foldetta, premPS, and FATHMM; FoldX and AlphaMissense‑Optimized are uncertain. 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 stability outputs) as Benign. Overall, the majority of evidence points to a pathogenic effect, aligning with the ClinVar classification and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | Likely Pathogenic | 1 | -12.823 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.53 | Ambiguous | 0.1 | 0.30 | Likely Benign | 0.42 | Likely Benign | 0.28 | Likely Benign | 0.484 | Likely Benign | -5.88 | Deleterious | 0.872 | Possibly Damaging | 0.839 | Possibly Damaging | 2.86 | Benign | 0.00 | Affected | 3.37 | 31 | 0.1899 | 0.3270 | 0 | -1 | 3.2 | -27.07 | 213.5 | -8.7 | -0.3 | 0.4 | 0.3 | 0.2 | X | Uncertain | The amino side chain of Lys642, located on the surface of an α helix (res. Ser641-Glu666), is not involved in any interactions in the WT simulations. In the variant simulations, the shorter side chain of Thr642 forms hydrogen bonds with Glu643 and Thr640 on the same α helix.Regardless, Lys642 is positioned directly at the GAP-Ras interface, and in the SynGAP-Ras WT simulations, its amino side chain forms salt bridges with the carboxylate groups of Ras residues Asp33 and Asp38. The shorter Thr642 is more likely to prefer hydrogen bonding with Glu643 and Thr640 on the same α helix, even in the Ras complex. Thus, the effect of the residue swap on the complex formation with the GTPase cannot be explored using solvent-only simulations. | ||||||||||||||||
| 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 | -0.54 | Neutral | 0.010 | Benign | 0.022 | Benign | 2.86 | Benign | 0.05 | Affected | 0.1209 | 0.5080 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.2605C>G | L869V 2D AIThe SynGAP1 missense variant L869V 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 is benign and the SGM‑Consensus is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods 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 | 0.501700 | Disordered | 0.688653 | Binding | 0.272 | 0.839 | 0.250 | -3.241 | Likely Benign | 0.161 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -0.33 | Neutral | 0.481 | Possibly Damaging | 0.300 | Benign | 2.86 | Benign | 0.11 | Tolerated | 0.1501 | 0.3616 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2680G>A | G894R 2D AISynGAP1 missense variant G894R has no ClinVar record and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Considering the consensus from high‑accuracy tools and the balance of individual predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for G894R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.425700 | Uncertain | 0.310 | 0.925 | 0.750 | -5.222 | Likely Benign | 0.922 | Likely Pathogenic | Ambiguous | 0.216 | Likely Benign | -1.68 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.86 | Benign | 0.01 | Affected | 0.0982 | 0.4332 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2680G>C | G894R 2D AISynGAP1 missense variant G894R has no ClinVar record and is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Considering the consensus from high‑accuracy tools and the balance of individual predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for G894R. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.425700 | Uncertain | 0.310 | 0.925 | 0.750 | -5.222 | Likely Benign | 0.922 | Likely Pathogenic | Ambiguous | 0.216 | Likely Benign | -1.68 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.86 | Benign | 0.01 | Affected | 0.0982 | 0.4332 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2710A>C | M904L 2D AIThe SynGAP1 missense variant M904L 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 | 0.671169 | Disordered | 0.589073 | Binding | 0.350 | 0.920 | 0.250 | -1.839 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.050 | Likely Benign | -0.24 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.86 | Benign | 0.17 | Tolerated | 0.1915 | 0.4584 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2710A>T | M904L 2D AIThe SynGAP1 missense variant M904L 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 | 0.671169 | Disordered | 0.589073 | Binding | 0.350 | 0.920 | 0.250 | -1.839 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.050 | Likely Benign | -0.24 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.86 | Benign | 0.17 | Tolerated | 0.1915 | 0.4584 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2726T>C | M909T 2D AIThe SynGAP1 missense variant M909T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the majority of evidence points to a benign impact for M909T, 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 | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | -3.053 | Likely Benign | 0.647 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | -0.74 | Neutral | 0.901 | Possibly Damaging | 0.430 | Benign | 2.86 | Benign | 1.00 | Tolerated | 0.2157 | 0.2085 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
| c.2728G>C | G910R 2D AIThe SynGAP1 missense variant G910R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because no ClinVar assertion exists. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.707319 | Binding | 0.264 | 0.917 | 0.250 | -4.566 | Likely Benign | 0.945 | Likely Pathogenic | Ambiguous | 0.235 | Likely Benign | -1.78 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.86 | Benign | 0.02 | Affected | 0.0875 | 0.4198 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.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 | 1.00 | Neutral | 0.411 | Benign | 0.062 | Benign | 2.86 | Benign | 0.94 | Tolerated | 4.32 | 4 | 0.0976 | 0.4933 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||
| c.3257C>G | P1086R 2D AIThe SynGAP1 missense variant P1086R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (two pathogenic vs. two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, more tools (five) predict pathogenicity than benign (three), and the high‑accuracy consensus is inconclusive. Therefore, 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 reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.849326 | Disordered | 0.977190 | Binding | 0.393 | 0.885 | 1.000 | -5.190 | Likely Benign | 0.848 | Likely Pathogenic | Ambiguous | 0.205 | Likely Benign | -3.42 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.86 | Benign | 0.00 | Affected | 0.1319 | 0.3551 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3541A>G | K1181E 2D  AIThe SynGAP1 missense variant K1181E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense (Default and Optimized) predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.622677 | Disordered | 0.539278 | Binding | 0.625 | 0.660 | 0.375 | -3.244 | Likely Benign | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.196 | Likely Benign | -1.19 | Neutral | 0.995 | Probably Damaging | 0.949 | Probably Damaging | 2.86 | Benign | 0.55 | Tolerated | 0.2862 | 0.0877 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3548A>C | Y1183S 2D AIThe SynGAP1 missense variant Y1183S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, PROVEAN, SIFT, ESM1b, FATHMM) and pathogenic predictions (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized). The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. 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 impact for Y1183S, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.527818 | Binding | 0.523 | 0.652 | 0.500 | -2.514 | Likely Benign | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.164 | Likely Benign | -1.57 | Neutral | 0.951 | Possibly Damaging | 0.619 | Possibly Damaging | 2.86 | Benign | 0.51 | Tolerated | 0.5346 | 0.1096 | Weaken | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||
| c.373C>T | P125S 2D AIThe SynGAP1 missense variant P125S is listed in ClinVar (ID 837156.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict the ClinVar designation, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.704227 | Binding | 0.373 | 0.878 | 0.625 | Uncertain | 1 | -3.769 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.121 | Likely Benign | -3.57 | Deleterious | 0.580 | Possibly Damaging | 0.140 | Benign | 2.86 | Benign | 0.02 | Affected | 3.61 | 5 | 0.3408 | 0.4594 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||
| c.3847C>T | P1283S 2D AIThe SynGAP1 missense variant P1283S is catalogued in gnomAD (ID 6‑33447895‑C‑T) 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 returns a benign prediction, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Therefore, the variant is most likely benign, and this assessment does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.819686 | Binding | 0.484 | 0.732 | 0.875 | 6-33447895-C-T | -4.289 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.040 | Likely Benign | 0.06 | Neutral | 0.292 | Benign | 0.110 | Benign | 2.86 | Benign | 0.30 | Tolerated | 3.77 | 5 | 0.2837 | 0.3719 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||
| c.3892C>A | Q1298K 2D AIThe SynGAP1 missense variant Q1298K is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is not contradicted by any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -3.415 | Likely Benign | 0.228 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -0.27 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.86 | Benign | 0.24 | Tolerated | 0.1360 | 0.2903 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3910C>A | P1304T 2D AIThe SynGAP1 missense variant P1304T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective evidence strongly supports a benign classification, and this conclusion does not contradict 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 | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | -4.454 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -0.42 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.86 | Benign | 0.14 | Tolerated | 0.1571 | 0.4914 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3913A>C | T1305P 2D  AIThe SynGAP1 missense variant T1305P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.894658 | Binding | 0.390 | 0.873 | 0.875 | -1.882 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.204 | Likely Benign | -1.41 | Neutral | 0.027 | Benign | 0.114 | Benign | 2.86 | Benign | 0.03 | Affected | 0.2157 | 0.5386 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.1693C>G | L565V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L565V has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two consensus groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and Foldetta. Two tools (AlphaMissense‑Optimized and Rosetta) give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic,” and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a pathogenic impact on protein stability. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.034884 | Structured | 0.045819 | Uncertain | 0.922 | 0.205 | 0.000 | -11.118 | Likely Pathogenic | 0.833 | Likely Pathogenic | Ambiguous | 2.69 | Destabilizing | 0.0 | 1.37 | Ambiguous | 2.03 | Destabilizing | 1.40 | Destabilizing | 0.303 | Likely Benign | -2.99 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.87 | Benign | 0.03 | Affected | 0.1558 | 0.2488 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1924A>C | K642Q 2D  3DClick to see structure in 3D Viewer AISynGAP1 K642Q is not reported in ClinVar and has no allele in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and polyPhen‑2 HumVar; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as Benign. No other high‑confidence predictions are available. Overall, the balance of evidence leans toward a benign effect, with the single high‑accuracy pathogenic signal from SGM‑Consensus not contradicting the lack of ClinVar annotation. Thus, the variant is most likely benign, and this assessment does not conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | -12.186 | Likely Pathogenic | 0.862 | Likely Pathogenic | Ambiguous | 0.08 | Likely Benign | 0.0 | 0.17 | Likely Benign | 0.13 | Likely Benign | 0.42 | Likely Benign | 0.380 | Likely Benign | -3.88 | Deleterious | 0.576 | Possibly Damaging | 0.383 | Benign | 2.87 | Benign | 0.02 | Affected | 0.4477 | 0.1253 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.2201C>A | P734Q 2D AIThe SynGAP1 missense variant P734Q 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. 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 | 0.879233 | Disordered | 0.411273 | Uncertain | 0.368 | 0.721 | 0.875 | -4.392 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.080 | Likely Benign | -1.92 | Neutral | 0.959 | Probably Damaging | 0.569 | Possibly Damaging | 2.87 | Benign | 0.06 | Tolerated | 0.1608 | 0.3364 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.2349G>A | M783I 2D AIThe SynGAP1 missense variant M783I is listed in ClinVar as a benign alteration (ClinVar ID 3618151.0) and is present in the gnomAD database (gnomAD ID 6‑33442901‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a likely benign effect. The Foldetta protein‑folding stability analysis is not available for this variant. Overall, the computational evidence strongly suggests that the variant is most likely benign, in agreement with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | Benign | 1 | 6-33442901-G-A | 6 | 3.72e-6 | -3.560 | Likely Benign | 0.418 | Ambiguous | Likely Benign | 0.042 | Likely Benign | -0.54 | Neutral | 0.004 | Benign | 0.006 | Benign | 2.87 | Benign | 0.22 | Tolerated | 3.64 | 6 | 0.1540 | 0.3710 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||
| c.2349G>C | M783I 2D AIThe SynGAP1 missense variant M783I is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Consensus from multiple in‑silico predictors classifies the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all return benign scores, and AlphaMissense‑Optimized also predicts a benign effect. No tool in the set indicates pathogenicity. The high‑accuracy assessments corroborate this view: AlphaMissense‑Optimized reports a benign outcome, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Benign classification, and Foldetta data are unavailable. Consequently, the aggregate evidence strongly supports a benign interpretation for M783I, 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 | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | -3.560 | Likely Benign | 0.418 | Ambiguous | Likely Benign | 0.042 | Likely Benign | -0.54 | Neutral | 0.004 | Benign | 0.006 | Benign | 2.87 | Benign | 0.22 | Tolerated | 3.64 | 6 | 0.1540 | 0.3710 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2349G>T | M783I 2D AIThe SynGAP1 missense variant M783I is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools uniformly indicate a benign effect. Benign calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts pathogenicity; AlphaMissense‑Default remains uncertain. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign outcome. Foldetta stability analysis is unavailable, so it does not influence the assessment. Overall, the computational evidence strongly supports a benign classification for M783I, 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 | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | -3.560 | Likely Benign | 0.418 | Ambiguous | Likely Benign | 0.042 | Likely Benign | -0.54 | Neutral | 0.004 | Benign | 0.006 | Benign | 2.87 | Benign | 0.22 | Tolerated | 3.64 | 6 | 0.1540 | 0.3710 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2530C>G | L844V 2D AIThe SynGAP1 missense variant L844V 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.595080 | Disordered | 0.611301 | Binding | 0.304 | 0.835 | 0.375 | 0.094 | Likely Benign | 0.240 | Likely Benign | Likely Benign | 0.043 | Likely Benign | 0.20 | Neutral | 0.409 | Benign | 0.253 | Benign | 2.87 | Benign | 0.62 | Tolerated | 0.1692 | 0.3744 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2597T>C | V866A 2D AIThe SynGAP1 missense variant V866A is reported in gnomAD (ID 6‑33443149‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict 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 (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 preponderance of evidence points to a benign impact, 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 | 0.599170 | Disordered | 0.638070 | Binding | 0.266 | 0.788 | 0.250 | 6-33443149-T-C | 1 | 6.20e-7 | -1.805 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -1.27 | Neutral | 0.889 | Possibly Damaging | 0.682 | Possibly Damaging | 2.87 | Benign | 0.37 | Tolerated | 3.82 | 4 | 0.3441 | 0.2512 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||||||
| c.2653C>T | P885S 2D AIThe SynGAP1 missense variant P885S is not reported 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 | 0.690604 | Disordered | 0.636133 | Binding | 0.344 | 0.917 | 0.250 | -4.089 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.037 | Likely Benign | -1.10 | Neutral | 0.369 | Benign | 0.222 | Benign | 2.87 | Benign | 0.00 | Affected | 0.3363 | 0.5881 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2742C>A | D914E 2D  AIThe SynGAP1 missense variant D914E is reported in gnomAD (ID 6‑33443294‑C‑A) 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 high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification, and AlphaMissense‑Optimized independently predicts benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance 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 existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | 6-33443294-C-A | 5 | 3.10e-6 | -3.231 | Likely Benign | 0.170 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -0.29 | Neutral | 0.893 | Possibly Damaging | 0.418 | Benign | 2.87 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1909 | 0.7088 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2742C>G | D914E 2D AIThe SynGAP1 missense variant D914E 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 supports a benign classification for D914E, 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 | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | -3.231 | Likely Benign | 0.170 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -0.29 | Neutral | 0.893 | Possibly Damaging | 0.418 | Benign | 2.87 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1909 | 0.7088 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.2744G>C | G915A 2D AIThe SynGAP1 missense variant G915A 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 returns Benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect for G915A, 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 | 0.657645 | Disordered | 0.808641 | Binding | 0.302 | 0.880 | 0.375 | -4.007 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -1.22 | Neutral | 0.900 | Possibly Damaging | 0.622 | Possibly Damaging | 2.87 | Benign | 0.05 | Affected | 0.3454 | 0.4930 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| 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 | 0.10 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.87 | Benign | 0.89 | Tolerated | 4.32 | 4 | 0.3415 | 0.4957 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2860C>T | P954S 2D AIThe SynGAP1 missense variant P954S is listed in ClinVar as Benign (ClinVar ID 833606.0) and is present in gnomAD (ID 6‑33443412‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, which is consistent with the ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | Likely Benign | 1 | 6-33443412-C-T | 1 | 6.20e-7 | -3.525 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.143 | Likely Benign | -0.25 | Neutral | 0.954 | Possibly Damaging | 0.812 | Possibly Damaging | 2.87 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.3088 | 0.5619 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||
| 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 | -2.05 | Neutral | 0.664 | Possibly Damaging | 0.283 | Benign | 2.87 | Benign | 0.07 | Tolerated | 0.3097 | 0.5322 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3777C>G | I1259M 2D  AIThe SynGAP1 missense variant I1259M is catalogued in gnomAD (ID 6‑33446769‑C‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score, whereas PolyPhen‑2 (HumDiv and HumVar) classify the change as pathogenic. The high‑accuracy AlphaMissense‑Optimized tool reports a benign effect, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment 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 | Coiled-coil | 0.494003 | Structured | 0.576405 | Binding | 0.885 | 0.574 | 0.250 | 6-33446769-C-G | 2 | 1.24e-6 | -5.177 | Likely Benign | 0.447 | Ambiguous | Likely Benign | 0.227 | Likely Benign | 1.35 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.87 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.0576 | 0.2358 | 1 | 2 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||
| c.3898C>A | P1300T 2D AIThe SynGAP1 missense variant P1300T 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 supports a benign classification, 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 | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | -4.522 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.070 | Likely Benign | -0.64 | Neutral | 0.649 | Possibly Damaging | 0.266 | Benign | 2.87 | Benign | 0.21 | Tolerated | 0.1546 | 0.4729 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3901C>A | P1301T 2D AIThe SynGAP1 missense variant P1301T is reported in gnomAD (ID 6‑33451775‑C‑A) 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, so the pathogenic group is empty. High‑accuracy assessments reinforce 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 conclusion does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | 6-33451775-C-A | 1 | 6.20e-7 | -4.945 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.090 | Likely Benign | 0.34 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.87 | Benign | 0.47 | Tolerated | 3.77 | 5 | 0.1255 | 0.3312 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||
| c.4015A>C | N1339H 2D  AIThe SynGAP1 missense variant N1339H 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, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, SGM‑Consensus likewise indicates likely benign, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the preponderance of evidence from both general and high‑accuracy predictors, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.977585 | Binding | 0.396 | 0.687 | 1.000 | -3.487 | Likely Benign | 0.338 | Likely Benign | Likely Benign | 0.234 | Likely Benign | -2.98 | Deleterious | 0.994 | Probably Damaging | 0.987 | Probably Damaging | 2.87 | Benign | 0.00 | Affected | 0.1585 | 0.7644 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.4015A>T | N1339Y 2D  AIThe SynGAP1 missense variant N1339Y is not 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 benign vs 2 pathogenic) and Foldetta data are unavailable. Overall, the majority of conventional predictors lean toward pathogenicity, but the single high‑accuracy benign prediction and the inconclusive consensus leave the variant’s impact uncertain. Thus, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.771762 | Disordered | 0.977585 | Binding | 0.396 | 0.687 | 1.000 | -3.808 | Likely Benign | 0.578 | Likely Pathogenic | Likely Benign | 0.319 | Likely Benign | -4.83 | Deleterious | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 2.87 | Benign | 0.00 | Affected | 0.0697 | 0.6573 | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||||||||||||||||
| c.4016A>T | N1339I 2D  AIThe SynGAP1 missense variant N1339I is not 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, 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 four benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic based on current computational evidence, 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. | 0.771762 | Disordered | 0.977585 | Binding | 0.396 | 0.687 | 1.000 | -3.104 | Likely Benign | 0.740 | Likely Pathogenic | Likely Benign | 0.306 | Likely Benign | -5.25 | Deleterious | 0.994 | Probably Damaging | 0.987 | Probably Damaging | 2.87 | Benign | 0.00 | Affected | 0.0747 | 0.6271 | -2 | -3 | 8.0 | -0.94 | ||||||||||||||||||||||||||||||||||||||||
| c.1542C>G | I514M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514M is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, while the SGM‑Consensus (majority of the four high‑accuracy inputs) remains Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is Uncertain. Overall, seven of the twelve evaluated tools predict pathogenicity versus four predicting benign, with no evidence from ClinVar 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 | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | -9.753 | Likely Pathogenic | 0.727 | Likely Pathogenic | Likely Benign | 0.48 | Likely Benign | 0.2 | 0.78 | Ambiguous | 0.63 | Ambiguous | 1.13 | Destabilizing | 0.335 | Likely Benign | -2.88 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.88 | Benign | 0.00 | Affected | 0.0647 | 0.1816 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.1903A>T | N635Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N635Y has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include Foldetta, premPS, FATHMM, AlphaMissense‑Optimized, and Rosetta. Those that predict a pathogenic impact are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX is uncertain and therefore treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicating likely pathogenic, and Foldetta predicting a benign outcome. Overall, the majority of tools lean toward a benign interpretation, 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 | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -14.931 | Likely Pathogenic | 0.662 | Likely Pathogenic | Likely Benign | 0.73 | Ambiguous | 0.3 | -0.11 | Likely Benign | 0.31 | Likely Benign | -0.16 | Likely Benign | 0.554 | Likely Pathogenic | -7.64 | Deleterious | 0.998 | Probably Damaging | 0.922 | Probably Damaging | 2.88 | Benign | 0.00 | Affected | 0.0750 | 0.3632 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.1904A>T | N635I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N635I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX is uncertain. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts a benign impact. Overall, the majority of tools lean toward a pathogenic interpretation, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -15.012 | Likely Pathogenic | 0.608 | Likely Pathogenic | Likely Benign | 0.94 | Ambiguous | 0.1 | -0.05 | Likely Benign | 0.45 | Likely Benign | -0.35 | Likely Benign | 0.363 | Likely Benign | -8.56 | Deleterious | 0.980 | Probably Damaging | 0.889 | Possibly Damaging | 2.88 | Benign | 0.00 | Affected | 0.0736 | 0.3776 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.1926G>C | K642N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K642N 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, Rosetta, Foldetta, premPS, FATHMM, and polyPhen‑2 HumVar. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. With two of the three high‑accuracy tools supporting pathogenicity and an overall balance of predictions, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | -11.423 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.25 | Likely Benign | 0.0 | 0.05 | Likely Benign | 0.15 | Likely Benign | 0.48 | Likely Benign | 0.273 | Likely Benign | -4.88 | Deleterious | 0.958 | Probably Damaging | 0.392 | Benign | 2.88 | Benign | 0.00 | Affected | 0.3553 | 0.1590 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1926G>T | K642N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K642N 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, Rosetta, Foldetta, premPS, and FATHMM, while those that predict a pathogenic impact are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar (benign). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, seven tools favor pathogenicity versus six favoring benign, and the high‑accuracy predictions are mixed. Thus, the variant is most likely pathogenic based on the preponderance of evidence, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | -11.423 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.25 | Likely Benign | 0.0 | 0.05 | Likely Benign | 0.15 | Likely Benign | 0.48 | Likely Benign | 0.274 | Likely Benign | -4.88 | Deleterious | 0.958 | Probably Damaging | 0.392 | Benign | 2.88 | Benign | 0.00 | Affected | 0.3553 | 0.1590 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.2696T>G | I899S 2D AIThe SynGAP1 missense variant I899S 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 call comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not conflict with the ClinVar record, which contains no assertion for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.443727 | Uncertain | 0.292 | 0.928 | 0.375 | -0.857 | Likely Benign | 0.340 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -0.38 | Neutral | 0.003 | Benign | 0.004 | Benign | 2.88 | Benign | 0.00 | Affected | 0.2838 | 0.0840 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2827G>A | G943S 2D AIThe SynGAP1 missense variant G943S 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. 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 | 0.973328 | Disordered | 0.860437 | Binding | 0.372 | 0.910 | 0.750 | -5.785 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.295 | Likely Benign | 0.34 | Neutral | 0.059 | Benign | 0.039 | Benign | 2.88 | Benign | 0.51 | Tolerated | 0.2482 | 0.5502 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2857C>A | P953T 2D AIThe SynGAP1 missense variant P953T is predicted to be benign by all evaluated in silico tools. Consensus predictions from SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classify the variant as Likely Benign. High‑accuracy predictors AlphaMissense‑Optimized also report a benign effect. Other pathogenicity predictors—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM)—uniformly predict benign. No tools predict pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its stability impact remains unknown. The variant is not listed in ClinVar and has no entry in gnomAD, so no population frequency or clinical classification is available. Based on the unanimous benign predictions, the variant is most likely benign, 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. | Likely Benign | 0.983019 | Disordered | 0.920633 | Binding | 0.403 | 0.926 | 0.750 | -6.646 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.80 | Neutral | 0.009 | Benign | 0.015 | Benign | 2.88 | Benign | 0.24 | Tolerated | 0.2261 | 0.6004 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3010C>A | H1004N 2D AIThe SynGAP1 missense variant H1004N is 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. 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 | -4.265 | Likely Benign | 0.601 | Likely Pathogenic | Likely Benign | 0.072 | Likely Benign | -1.18 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.88 | Benign | 0.35 | Tolerated | 0.2056 | 0.3580 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3090C>A | H1030Q 2D AIThe SynGAP1 missense variant H1030Q is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -2.548 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.01 | Neutral | 0.004 | Benign | 0.004 | Benign | 2.88 | Benign | 0.53 | Tolerated | 0.1538 | 0.4001 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3090C>G | H1030Q 2D AIThe SynGAP1 missense variant H1030Q is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.995856 | Binding | 0.375 | 0.735 | 0.500 | -2.548 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.01 | Neutral | 0.004 | Benign | 0.004 | Benign | 2.88 | Benign | 0.53 | Tolerated | 0.1538 | 0.4001 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3344T>G | I1115S 2D AIThe SynGAP1 missense variant I1115S is catalogued in gnomAD (ID 6‑33443896‑T‑G) 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 variant 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 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 | 0.889439 | Disordered | 0.892339 | Binding | 0.308 | 0.912 | 0.750 | 6-33443896-T-G | -0.579 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.128 | Likely Benign | 0.67 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.88 | Benign | 0.14 | Tolerated | 4.32 | 2 | 0.2986 | 0.1453 | -2 | -1 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||
| c.3547T>A | Y1183N 2D AIThe SynGAP1 missense variant Y1183N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus score (Likely Benign). In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default all predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta predictions are unavailable. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.527818 | Binding | 0.523 | 0.652 | 0.500 | -3.413 | Likely Benign | 0.890 | Likely Pathogenic | Ambiguous | 0.083 | Likely Benign | -1.44 | Neutral | 0.905 | Possibly Damaging | 0.543 | Possibly Damaging | 2.88 | Benign | 0.35 | Tolerated | 0.2368 | 0.0243 | -2 | -2 | -2.2 | -49.07 | ||||||||||||||||||||||||||||||||||||||
| c.373C>G | P125A 2D AIThe SynGAP1 missense variant P125A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the majority of predictions and the high‑accuracy consensus, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.704227 | Binding | 0.373 | 0.878 | 0.625 | -3.936 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -3.55 | Deleterious | 0.580 | Possibly Damaging | 0.140 | Benign | 2.88 | Benign | 0.02 | Affected | 0.3341 | 0.4245 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.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 | -1.78 | Neutral | 0.953 | Possibly Damaging | 0.935 | Probably Damaging | 2.88 | Benign | 0.00 | Affected | 0.1989 | 0.5029 | 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 | -1.78 | Neutral | 0.953 | Possibly Damaging | 0.935 | Probably Damaging | 2.88 | Benign | 0.00 | Affected | 0.1989 | 0.5029 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1540A>T | I514F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514F is listed in ClinVar with an uncertain significance 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 (uncertain), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—report it as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, classifies the variant as pathogenic. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, 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 Pathogenic | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | Uncertain | 1 | -13.383 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 2.35 | Destabilizing | 0.3 | 3.74 | Destabilizing | 3.05 | Destabilizing | 0.93 | Ambiguous | 0.601 | Likely Pathogenic | -3.98 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 2.89 | Benign | 0.00 | Affected | 3.37 | 35 | 0.0574 | 0.1629 | 0 | 1 | -1.7 | 34.02 | |||||||||||||||||||||||||
| c.1928A>T | E643V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E643V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from Rosetta, premPS, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Three tools (FoldX, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments show that the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic (3 pathogenic vs. 1 benign). AlphaMissense‑Optimized remains uncertain, and Foldetta also yields an uncertain stability change. Overall, the preponderance of evidence points to a pathogenic effect for E643V, and this conclusion does not contradict any existing ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -12.975 | Likely Pathogenic | 0.893 | Likely Pathogenic | Ambiguous | 1.13 | Ambiguous | 0.1 | -0.06 | Likely Benign | 0.54 | Ambiguous | -0.28 | Likely Benign | 0.554 | Likely Pathogenic | -6.85 | Deleterious | 0.727 | Possibly Damaging | 0.145 | Benign | 2.89 | Benign | 0.00 | Affected | 0.0948 | 0.6637 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.2343G>A | M781I 2D AIThe SynGAP1 missense variant M781I is listed in ClinVar (ID 2802065.0) as Benign and is not reported in gnomAD. All available in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions strongly support a benign effect, consistent with the ClinVar designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | Benign | 1 | -2.484 | Likely Benign | 0.323 | Likely Benign | Likely Benign | 0.101 | Likely Benign | 0.05 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.89 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1405 | 0.2793 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.2343G>C | M781I 2D AIThe SynGAP1 missense variant M781I is catalogued in gnomAD (ID 6‑33442895‑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 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, 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 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 | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | 6-33442895-G-C | 1 | 6.21e-7 | -2.484 | Likely Benign | 0.323 | Likely Benign | Likely Benign | 0.101 | Likely Benign | 0.05 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.89 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1405 | 0.2793 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||
| c.2343G>T | M781I 2D AIThe SynGAP1 missense variant M781I 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 from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the evidence strongly suggests that M781I 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 | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | -2.484 | Likely Benign | 0.323 | Likely Benign | Likely Benign | 0.101 | Likely Benign | 0.05 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.89 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1405 | 0.2793 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.2434C>T | P812S 2D AIThe SynGAP1 missense variant P812S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33442986‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default remains uncertain, and no Foldetta stability result is available. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta data are missing. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | Uncertain | 1 | 6-33442986-C-T | 1 | 6.20e-7 | -5.689 | Likely Benign | 0.456 | Ambiguous | Likely Benign | 0.162 | Likely Benign | -0.62 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.89 | Benign | 0.95 | Tolerated | 4.32 | 4 | 0.3417 | 0.5699 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||
| c.2507G>A | S836N 2D  AIThe SynGAP1 missense variant S836N 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 show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign and does not contradict any existing ClinVar status. 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 | -3.881 | Likely Benign | 0.269 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 0.75 | Neutral | 0.901 | Possibly Damaging | 0.636 | Possibly Damaging | 2.89 | Benign | 0.85 | Tolerated | 0.1053 | 0.3831 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.2952G>C | K984N 2D AIThe SynGAP1 missense variant K984N is catalogued in gnomAD (6‑33443504‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized rates the variant as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it “Likely Benign,” and Foldetta (which integrates FoldX‑MD and Rosetta outputs) has no available result for this residue. Overall, the balance of evidence leans toward a benign effect, with no pathogenic ClinVar classification to contradict this inference. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.951648 | Binding | 0.288 | 0.895 | 0.750 | 6-33443504-G-C | 1 | 6.20e-7 | -3.020 | Likely Benign | 0.955 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | 0.52 | Neutral | 0.951 | Possibly Damaging | 0.637 | Possibly Damaging | 2.89 | Benign | 0.00 | Affected | 4.32 | 1 | 0.4138 | 0.1677 | 0 | 1 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||
| c.2952G>T | K984N 2D AISynGAP1 missense variant K984N has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is Uncertain, SGM‑Consensus is Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, 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 | 0.703578 | Disordered | 0.951648 | Binding | 0.288 | 0.895 | 0.750 | -3.020 | Likely Benign | 0.955 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | 0.52 | Neutral | 0.951 | Possibly Damaging | 0.637 | Possibly Damaging | 2.89 | Benign | 0.00 | Affected | 4.32 | 1 | 0.4138 | 0.1677 | 0 | 1 | 0.4 | -14.07 | |||||||||||||||||||||||||||||||||||||
| c.2968T>A | S990T 2D  AIThe SynGAP1 missense variant S990T 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 | 0.816150 | Disordered | 0.902387 | Binding | 0.301 | 0.919 | 0.750 | -4.439 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -0.06 | Neutral | 0.001 | Benign | 0.007 | Benign | 2.89 | Benign | 1.00 | Tolerated | 0.1524 | 0.5598 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3032G>C | G1011A 2D AIThe SynGAP1 missense variant G1011A is catalogued in gnomAD (ID 6‑33443584‑G‑C) 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 reports a pathogenic outcome. High‑accuracy assessments concur: 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. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.898380 | Binding | 0.332 | 0.869 | 0.625 | 6-33443584-G-C | -4.349 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.04 | Neutral | 0.139 | Benign | 0.089 | Benign | 2.89 | Benign | 0.64 | Tolerated | 3.77 | 5 | 0.3641 | 0.4571 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3035C>G | P1012R 2D AIThe SynGAP1 missense variant P1012R is not reported in ClinVar and is absent from gnomAD, indicating no documented population frequency. 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, is not available for this variant. Overall, the consensus of all available predictions strongly supports a benign classification, with no contradiction to ClinVar status. 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 | -4.413 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.034 | Likely Benign | 1.24 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.89 | Benign | 0.88 | Tolerated | 0.1339 | 0.3083 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3104C>G | P1035R 2D AIThe SynGAP1 missense variant P1035R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 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 | 0.945666 | Disordered | 0.989572 | Binding | 0.300 | 0.756 | 0.625 | -4.534 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 0.119 | Likely Benign | 1.07 | Neutral | 0.970 | Probably Damaging | 0.728 | Possibly Damaging | 2.89 | Benign | 0.93 | Tolerated | 0.1424 | 0.4201 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3553A>G | K1185E 2D AISynGAP1 K1185E is not reported in ClinVar and has no gnomAD allele. Functional prediction tools show a split: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further highlight this divergence: AlphaMissense‑Optimized predicts pathogenic, whereas the SGM‑Consensus (a majority‑vote method) indicates benign; Foldetta results are unavailable. Overall, the balance of evidence, including the consensus from multiple predictors, points to a benign effect. Thus, 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. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.510264 | Binding | 0.642 | 0.638 | 0.625 | -4.465 | Likely Benign | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.148 | Likely Benign | -1.34 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.89 | Benign | 0.19 | Tolerated | 0.3715 | 0.0720 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3703A>C | M1235L 2D AIThe SynGAP1 missense variant M1235L is reported as “Likely Benign” by the SGM‑Consensus method and has no ClinVar entry, indicating it has not been classified in that database. It is also absent from gnomAD, so its allele frequency is not documented there. Across the spectrum of in‑silico predictors, all tools that provide a verdict—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—concur that the substitution is benign; none predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Based on the unanimous benign predictions and the lack of ClinVar classification, the variant is most likely benign, with no contradiction to existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.690604 | Disordered | 0.577958 | Binding | 0.872 | 0.532 | 0.125 | -2.013 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.38 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.89 | Benign | 1.00 | Tolerated | 0.1363 | 0.3935 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3703A>T | M1235L 2D AIThe SynGAP1 missense variant M1235L is reported as “Likely Benign” in the SGM‑Consensus and has no ClinVar entry, and it is not listed in gnomAD. All available in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta results are not available. Based on the unanimous benign predictions and lack of ClinVar or gnomAD 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 | Coiled-coil | 0.690604 | Disordered | 0.577958 | Binding | 0.872 | 0.532 | 0.125 | -2.013 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.38 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.89 | Benign | 1.00 | Tolerated | 0.1363 | 0.3935 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3736A>G | K1246E 2D AIThe SynGAP1 missense variant K1246E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion 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 | Coiled-coil | 0.750527 | Disordered | 0.375382 | Uncertain | 0.887 | 0.564 | 0.625 | -2.052 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.127 | Likely Benign | 0.80 | Neutral | 0.910 | Possibly Damaging | 0.630 | Possibly Damaging | 2.89 | Benign | 1.00 | Tolerated | 0.3328 | 0.0514 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3836C>A | A1279D 2D  AIThe SynGAP1 missense variant A1279D is catalogued in gnomAD (ID 6‑33447884‑C‑A) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool listed—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. Grouping by agreement, all available tools fall into the benign category, with no tools indicating pathogenicity. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from 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 result for this variant and is therefore considered unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.814139 | Binding | 0.485 | 0.724 | 0.750 | 6-33447884-C-A | -3.914 | Likely Benign | 0.172 | Likely Benign | Likely Benign | 0.087 | Likely Benign | 1.38 | Neutral | 0.000 | Benign | 0.000 | Benign | 2.89 | Benign | 0.35 | Tolerated | 3.77 | 5 | 0.1505 | 0.2062 | -2 | 0 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||
| c.3895C>G | L1299V 2D AIThe SynGAP1 missense variant L1299V is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification—there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.896323 | Binding | 0.398 | 0.832 | 0.750 | -4.502 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.385 | Likely Benign | -0.02 | Neutral | 0.124 | Benign | 0.025 | Benign | 2.89 | Benign | 0.09 | Tolerated | 0.1726 | 0.3544 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3898C>T | P1300S 2D AIThe SynGAP1 missense variant P1300S is reported in gnomAD (variant ID 6‑33451772‑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, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: 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 the majority of prediction tools and the high‑accuracy methods indicates that P1300S 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 | 0.788093 | Disordered | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | 6-33451772-C-T | 1 | 6.20e-7 | -3.476 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.036 | Likely Benign | -0.29 | Neutral | 0.481 | Possibly Damaging | 0.157 | Benign | 2.89 | Benign | 0.27 | Tolerated | 3.77 | 5 | 0.3242 | 0.4139 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3931C>G | L1311V 2D AIThe SynGAP1 missense variant L1311V is catalogued in gnomAD (ID 6‑33451805‑C‑G) 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 returns a benign prediction, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status remains unavailable. Overall, the computational evidence overwhelmingly supports 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. | Likely Benign | 0.816150 | Disordered | 0.968153 | Binding | 0.393 | 0.907 | 0.750 | 6-33451805-C-G | 1 | 6.20e-7 | -3.645 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.025 | Likely Benign | -0.05 | Neutral | 0.362 | Benign | 0.193 | Benign | 2.89 | Benign | 0.32 | Tolerated | 3.77 | 5 | 0.1666 | 0.3518 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.4016A>C | N1339T 2D AIThe SynGAP1 missense variant N1339T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, and Foldetta results are unavailable. Based on the most reliable predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.771762 | Disordered | 0.977585 | Binding | 0.396 | 0.687 | 1.000 | -2.682 | Likely Benign | 0.448 | Ambiguous | Likely Benign | 0.251 | Likely Benign | -3.31 | Deleterious | 0.980 | Probably Damaging | 0.956 | Probably Damaging | 2.89 | Benign | 0.00 | Affected | 0.1443 | 0.7598 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||||||||||||||||
| c.1575G>C | E525D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E525D 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, FATHMM, and Foldetta, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Rosetta provide uncertain results and are therefore not used to weigh the overall assessment. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic, while Foldetta predicts benign. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic effect for E525D. This conclusion does not contradict ClinVar status, as 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 | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | -11.207 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.78 | Ambiguous | 0.6 | -0.55 | Ambiguous | 0.12 | Likely Benign | 1.00 | Destabilizing | 0.362 | Likely Benign | -2.98 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | 2.90 | Benign | 0.00 | Affected | 0.1876 | 0.2197 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1575G>T | E525D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E525D 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, FATHMM, and Foldetta, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Rosetta provide uncertain results and are not counted as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as benign. Overall, the balance of evidence (nine pathogenic versus three benign predictions) indicates that the variant is most likely pathogenic, 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 | 0.206376 | Structured | 0.023618 | Uncertain | 0.937 | 0.382 | 0.125 | -11.207 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.78 | Ambiguous | 0.6 | -0.55 | Ambiguous | 0.12 | Likely Benign | 1.00 | Destabilizing | 0.362 | Likely Benign | -2.98 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | 2.90 | Benign | 0.00 | Affected | 0.1876 | 0.2197 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1903A>C | N635H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N635H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Three tools (FoldX, premPS, AlphaMissense‑Default) give uncertain results. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic; and Foldetta predicts benign. No prediction or folding‑stability result is missing or inconclusive. Based on the available evidence, the variant is most likely benign, 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 | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -12.507 | Likely Pathogenic | 0.419 | Ambiguous | Likely Benign | 1.07 | Ambiguous | 0.2 | -0.10 | Likely Benign | 0.49 | Likely Benign | 0.91 | Ambiguous | 0.429 | Likely Benign | -4.78 | Deleterious | 0.993 | Probably Damaging | 0.879 | Possibly Damaging | 2.90 | Benign | 0.00 | Affected | 0.1184 | 0.3720 | 2 | 1 | 0.3 | 23.04 | ||||||||||||||||||||||||||||||
| c.3296A>C | Y1099S 2D AIThe SynGAP1 missense variant Y1099S 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 from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this trend: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.974267 | Binding | 0.400 | 0.862 | 1.000 | -1.775 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -0.23 | Neutral | 0.149 | Benign | 0.026 | Benign | 2.90 | Benign | 0.62 | Tolerated | 0.4564 | 0.2298 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||||
| c.4017C>A | N1339K 2D AIThe SynGAP1 missense variant N1339K is listed in gnomAD (ID 6‑33451891‑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 returns an uncertain result. The high‑accuracy consensus (SGM Consensus) – a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN – is inconclusive (two pathogenic, two benign). Foldetta, a protein‑folding stability method, has no reported output for this variant. Overall, the majority of available tools (five pathogenic vs. three benign) predict a deleterious effect. The variant is most likely pathogenic based on current predictions, 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. | 0.771762 | Disordered | 0.977585 | Binding | 0.396 | 0.687 | 1.000 | 6-33451891-C-A | -3.009 | Likely Benign | 0.872 | Likely Pathogenic | Ambiguous | 0.169 | Likely Benign | -3.56 | Deleterious | 0.980 | Probably Damaging | 0.968 | Probably Damaging | 2.90 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2201 | 0.6507 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||
| c.4017C>G | N1339K 2D AISynGAP1 missense variant N1339K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain, the SGM Consensus (a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑to‑2 tie, and Foldetta results are unavailable. Overall, the balance of evidence favors a pathogenic classification, and this assessment 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. | 0.771762 | Disordered | 0.977585 | Binding | 0.396 | 0.687 | 1.000 | -3.009 | Likely Benign | 0.872 | Likely Pathogenic | Ambiguous | 0.181 | Likely Benign | -3.56 | Deleterious | 0.980 | Probably Damaging | 0.968 | Probably Damaging | 2.90 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2201 | 0.6507 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||||
| c.1292T>C | L431P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L431P (ClinVar ID 661045.0) is reported as Pathogenic and is not present in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Based on the overwhelming consensus of pathogenic predictions and the ClinVar designation, the variant is most likely pathogenic, with no contradiction to its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.374755 | Uncertain | 0.959 | 0.300 | 0.000 | Likely Pathogenic | 1 | -14.222 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 6.78 | Destabilizing | 0.3 | 11.59 | Destabilizing | 9.19 | Destabilizing | 2.29 | Destabilizing | 0.659 | Likely Pathogenic | -6.39 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.91 | Benign | 0.05 | Affected | 3.37 | 29 | 0.3484 | 0.2163 | -3 | -3 | -5.4 | -16.04 | 222.4 | 62.8 | 0.1 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | The iso-butyl side chain of Leu431, located in an α helix (res. Met414-Glu436), packs against other hydrophobic residues in an interhelix space (e.g., Val434, Leu435, Leu696, Leu711) in the WT simulations. While the backbone amide group of Leu431 forms an H-bond with the carbonyl group of His427, the cyclic five-membered pyrrolidine ring of Pro431, lacking the necessary amide group, cannot do the same. Thus, although the cyclic five-membered pyrrolidine ring of Pro431 packs almost as favorably as the side chain of Leu431 in the hydrophobic niche, the residue swap causes the α helix to partially unfold in the variant simulations. | ||||||||||||||||
| c.1925A>G | K642R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K642R is not reported in ClinVar and has no entries in gnomAD. Prediction tools that assess pathogenicity largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign. In contrast, PROVEAN, SIFT, and ESM1b predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, Foldetta is benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the balance of evidence favors a benign classification, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | -10.562 | Likely Pathogenic | 0.192 | Likely Benign | Likely Benign | -0.13 | Likely Benign | 0.1 | 0.39 | Likely Benign | 0.13 | Likely Benign | 0.04 | Likely Benign | 0.319 | Likely Benign | -2.79 | Deleterious | 0.001 | Benign | 0.001 | Benign | 2.91 | Benign | 0.02 | Affected | 0.4962 | 0.1262 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||
| c.1990T>G | L664V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Rosetta and Foldetta are uncertain, providing no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic (3 pathogenic vs 1 benign). Foldetta’s stability prediction is uncertain. Overall, the majority of reliable tools predict a pathogenic impact. 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 | GAP | 0.100716 | Structured | 0.089318 | Uncertain | 0.937 | 0.339 | 0.000 | -11.515 | Likely Pathogenic | 0.755 | Likely Pathogenic | Likely Benign | 2.01 | Destabilizing | 0.1 | 1.13 | Ambiguous | 1.57 | Ambiguous | 1.37 | Destabilizing | 0.378 | Likely Benign | -2.99 | Deleterious | 0.993 | Probably Damaging | 0.776 | Possibly Damaging | 2.91 | Benign | 0.01 | Affected | 0.0984 | 0.2628 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.2461T>A | C821S 2D  AIThe SynGAP1 missense variant C821S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus (majority vote) supports a benign outcome. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for C821S, 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 | 0.745909 | Disordered | 0.672821 | Binding | 0.351 | 0.883 | 0.750 | -0.425 | Likely Benign | 0.898 | Likely Pathogenic | Ambiguous | 0.190 | Likely Benign | -0.47 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.91 | Benign | 1.00 | Tolerated | 0.5284 | 0.2012 | Weaken | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||||||||||||
| c.2462G>C | C821S 2D AIThe SynGAP1 missense variant C821S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, whereas the SGM‑Consensus (majority vote) supports a benign outcome. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for C821S, 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 | 0.745909 | Disordered | 0.672821 | Binding | 0.351 | 0.883 | 0.750 | -0.425 | Likely Benign | 0.898 | Likely Pathogenic | Ambiguous | 0.314 | Likely Benign | -0.47 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.91 | Benign | 1.00 | Tolerated | 0.5284 | 0.2012 | Weaken | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||||||||||||
| c.2747T>C | V916A 2D AIThe SynGAP1 missense variant V916A 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, so the pathogenic‑prediction group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign,” and the Foldetta stability analysis is not available. Based on the collective predictions, 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 | 0.642678 | Disordered | 0.835395 | Binding | 0.308 | 0.879 | 0.250 | -2.524 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -0.18 | Neutral | 0.244 | Benign | 0.171 | Benign | 2.91 | Benign | 1.00 | Tolerated | 0.3455 | 0.2841 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.2860C>G | P954A 2D AIThe SynGAP1 missense variant P954A is not reported 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. There is no ClinVar classification to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984159 | Disordered | 0.932268 | Binding | 0.465 | 0.926 | 0.750 | -4.985 | Likely Benign | 0.051 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.21 | Neutral | 0.856 | Possibly Damaging | 0.652 | Possibly Damaging | 2.91 | Benign | 0.90 | Tolerated | 0.3103 | 0.5550 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2968T>G | S990A 2D AIThe SynGAP1 missense variant S990A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.902387 | Binding | 0.301 | 0.919 | 0.750 | -3.554 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.020 | Likely Benign | -0.51 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.91 | Benign | 0.03 | Affected | 0.4537 | 0.4509 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3199C>T | P1067S 2D AIThe SynGAP1 missense variant P1067S 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. 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 | 0.966441 | Disordered | 0.975099 | Binding | 0.459 | 0.907 | 0.875 | -4.673 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -1.43 | Neutral | 0.271 | Benign | 0.054 | Benign | 2.91 | Benign | 0.48 | Tolerated | 0.3086 | 0.5753 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3859C>G | P1287A 2D AIThe SynGAP1 missense variant P1287A 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 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 | 0.827927 | Disordered | 0.813701 | Binding | 0.538 | 0.777 | 0.750 | -3.064 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.090 | Likely Benign | 0.51 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.91 | Benign | 0.57 | Tolerated | 0.2885 | 0.3222 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.4016A>G | N1339S 2D AIThe SynGAP1 missense variant N1339S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.977585 | Binding | 0.396 | 0.687 | 1.000 | -2.331 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -2.66 | Deleterious | 0.980 | Probably Damaging | 0.935 | Probably Damaging | 2.91 | Benign | 0.00 | Affected | 0.3735 | 0.7283 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||||||
| c.1292T>A | L431Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L431Q resides in the GAP domain. ClinVar has no entry for this variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM; all other evaluated algorithms—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among pathogenic predictions and the high‑accuracy tools, the variant is most likely pathogenic; this conclusion is not contradicted by ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.374755 | Uncertain | 0.959 | 0.300 | 0.000 | -12.399 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 2.69 | Destabilizing | 0.0 | 2.37 | Destabilizing | 2.53 | Destabilizing | 1.99 | Destabilizing | 0.493 | Likely Benign | -5.40 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 2.92 | Benign | 0.01 | Affected | 0.1036 | 0.1088 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1476A>C | K492N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K492N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No folding‑stability predictions are definitive. Based on the preponderance of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -14.048 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 1.09 | Ambiguous | 1.01 | Ambiguous | 1.25 | Destabilizing | 0.512 | Likely Pathogenic | -4.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.92 | Benign | 0.00 | Affected | 0.2814 | 0.0926 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1476A>T | K492N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K492N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No folding‑stability predictions are definitive. Based on the preponderance of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -14.048 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 1.09 | Ambiguous | 1.01 | Ambiguous | 1.25 | Destabilizing | 0.512 | Likely Pathogenic | -4.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.92 | Benign | 0.00 | Affected | 0.2814 | 0.0926 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1903A>G | N635D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N635D is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, and FATHMM. Those that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Predictions that are inconclusive are Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy methods give an uncertain result for AlphaMissense‑Optimized, a Likely Pathogenic verdict from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an uncertain outcome from Foldetta. Overall, the majority of computational 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 | GAP | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -14.453 | Likely Pathogenic | 0.799 | Likely Pathogenic | Ambiguous | 0.47 | Likely Benign | 0.1 | 0.73 | Ambiguous | 0.60 | Ambiguous | 1.26 | Destabilizing | 0.432 | Likely Benign | -4.71 | Deleterious | 0.955 | Possibly Damaging | 0.628 | Possibly Damaging | 2.92 | Benign | 0.01 | Affected | 0.1725 | 0.1937 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.1905C>A | N635K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N635K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict pathogenicity: 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, also indicates a likely pathogenic outcome. Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for N635K, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -13.144 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.60 | Ambiguous | 0.1 | 0.75 | Ambiguous | 0.68 | Ambiguous | 0.85 | Ambiguous | 0.332 | Likely Benign | -5.64 | Deleterious | 0.949 | Possibly Damaging | 0.550 | Possibly Damaging | 2.92 | Benign | 0.00 | Affected | 0.2125 | 0.2510 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1905C>G | N635K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N635K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: 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, also classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM Consensus as Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. Overall, the preponderance of evidence from multiple in silico predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -13.144 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.60 | Ambiguous | 0.1 | 0.75 | Ambiguous | 0.68 | Ambiguous | 0.85 | Ambiguous | 0.332 | Likely Benign | -5.64 | Deleterious | 0.949 | Possibly Damaging | 0.550 | Possibly Damaging | 2.92 | Benign | 0.00 | Affected | 0.2125 | 0.2510 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1928A>C | E643A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E643A 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, Rosetta, premPS, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. FoldX and Foldetta give uncertain results. 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 remains uncertain. Overall, the majority of tools lean toward a benign interpretation, and this assessment does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -12.562 | Likely Pathogenic | 0.733 | Likely Pathogenic | Likely Benign | 0.80 | Ambiguous | 0.2 | 0.39 | Likely Benign | 0.60 | Ambiguous | 0.21 | Likely Benign | 0.469 | Likely Benign | -5.81 | Deleterious | 0.771 | Possibly Damaging | 0.233 | Benign | 2.92 | Benign | 0.01 | Affected | 0.4074 | 0.6096 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1990T>A | L664M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also uncertain due to a 2‑vs‑2 split; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. Overall, the majority of conventional tools predict a pathogenic impact, whereas the high‑accuracy methods do not provide a definitive verdict. Consequently, the variant is most likely pathogenic 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. | GAP | 0.100716 | Structured | 0.089318 | Uncertain | 0.937 | 0.339 | 0.000 | -11.819 | Likely Pathogenic | 0.807 | Likely Pathogenic | Ambiguous | 0.49 | Likely Benign | 0.1 | 1.35 | Ambiguous | 0.92 | Ambiguous | 0.96 | Ambiguous | 0.429 | Likely Benign | -2.00 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.92 | Benign | 0.01 | Affected | 0.0620 | 0.2541 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.2221C>T | P741S 2D AIThe SynGAP1 missense variant P741S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33441686‑C‑T). 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. Grouping by consensus, the benign‑predicting tools outnumber the pathogenic one. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” No Foldetta stability data are available, so it does not influence the conclusion. Overall, the computational evidence indicates that 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 | 0.885302 | Disordered | 0.493550 | Uncertain | 0.354 | 0.859 | 0.875 | Uncertain | 2 | 6-33441686-C-T | 3 | 1.86e-6 | -3.700 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.27 | Neutral | 0.270 | Benign | 0.136 | Benign | 2.92 | Benign | 0.00 | Affected | 4.32 | 2 | 0.2888 | 0.4278 | 1 | -1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.2350G>A | A784T 2D AIThe SynGAP1 missense variant A784T is listed in ClinVar (ID 962668.0) as Benign and is not reported in 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 tool predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. A Foldetta stability analysis is unavailable, so it does not influence the overall interpretation. Based on the unanimous benign predictions and the ClinVar designation, the variant is most likely benign, with no contradiction to the ClinVar status. 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 | Benign | 1 | -3.579 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.046 | Likely Benign | 1.23 | Neutral | 0.001 | Benign | 0.006 | Benign | 2.92 | Benign | 1.00 | Tolerated | 3.64 | 6 | 0.1493 | 0.6659 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.2420A>T | Y807F 2D  AIThe SynGAP1 missense variant Y807F is listed in ClinVar (ID 1491782.0) with an “Uncertain” status and is not reported in gnomAD. All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. No tool in the set predicts pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the four high‑accuracy predictors) is benign. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, has no available result for this variant. Overall, the computational evidence strongly supports a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.699094 | Disordered | 0.853760 | Binding | 0.336 | 0.901 | 0.500 | Uncertain | 1 | -3.667 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.057 | Likely Benign | 0.14 | Neutral | 0.012 | Benign | 0.022 | Benign | 2.92 | Benign | 0.98 | Tolerated | 3.77 | 5 | 0.2485 | 0.2500 | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||||||||||
| c.2478C>A | D826E 2D AIThe SynGAP1 missense variant D826E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -4.172 | Likely Benign | 0.859 | Likely Pathogenic | Ambiguous | 0.164 | Likely Benign | -0.66 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.92 | Benign | 0.56 | Tolerated | 0.1795 | 0.7687 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2478C>G | D826E 2D AIThe SynGAP1 missense variant D826E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is 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 | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -4.172 | Likely Benign | 0.859 | Likely Pathogenic | Ambiguous | 0.164 | Likely Benign | -0.66 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.92 | Benign | 0.56 | Tolerated | 0.1795 | 0.7687 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2527A>C | M843L 2D AIThe SynGAP1 missense variant M843L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is classified 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 benign predictions and the lack of pathogenic evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.617934 | Binding | 0.327 | 0.854 | 0.375 | -4.406 | Likely Benign | 0.426 | Ambiguous | Likely Benign | 0.181 | Likely Benign | -1.02 | Neutral | 0.699 | Possibly Damaging | 0.833 | Possibly Damaging | 2.92 | Benign | 0.33 | Tolerated | 0.1717 | 0.4571 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2527A>T | M843L 2D AIThe SynGAP1 missense variant M843L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) 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 because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.617934 | Binding | 0.327 | 0.854 | 0.375 | -4.406 | Likely Benign | 0.426 | Ambiguous | Likely Benign | 0.181 | Likely Benign | -1.02 | Neutral | 0.699 | Possibly Damaging | 0.833 | Possibly Damaging | 2.92 | Benign | 0.33 | Tolerated | 0.1717 | 0.4571 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2819G>T | G940V 2D AIThe SynGAP1 missense variant G940V 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, and this is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.920635 | Binding | 0.383 | 0.902 | 0.625 | -6.252 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.110 | Likely Benign | 0.36 | Neutral | 0.626 | Possibly Damaging | 0.419 | Benign | 2.92 | Benign | 0.31 | Tolerated | 0.1222 | 0.3822 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3850C>G | L1284V 2D AIThe SynGAP1 missense variant L1284V 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 | 0.812494 | Disordered | 0.824557 | Binding | 0.441 | 0.748 | 0.875 | -4.329 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.90 | Neutral | 0.008 | Benign | 0.006 | Benign | 2.92 | Benign | 1.00 | Tolerated | 0.1419 | 0.1883 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.4015A>G | N1339D 2D AIThe SynGAP1 missense variant N1339D is catalogued in gnomAD (ID 6‑33451889‑A‑G) but has no ClinVar submission. Functional prediction tools show mixed results: benign calls come from REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. When aggregated into a consensus, the four contributing scores (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) split evenly, leaving the SGM Consensus inconclusive. High‑accuracy assessments further indicate a benign outcome from AlphaMissense‑Optimized; the SGM Consensus and Foldetta predictions are unavailable. Overall, the majority of individual tools predict pathogenicity, and the high‑accuracy benign prediction does 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. | 0.771762 | Disordered | 0.977585 | Binding | 0.396 | 0.687 | 1.000 | 6-33451889-A-G | -2.533 | Likely Benign | 0.634 | Likely Pathogenic | Likely Benign | 0.186 | Likely Benign | -3.04 | Deleterious | 0.980 | Probably Damaging | 0.956 | Probably Damaging | 2.92 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2087 | 0.4721 | 1 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||
| c.1292T>G | L431R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L431R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.374755 | Uncertain | 0.959 | 0.300 | 0.000 | -14.777 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.45 | Destabilizing | 0.0 | 4.76 | Destabilizing | 4.11 | Destabilizing | 1.93 | Destabilizing | 0.654 | Likely Pathogenic | -5.47 | Deleterious | 0.997 | Probably Damaging | 0.833 | Possibly Damaging | 2.93 | Benign | 0.00 | Affected | 0.1191 | 0.0730 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1514A>T | Y505F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505F is not 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, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools (five benign versus four pathogenic) lean toward a benign interpretation, 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 | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | -8.855 | Likely Pathogenic | 0.437 | Ambiguous | Likely Benign | 0.40 | Likely Benign | 0.0 | 0.76 | Ambiguous | 0.58 | Ambiguous | 0.69 | Ambiguous | 0.434 | Likely Benign | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.93 | Benign | 0.07 | Tolerated | 0.2409 | 0.2598 | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||||||
| c.2227C>T | P743S 2D AIThe SynGAP1 missense variant P743S is listed in gnomAD (ID 6‑33441692‑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, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as benign. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence indicates that P743S is most likely benign, and this conclusion is not contradicted by any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.526809 | Binding | 0.317 | 0.862 | 0.875 | 6-33441692-C-T | 1 | 6.19e-7 | -4.286 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -0.33 | Neutral | 0.021 | Benign | 0.015 | Benign | 2.93 | Benign | 0.00 | Affected | 4.32 | 2 | 0.3087 | 0.3948 | -1 | 1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||||
| c.3024T>A | D1008E 2D AIThe SynGAP1 D1008E missense variant is catalogued in gnomAD (6‑33443576‑T‑A) 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 both predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, providing no definitive signal. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also reports it as likely benign. No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the preponderance of evidence from both general and high‑accuracy predictors, 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 | 0.694846 | Disordered | 0.919416 | Binding | 0.280 | 0.899 | 0.625 | 6-33443576-T-A | 1 | 6.20e-7 | -2.809 | Likely Benign | 0.428 | Ambiguous | Likely Benign | 0.151 | Likely Benign | -0.53 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.93 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2315 | 0.6303 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.3024T>G | D1008E 2D AIThe SynGAP1 missense variant D1008E is listed in gnomAD (ID 6‑33443576‑T‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and Foldetta results are unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta provides no data. Overall, 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. | Likely Benign | 0.694846 | Disordered | 0.919416 | Binding | 0.280 | 0.899 | 0.625 | 6-33443576-T-G | -2.809 | Likely Benign | 0.428 | Ambiguous | Likely Benign | 0.151 | Likely Benign | -0.53 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.93 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2315 | 0.6303 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3911C>G | P1304R 2D AIThe SynGAP1 missense variant P1304R 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, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenicity, but these two tools represent a minority of the evidence. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of predictions supports a benign classification for P1304R, 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 | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | -4.518 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.108 | Likely Benign | -1.21 | Neutral | 0.586 | Possibly Damaging | 0.172 | Benign | 2.93 | Benign | 0.04 | Affected | 0.1717 | 0.3150 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.1291C>A | L431M 2D AIThe SynGAP1 missense variant L431M (ClinVar ID 4327026) is not found in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, FATHMM, AlphaMissense‑Optimized, and Foldetta, whereas premPS, polyPhen‑2 (HumDiv and HumVar), and SIFT all predict a pathogenic outcome. 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, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. No predictions or stability results are missing or inconclusive. Overall, the majority of computational evidence indicates that the variant is most likely benign, which contradicts the ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.094817 | Structured | 0.374755 | Uncertain | 0.959 | 0.300 | 0.000 | 1 | -7.471 | In-Between | 0.375 | Ambiguous | Likely Benign | 0.18 | Likely Benign | 0.3 | 0.50 | Ambiguous | 0.34 | Likely Benign | 1.07 | Destabilizing | 0.102 | Likely Benign | -1.50 | Neutral | 0.995 | Probably Damaging | 0.849 | Possibly Damaging | 2.94 | Benign | 0.02 | Affected | 0.0748 | 0.3121 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1475A>T | K492I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K492I is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions from premPS and FATHMM; pathogenic predictions from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results come from FoldX, Rosetta, and Foldetta. High‑accuracy methods give a pathogenic verdict: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts pathogenic (3/4 votes). Foldetta remains inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -18.661 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.54 | Ambiguous | 0.1 | -0.59 | Ambiguous | -0.57 | Ambiguous | 0.49 | Likely Benign | 0.645 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.94 | Benign | 0.00 | Affected | 0.0875 | 0.2810 | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||||||
| c.1927G>C | E643Q 2D AIThe SynGAP1 missense variant E643Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus (Likely Pathogenic), PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized predicts a benign outcome, while premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of predictions (8 benign vs. 5 pathogenic) and the two of three high‑accuracy tools favor a benign classification. Thus, 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 Pathogenic | GAP | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -12.404 | Likely Pathogenic | 0.688 | Likely Pathogenic | Likely Benign | 0.49 | Likely Benign | 0.6 | 0.15 | Likely Benign | 0.32 | Likely Benign | 0.83 | Ambiguous | 0.341 | Likely Benign | -2.86 | Deleterious | 0.446 | Benign | 0.038 | Benign | 2.94 | Benign | 0.01 | Affected | 0.1603 | 0.6308 | 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 | 1.45 | Ambiguous | 0.3 | 2.06 | Destabilizing | 1.76 | Ambiguous | 1.01 | Destabilizing | 0.520 | Likely Pathogenic | -6.81 | Deleterious | 0.983 | Probably Damaging | 0.390 | Benign | 2.94 | Benign | 0.00 | Affected | 0.2821 | 0.5319 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.2252C>T | P751L 2D AIThe SynGAP1 missense variant P751L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this trend: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.667683 | Binding | 0.386 | 0.866 | 0.625 | -3.558 | Likely Benign | 0.143 | Likely Benign | Likely Benign | 0.207 | Likely Benign | -1.62 | Neutral | 0.316 | Benign | 0.062 | Benign | 2.94 | Benign | 0.24 | Tolerated | 0.2318 | 0.6451 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2261A>G | E754G 2D AIThe SynGAP1 missense variant E754G is not reported 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 not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.750531 | Binding | 0.357 | 0.872 | 0.500 | -5.029 | Likely Benign | 0.313 | Likely Benign | Likely Benign | 0.080 | Likely Benign | -0.52 | Neutral | 0.801 | Possibly Damaging | 0.339 | Benign | 2.94 | Benign | 0.13 | Tolerated | 0.2631 | 0.5820 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3727C>G | Q1243E 2D AIThe SynGAP1 missense variant Q1243E 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 indicate a benign effect, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports “Likely Benign.” No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome; 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 | Coiled-coil | 0.545602 | Disordered | 0.433693 | Uncertain | 0.887 | 0.551 | 0.500 | -1.439 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.068 | Likely Benign | 0.88 | Neutral | 0.166 | Benign | 0.146 | Benign | 2.94 | Benign | 1.00 | Tolerated | 0.1067 | 0.0930 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||||||
| c.3790G>A | G1264S 2D AIThe SynGAP1 missense variant G1264S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: benign predictions are made by 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 classifies the variant as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. Foldetta results are unavailable. 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 | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -0.797 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.147 | Likely Benign | 0.82 | Neutral | 0.062 | Benign | 0.033 | Benign | 2.94 | Benign | 1.00 | Tolerated | 0.2376 | 0.4256 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||||||
| 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 | 0.52 | Neutral | 0.026 | Benign | 0.018 | Benign | 2.94 | Benign | 0.38 | Tolerated | 0.3411 | 0.5358 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.1250A>G | Y417C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y417C 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: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also classifies the variant as pathogenic. 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 | GAP | 0.179055 | Structured | 0.346865 | Uncertain | 0.958 | 0.250 | 0.000 | -12.021 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 4.03 | Destabilizing | 0.1 | 3.81 | Destabilizing | 3.92 | Destabilizing | 2.52 | Destabilizing | 0.597 | Likely Pathogenic | -8.59 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.95 | Benign | 0.00 | Affected | 0.2960 | 0.2005 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.1777C>T | L593F 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant L593F is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions that are inconclusive—FoldX, Foldetta, premPS, and AlphaMissense‑Optimized—are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. 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 | 0.009728 | Structured | 0.110534 | Uncertain | 0.941 | 0.151 | 0.000 | -12.723 | Likely Pathogenic | 0.954 | Likely Pathogenic | Ambiguous | 1.46 | Ambiguous | 0.4 | 0.24 | Likely Benign | 0.85 | Ambiguous | 0.62 | Ambiguous | 0.304 | Likely Benign | -3.78 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.95 | Benign | 0.01 | Affected | 0.0884 | 0.2631 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1927G>A | E643K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E643K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign calls come from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while pathogenic calls arise from SGM‑Consensus (Likely Pathogenic), PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. Four tools (Foldetta, premPS, AlphaMissense‑Optimized, and Rosetta) give uncertain results. High‑accuracy assessments focus on AlphaMissense‑Optimized (Uncertain), SGM‑Consensus (Likely Pathogenic), and Foldetta (Uncertain). Because the consensus of the most reliable predictors leans toward pathogenicity, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -14.318 | Likely Pathogenic | 0.868 | Likely Pathogenic | Ambiguous | 0.39 | Likely Benign | 0.2 | 1.44 | Ambiguous | 0.92 | Ambiguous | 0.82 | Ambiguous | 0.449 | Likely Benign | -3.79 | Deleterious | 0.042 | Benign | 0.004 | Benign | 2.95 | Benign | 0.04 | Affected | 0.2961 | 0.6269 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.2000T>A | I667N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I667N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.142424 | Structured | 0.083597 | Uncertain | 0.927 | 0.379 | 0.000 | -15.730 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 2.89 | Destabilizing | 0.2 | 2.84 | Destabilizing | 2.87 | Destabilizing | 2.56 | Destabilizing | 0.572 | Likely Pathogenic | -6.73 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.95 | Benign | 0.00 | Affected | 0.0841 | 0.0470 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.2426G>C | S809T 2D AIThe SynGAP1 missense variant S809T 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 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) also reports a likely benign outcome. Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -3.865 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.076 | Likely Benign | 0.68 | Neutral | 0.003 | Benign | 0.010 | Benign | 2.95 | Benign | 0.82 | Tolerated | 0.1430 | 0.6617 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2543G>A | G848D 2D AIThe SynGAP1 missense variant G848D 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 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 | 0.724957 | Disordered | 0.563942 | Binding | 0.287 | 0.816 | 0.500 | -0.059 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.121 | Likely Benign | 2.94 | Neutral | 0.008 | Benign | 0.019 | Benign | 2.95 | Benign | 0.81 | Tolerated | 0.1702 | 0.1392 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| 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 | -0.60 | Neutral | 0.068 | Benign | 0.039 | Benign | 2.95 | Benign | 0.50 | Tolerated | 0.2677 | 0.5408 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.319A>T | R107W 2D  AIThe SynGAP1 missense variant R107W is not 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 predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (two pathogenic vs two benign), and Foldetta results are unavailable. Overall, the majority of evidence (six pathogenic vs three benign) points to a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.663448 | Binding | 0.331 | 0.863 | 0.875 | -4.963 | Likely Benign | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.328 | Likely Benign | -2.99 | Deleterious | 0.983 | Probably Damaging | 0.624 | Possibly Damaging | 2.95 | Benign | 0.00 | Affected | 0.1146 | 0.4228 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3697A>C | I1233L 2D AIThe SynGAP1 missense variant I1233L 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, and FATHMM all score the substitution as benign, and AlphaMissense‑Optimized also predicts a benign outcome. No tool predicts pathogenicity; 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 corroborate this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also indicates likely benign; Foldetta data are not available. Overall, the consensus of available predictions points to a benign effect, and this is consistent with the lack of ClinVar evidence or gnomAD observation. Thus, the variant is most likely benign, and this conclusion does not contradict ClinVar status, which has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.525368 | Disordered | 0.564054 | Binding | 0.881 | 0.531 | 0.125 | -3.031 | Likely Benign | 0.382 | Ambiguous | Likely Benign | 0.113 | Likely Benign | -0.01 | Neutral | 0.211 | Benign | 0.108 | Benign | 2.95 | Benign | 1.00 | Tolerated | 0.0631 | 0.3246 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||||
| 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 | -3.12 | Deleterious | 0.994 | Probably Damaging | 0.981 | Probably Damaging | 2.95 | Benign | 0.00 | Affected | 0.2185 | 0.5308 | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||||||||||||
| c.3995C>T | T1332M 2D AISynGAP1 missense variant T1332M is listed as Benign in ClinVar (ID 794425) and is present in gnomAD (6‑33451869‑C‑T). Functional prediction tools show mixed results: benign calls come from REVEL, ESM1b, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized returned an uncertain result, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and no Foldetta stability data are available. Overall, the majority of evidence points toward a pathogenic effect, which contradicts the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.948427 | Binding | 0.442 | 0.754 | 0.875 | Likely Benign | 1 | 6-33451869-C-T | 20 | 1.86e-5 | -4.107 | Likely Benign | 0.948 | Likely Pathogenic | Ambiguous | 0.252 | Likely Benign | -3.63 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 2.95 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1551 | 0.6513 | -1 | -1 | 2.6 | 30.09 | |||||||||||||||||||||||||||||||||
| c.1249T>G | Y417D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y417D 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 only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any existing 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 | 0.179055 | Structured | 0.346865 | Uncertain | 0.958 | 0.250 | 0.000 | -14.955 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.13 | Destabilizing | 0.1 | 5.37 | Destabilizing | 5.25 | Destabilizing | 2.43 | Destabilizing | 0.688 | Likely Pathogenic | -9.55 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.96 | Benign | 0.00 | Affected | 0.4388 | 0.0400 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.1475A>C | K492T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K492T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the majority—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized—predict a pathogenic impact. Four methods (FoldX, Rosetta, Foldetta, premPS) return uncertain results. High‑accuracy predictors give a consistent pathogenic signal: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta remains uncertain. Overall, the evidence strongly favors a pathogenic classification, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -16.126 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.09 | Ambiguous | 0.1 | 0.88 | Ambiguous | 0.99 | Ambiguous | 0.98 | Ambiguous | 0.595 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.96 | Benign | 0.04 | Affected | 0.1691 | 0.2825 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1924A>G | K642E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K642E is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM) and pathogenic predictions (SGM‑Consensus, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized). High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. No prediction is inconclusive. Overall, the majority of tools lean toward pathogenicity, and this is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | -11.287 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.26 | Likely Benign | 0.1 | -0.13 | Likely Benign | 0.07 | Likely Benign | 0.40 | Likely Benign | 0.404 | Likely Benign | -3.92 | Deleterious | 0.116 | Benign | 0.011 | Benign | 2.96 | Benign | 0.03 | Affected | 0.3865 | 0.1013 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1988T>G | F663C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) 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 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 | GAP | 0.056825 | Structured | 0.093963 | Uncertain | 0.944 | 0.355 | 0.000 | -13.544 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.83 | Destabilizing | 0.1 | 4.54 | Destabilizing | 4.19 | Destabilizing | 1.91 | Destabilizing | 0.772 | Likely Pathogenic | -7.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.96 | Benign | 0.00 | Affected | 0.2343 | 0.0783 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1999A>T | I667F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I667F missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign calls are limited to FATHMM, while the remaining 11 predictors—SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta—classify the change as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a pathogenic effect. No prediction is 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 | 0.142424 | Structured | 0.083597 | Uncertain | 0.927 | 0.379 | 0.000 | -14.389 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 7.55 | Destabilizing | 0.3 | 1.80 | Ambiguous | 4.68 | Destabilizing | 0.86 | Ambiguous | 0.569 | Likely Pathogenic | -3.98 | Deleterious | 0.998 | Probably Damaging | 0.790 | Possibly Damaging | 2.96 | Benign | 0.00 | Affected | 0.0668 | 0.2648 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.2000T>G | I667S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I667S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) 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 because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.142424 | Structured | 0.083597 | Uncertain | 0.927 | 0.379 | 0.000 | -14.328 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 3.69 | Destabilizing | 0.1 | 3.97 | Destabilizing | 3.83 | Destabilizing | 2.48 | Destabilizing | 0.690 | Likely Pathogenic | -5.90 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 2.96 | Benign | 0.00 | Affected | 0.2462 | 0.0858 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.2632A>C | T878P 2D AIThe SynGAP1 missense variant T878P 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; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.622677 | Disordered | 0.628767 | Binding | 0.288 | 0.878 | 0.250 | -3.130 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -1.41 | Neutral | 0.761 | Possibly Damaging | 0.478 | Possibly Damaging | 2.96 | Benign | 0.01 | Affected | 0.2026 | 0.5538 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| 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 | -0.35 | Neutral | 0.009 | Benign | 0.008 | Benign | 2.96 | Benign | 0.37 | Tolerated | 0.3359 | 0.5184 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.320G>T | R107M 2D  AIThe SynGAP1 missense variant R107M is not 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, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not conflict with the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.663448 | Binding | 0.331 | 0.863 | 0.875 | -4.873 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.233 | Likely Benign | -2.65 | Deleterious | 0.028 | Benign | 0.011 | Benign | 2.96 | Benign | 0.00 | Affected | 0.1605 | 0.4415 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.3535A>G | K1179E 2D AIThe SynGAP1 missense variant K1179E is reported in gnomAD (ID 6‑33444570‑A‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic impact are polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the majority of individual predictors (five versus four) lean toward pathogenicity, and the high‑accuracy AlphaMissense‑Optimized result supports this. No ClinVar status is available to contradict these findings. 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. | Likely Benign | Coiled-coil | 0.637480 | Disordered | 0.558455 | Binding | 0.575 | 0.678 | 0.250 | 6-33444570-A-G | 1 | 6.20e-7 | -4.040 | Likely Benign | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.143 | Likely Benign | -1.02 | Neutral | 0.800 | Possibly Damaging | 0.525 | Possibly Damaging | 2.96 | Benign | 0.00 | Affected | 4.32 | 2 | 0.3476 | 0.0876 | 1 | 0 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||
| c.3832C>T | P1278S 2D AIThe SynGAP1 missense variant P1278S 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 | 0.788093 | Disordered | 0.806955 | Binding | 0.532 | 0.722 | 0.750 | -4.383 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.077 | Likely Benign | 0.28 | Neutral | 0.004 | Benign | 0.003 | Benign | 2.96 | Benign | 0.35 | Tolerated | 0.3616 | 0.3697 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3858A>C | E1286D 2D AIThe SynGAP1 missense variant E1286D is not reported in ClinVar and is absent from gnomAD. All available in silico predictors classify it as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments 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 results are not available. Based on the unanimous benign predictions and lack 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 | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | -4.010 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.036 | Likely Benign | 1.02 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.96 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2114 | 0.3141 | 3 | 2 | 0.0 | -14.03 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||||||||||||
| c.3858A>T | E1286D 2D AIThe SynGAP1 missense variant E1286D is listed in ClinVar (ID 469159.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33447906‑A‑T). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool in the set predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence strongly supports a benign effect, and this conclusion does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | Conflicting | 4 | 6-33447906-A-T | 143 | 9.22e-5 | -4.010 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.036 | Likely Benign | 1.02 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.96 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2114 | 0.3141 | 3 | 2 | 0.0 | -14.03 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.3859C>T | P1287S 2D AIThe SynGAP1 missense variant P1287S is catalogued in gnomAD (ID 6‑33447907‑C‑T) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool listed—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently scores the variant as benign. No pathogenic predictions are reported. Grouping by agreement, the benign‑predicting tools comprise the entire set, while the pathogenic group is empty. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining 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 (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.813701 | Binding | 0.538 | 0.777 | 0.750 | 6-33447907-C-T | -3.258 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.055 | Likely Benign | 0.70 | Neutral | 0.004 | Benign | 0.004 | Benign | 2.96 | Benign | 0.96 | Tolerated | 3.77 | 5 | 0.2820 | 0.3566 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||
| c.3995C>A | T1332K 2D AIThe SynGAP1 missense variant T1332K is catalogued in gnomAD (ID 6‑33451869‑C‑A) but has no ClinVar submission. Functional prediction tools cluster into two groups: benign predictions from REVEL, ESM1b, and FATHMM; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. A high‑accuracy consensus (SGM) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a 2‑to‑2 split, leaving the consensus inconclusive. No Foldetta stability assessment is available. Overall, the majority of evidence (five pathogenic versus three benign) 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. | 0.915074 | Disordered | 0.948427 | Binding | 0.442 | 0.754 | 0.875 | 6-33451869-C-A | -3.264 | Likely Benign | 0.935 | Likely Pathogenic | Ambiguous | 0.247 | Likely Benign | -3.48 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | 2.96 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1424 | 0.4376 | -1 | 0 | -3.2 | 27.07 | |||||||||||||||||||||||||||||||||||||
| c.3995C>G | T1332R 2D AIThe SynGAP1 missense variant T1332R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie and therefore unavailable; Foldetta results are not provided. Overall, the balance of evidence (five pathogenic versus three benign predictions) indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.948427 | Binding | 0.442 | 0.754 | 0.875 | -3.354 | Likely Benign | 0.878 | Likely Pathogenic | Ambiguous | 0.271 | Likely Benign | -3.59 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 2.96 | Benign | 0.00 | Affected | 0.1173 | 0.3867 | -1 | -1 | -3.8 | 55.08 | ||||||||||||||||||||||||||||||||||||||||
| c.1249T>A | Y417N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y417N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, while the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.346865 | Uncertain | 0.958 | 0.250 | 0.000 | -13.912 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.94 | Destabilizing | 0.2 | 3.69 | Destabilizing | 3.82 | Destabilizing | 2.60 | Destabilizing | 0.561 | Likely Pathogenic | -8.59 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.97 | Benign | 0.00 | Affected | 0.2482 | 0.0728 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1249T>C | Y417H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y417H 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 only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta (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 conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for Y417H. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.346865 | Uncertain | 0.958 | 0.250 | 0.000 | -11.447 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.22 | Destabilizing | 0.1 | 2.80 | Destabilizing | 3.01 | Destabilizing | 1.54 | Destabilizing | 0.513 | Likely Pathogenic | -4.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.97 | Benign | 0.00 | Affected | 0.2596 | 0.0668 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
| c.2725A>G | M909V 2D AIThe SynGAP1 missense variant M909V 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 | 0.642678 | Disordered | 0.696196 | Binding | 0.314 | 0.914 | 0.250 | -2.906 | Likely Benign | 0.230 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -0.88 | Neutral | 0.288 | Benign | 0.147 | Benign | 2.97 | Benign | 0.45 | Tolerated | 0.3295 | 0.3600 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||||||||||
| c.3269A>G | N1090S 2D AIThe SynGAP1 missense variant N1090S 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 pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -2.451 | Likely Benign | 0.228 | Likely Benign | Likely Benign | 0.135 | Likely Benign | -0.49 | Neutral | 0.997 | Probably Damaging | 0.983 | Probably Damaging | 2.97 | Benign | 0.38 | Tolerated | 0.3980 | 0.7620 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||||||||||||
| c.1250A>C | Y417S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y417S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are limited to FATHMM, while all other evaluated algorithms—including SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic 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 | GAP | 0.179055 | Structured | 0.346865 | Uncertain | 0.958 | 0.250 | 0.000 | -14.339 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 4.36 | Destabilizing | 0.1 | 5.32 | Destabilizing | 4.84 | Destabilizing | 2.17 | Destabilizing | 0.593 | Likely Pathogenic | -8.59 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.98 | Benign | 0.00 | Affected | 0.4408 | 0.1961 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.1474A>C | K492Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K492Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and FATHMM, whereas pathogenic predictions are made by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, SGM Consensus confirms a likely pathogenic status, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No evidence from ClinVar contradicts these findings. Therefore, the variant is most likely pathogenic based on the collective predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -14.685 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.34 | Likely Benign | 0.0 | 0.93 | Ambiguous | 0.64 | Ambiguous | 1.13 | Destabilizing | 0.463 | Likely Benign | -3.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.98 | Benign | 0.02 | Affected | 0.3534 | 0.0830 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1874T>A | L625H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L625H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) 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 because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.045896 | Uncertain | 0.966 | 0.215 | 0.000 | -14.264 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.85 | Destabilizing | 0.3 | 2.96 | Destabilizing | 2.91 | Destabilizing | 2.02 | Destabilizing | 0.738 | Likely Pathogenic | -6.87 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.98 | Benign | 0.00 | Affected | 0.0954 | 0.0541 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.1874T>C | L625P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L625P 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 give consistent results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.045896 | Uncertain | 0.966 | 0.215 | 0.000 | -14.819 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.47 | Destabilizing | 0.6 | 12.49 | Destabilizing | 8.98 | Destabilizing | 1.98 | Destabilizing | 0.746 | Likely Pathogenic | -6.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.98 | Benign | 0.00 | Affected | 0.3294 | 0.1313 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1904A>C | N635T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N635T is not 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and ESM1b; polyPhen‑2 HumVar, however, classifies it as benign. 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, is uncertain, and FoldX and premPS also yield uncertain results. Overall, the majority of evidence (five benign vs. four pathogenic) supports a benign classification. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -11.705 | Likely Pathogenic | 0.256 | Likely Benign | Likely Benign | 1.50 | Ambiguous | 0.1 | 0.44 | Likely Benign | 0.97 | Ambiguous | 0.81 | Ambiguous | 0.240 | Likely Benign | -5.58 | Deleterious | 0.536 | Possibly Damaging | 0.184 | Benign | 2.98 | Benign | 0.04 | Affected | 0.1206 | 0.4032 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||||||
| c.1929G>C | E643D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E643D is not 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, AlphaMissense‑Default, AlphaMissense‑Optimized, FATHMM, and polyPhen2_HumVar. Tools that predict a pathogenic effect are premPS, PROVEAN, polyPhen2_HumDiv, SIFT, 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 due to a 2‑vs‑2 split. Overall, the majority of predictions (8 benign vs. 5 pathogenic) support a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -8.083 | Likely Pathogenic | 0.223 | Likely Benign | Likely Benign | 0.46 | Likely Benign | 0.2 | -0.34 | Likely Benign | 0.06 | Likely Benign | 1.09 | Destabilizing | 0.292 | Likely Benign | -2.96 | Deleterious | 0.694 | Possibly Damaging | 0.064 | Benign | 2.98 | Benign | 0.01 | Affected | 0.2040 | 0.4276 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1929G>T | E643D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E643D is not 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, AlphaMissense‑Default, AlphaMissense‑Optimized, FATHMM, and polyPhen2_HumVar. Tools that predict a pathogenic effect are premPS, PROVEAN, polyPhen2_HumDiv, SIFT, 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 due to a 2‑vs‑2 split. Overall, the majority of predictions (8 benign vs. 5 pathogenic) support a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -8.083 | Likely Pathogenic | 0.223 | Likely Benign | Likely Benign | 0.46 | Likely Benign | 0.2 | -0.34 | Likely Benign | 0.06 | Likely Benign | 1.09 | Destabilizing | 0.292 | Likely Benign | -2.96 | Deleterious | 0.694 | Possibly Damaging | 0.064 | Benign | 2.98 | Benign | 0.01 | Affected | 0.2040 | 0.4276 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1988T>C | F663S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy predictors, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.056825 | Structured | 0.093963 | Uncertain | 0.944 | 0.355 | 0.000 | -14.800 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 4.15 | Destabilizing | 0.0 | 4.69 | Destabilizing | 4.42 | Destabilizing | 2.50 | Destabilizing | 0.800 | Likely Pathogenic | -7.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.98 | Benign | 0.00 | Affected | 0.3965 | 0.0200 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.2000T>C | I667T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I667T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.142424 | Structured | 0.083597 | Uncertain | 0.927 | 0.379 | 0.000 | -11.917 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 3.29 | Destabilizing | 0.1 | 2.44 | Destabilizing | 2.87 | Destabilizing | 2.23 | Destabilizing | 0.676 | Likely Pathogenic | -4.81 | Deleterious | 1.000 | Probably Damaging | 0.985 | Probably Damaging | 2.98 | Benign | 0.00 | Affected | 0.0967 | 0.0608 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.2001C>G | I667M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I667M 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, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy methods give AlphaMissense‑Optimized a benign prediction, SGM‑Consensus a pathogenic prediction (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta an uncertain result. Overall, the majority of evidence—including the high‑accuracy consensus—points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.142424 | Structured | 0.083597 | Uncertain | 0.927 | 0.379 | 0.000 | -10.679 | Likely Pathogenic | 0.579 | Likely Pathogenic | Likely Benign | 1.29 | Ambiguous | 0.3 | 1.68 | Ambiguous | 1.49 | Ambiguous | 0.92 | Ambiguous | 0.360 | Likely Benign | -2.90 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 2.98 | Benign | 0.00 | Affected | 0.0746 | 0.2612 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.3112A>T | T1038S 2D AIThe SynGAP1 missense variant T1038S 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 supports a benign classification, 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 | 0.938133 | Disordered | 0.982911 | Binding | 0.279 | 0.794 | 0.625 | -2.693 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -0.17 | Neutral | 0.649 | Possibly Damaging | 0.209 | Benign | 2.98 | Benign | 0.74 | Tolerated | 0.2879 | 0.4035 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3113C>G | T1038S 2D AIThe SynGAP1 missense variant T1038S 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 supports a benign classification, 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 | 0.938133 | Disordered | 0.982911 | Binding | 0.279 | 0.794 | 0.625 | -2.693 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -0.17 | Neutral | 0.649 | Possibly Damaging | 0.209 | Benign | 2.98 | Benign | 0.74 | Tolerated | 0.2879 | 0.4035 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.319A>G | R107G 2D AIThe SynGAP1 missense variant R107G is not 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, 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 from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a tie and thus unavailable, and Foldetta stability analysis is missing. Overall, the majority of tools (five benign vs. three pathogenic) suggest a benign impact, but the lack of consensus from the most accurate predictors means the variant’s effect remains uncertain. 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. | 0.666105 | Disordered | 0.663448 | Binding | 0.331 | 0.863 | 0.875 | -3.486 | Likely Benign | 0.948 | Likely Pathogenic | Ambiguous | 0.180 | Likely Benign | -3.15 | Deleterious | 0.421 | Benign | 0.050 | Benign | 2.98 | Benign | 0.00 | Affected | 0.3280 | 0.4000 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.320G>C | R107T 2D  AIThe SynGAP1 missense variant R107T is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign) and Foldetta results are unavailable. Overall, the majority of predictions (five benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.663448 | Binding | 0.331 | 0.863 | 0.875 | -2.902 | Likely Benign | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.191 | Likely Benign | -2.63 | Deleterious | 0.421 | Benign | 0.050 | Benign | 2.98 | Benign | 0.00 | Affected | 0.1549 | 0.4761 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3929C>T | T1310M 2D AIThe SynGAP1 missense variant T1310M is listed in ClinVar (ID 2160201.0) as Benign and is present in gnomAD (gnomAD ID 6‑33451803‑C‑T). All evaluated in‑silico predictors report a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign classification, which aligns with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 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 | 2.19 | Neutral | 0.021 | Benign | 0.005 | Benign | 2.98 | Benign | 0.93 | Tolerated | 3.77 | 5 | 0.1144 | 0.5397 | -1 | -1 | 2.6 | 30.09 | ||||||||||||||||||||||||||||||||
| c.1376G>T | G459V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G459V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; premPS is inconclusive and therefore not counted. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the consensus of these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for G459V. 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 | -13.606 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.79 | Destabilizing | 0.1 | 5.01 | Destabilizing | 4.40 | Destabilizing | 0.71 | Ambiguous | 0.605 | Likely Pathogenic | -8.46 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.99 | Benign | 0.00 | Affected | 0.0997 | 0.4240 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1474A>G | K492E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K492E is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. The remaining tools—REVEL, 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) reports it as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, which contradicts its current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | Conflicting | 2 | -16.175 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.53 | Ambiguous | 0.1 | 1.90 | Ambiguous | 1.72 | Ambiguous | 1.42 | Destabilizing | 0.510 | Likely Pathogenic | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.99 | Benign | 0.01 | Affected | 3.37 | 35 | 0.2968 | 0.0650 | 1 | 0 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.1874T>G | L625R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L625R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Based on the preponderance of evidence, 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 | GAP | 0.229226 | Structured | 0.045896 | Uncertain | 0.966 | 0.215 | 0.000 | -14.507 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 2.31 | Destabilizing | 0.7 | 4.21 | Destabilizing | 3.26 | Destabilizing | 1.88 | Destabilizing | 0.733 | Likely Pathogenic | -5.93 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.99 | Benign | 0.00 | Affected | 0.1091 | 0.0615 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1948A>G | N650D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Stability‑based methods (FoldX, Rosetta, premPS, Foldetta) yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the majority of available predictions support a pathogenic impact. The variant is most likely pathogenic based on the consensus of predictive tools, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -14.267 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 1.14 | Ambiguous | 0.3 | 0.61 | Ambiguous | 0.88 | Ambiguous | 0.91 | Ambiguous | 0.389 | Likely Benign | -4.98 | Deleterious | 0.591 | Possibly Damaging | 0.185 | Benign | 2.99 | Benign | 0.03 | Affected | 0.2320 | 0.2973 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.1955T>G | F652C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F652C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the change as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. No prediction is inconclusive or missing. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.098513 | Structured | 0.356594 | Uncertain | 0.966 | 0.338 | 0.000 | -12.023 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.27 | Destabilizing | 0.1 | 4.35 | Destabilizing | 3.81 | Destabilizing | 2.54 | Destabilizing | 0.695 | Likely Pathogenic | -7.74 | Deleterious | 1.000 | Probably Damaging | 0.983 | Probably Damaging | 2.99 | Benign | 0.00 | Affected | 0.2293 | 0.0783 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.2347A>C | M783L 2D AIThe SynGAP1 missense variant M783L 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 | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | -1.915 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.108 | Likely Benign | -0.48 | Neutral | 0.004 | Benign | 0.006 | Benign | 2.99 | Benign | 1.00 | Tolerated | 0.1727 | 0.4461 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2347A>T | M783L 2D AIThe SynGAP1 missense variant M783L 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 consensus methods reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability approach, has no available result for this variant. Overall, the collective evidence strongly supports a benign interpretation, and this conclusion is consistent with the lack of a ClinVar classification—there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | -1.915 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.110 | Likely Benign | -0.48 | Neutral | 0.004 | Benign | 0.006 | Benign | 2.99 | Benign | 1.00 | Tolerated | 0.1727 | 0.4461 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.321G>C | R107S 2D  AIThe SynGAP1 missense variant R107S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of predictions lean toward a benign impact, and this is not contradicted by any ClinVar annotation. Thus, the variant is most likely benign, although high‑accuracy tools provide conflicting evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.666105 | Disordered | 0.663448 | Binding | 0.331 | 0.863 | 0.875 | -1.162 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.147 | Likely Benign | -2.37 | Neutral | 0.231 | Benign | 0.037 | Benign | 2.99 | Benign | 0.00 | Affected | 0.2771 | 0.4148 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.321G>T | R107S 2D AIThe SynGAP1 missense variant R107S is 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 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of predictions lean toward a benign impact, but the high‑accuracy tools provide conflicting evidence. Thus, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.666105 | Disordered | 0.663448 | Binding | 0.331 | 0.863 | 0.875 | -1.162 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.147 | Likely Benign | -2.37 | Neutral | 0.231 | Benign | 0.037 | Benign | 2.99 | Benign | 0.00 | Affected | 0.2771 | 0.4148 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3925G>C | V1309L 2D AIThe SynGAP1 missense variant V1309L 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 trend: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.712013 | Disordered | 0.948596 | Binding | 0.402 | 0.907 | 0.750 | -2.543 | Likely Benign | 0.102 | Likely Benign | Likely Benign | 0.108 | Likely Benign | 1.41 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.99 | Benign | 1.00 | Tolerated | 0.0944 | 0.4212 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3925G>T | V1309L 2D AIThe SynGAP1 missense variant V1309L 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, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the computational evidence strongly supports a benign impact, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.712013 | Disordered | 0.948596 | Binding | 0.402 | 0.907 | 0.750 | -2.543 | Likely Benign | 0.102 | Likely Benign | Likely Benign | 0.108 | Likely Benign | 1.41 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.99 | Benign | 1.00 | Tolerated | 0.0944 | 0.4212 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1375G>T | G459C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G459C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the majority of algorithms (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. Uncertain or inconclusive results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence points to a pathogenic effect for G459C, 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 | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -12.109 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 2.46 | Destabilizing | 0.2 | 1.49 | Ambiguous | 1.98 | Ambiguous | 0.65 | Ambiguous | 0.586 | Likely Pathogenic | -8.46 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.00 | Benign | 0.00 | Affected | 0.0960 | 0.4103 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||
| c.2087T>A | L696H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L696H is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: all available predictors except FATHMM classify the variant as pathogenic (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized). Only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Taken together, the overwhelming majority of computational evidence supports a pathogenic classification, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.390093 | Uncertain | 0.962 | 0.267 | 0.000 | -17.042 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.56 | Destabilizing | 0.0 | 2.55 | Destabilizing | 2.56 | Destabilizing | 2.07 | Destabilizing | 0.569 | Likely Pathogenic | -6.58 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.00 | Benign | 0.00 | Affected | 0.1009 | 0.0488 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.2087T>C | L696P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L696P is listed in ClinVar as Pathogenic (ClinVar ID 1699350.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM; all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—report it as pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a pathogenic effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote) is pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a destabilizing, pathogenic outcome. Taken together, the overwhelming majority of predictions and the high‑accuracy tools classify the variant as pathogenic, fully consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.390093 | Uncertain | 0.962 | 0.267 | 0.000 | Likely Pathogenic | 1 | -16.926 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 6.66 | Destabilizing | 0.2 | 10.84 | Destabilizing | 8.75 | Destabilizing | 2.13 | Destabilizing | 0.678 | Likely Pathogenic | -6.58 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.00 | Benign | 0.00 | Affected | 3.46 | 13 | 0.3065 | 0.1995 | -3 | -3 | -5.4 | -16.04 | 180.6 | 65.9 | 0.1 | 0.0 | -0.6 | 0.1 | X | Potentially Pathogenic | The isobutyl side chain of Leu696, located in the middle of an α-helix (res. Leu685-Gln702), engages in hydrophobic packing with nearby residues (e.g., Leu441, Leu431, Leu692, Leu714) in the inter-helix space. Prolines lack a free amide group necessary for hydrogen bonding with the carbonyl group of Leu692 in the same manner as Leu696 in the WT. Consequently, the residue swap with proline disrupts the continuity of the secondary structure element in the variant simulations. Additionally, the side chain of Pro696 is not as optimal as Leu696 for hydrophobic packing in the inter-helix space. | ||||||||||||||||
| 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 | -2.29 | Neutral | 0.980 | Probably Damaging | 0.935 | Probably Damaging | 3.00 | Benign | 0.00 | Affected | 3.77 | 5 | 0.3451 | 0.5007 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.1873C>T | L625F 2D AIThe SynGAP1 missense variant L625F is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Tools that predict a pathogenic effect include SGM‑Consensus (Likely Pathogenic), Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are uncertain or inconclusive are FoldX, premPS, and Foldetta. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is Uncertain. Overall, the majority 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 | GAP | 0.229226 | Structured | 0.045896 | Uncertain | 0.966 | 0.215 | 0.000 | -12.989 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 1.70 | Ambiguous | 1.3 | 2.26 | Destabilizing | 1.98 | Ambiguous | 0.74 | Ambiguous | 0.479 | Likely Benign | -3.82 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.01 | Benign | 0.01 | Affected | 0.0586 | 0.2998 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1948A>C | N650H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650H 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 predict a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, FoldX, and the SGM‑Consensus (majority vote). Uncertain or inconclusive results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments: AlphaMissense‑Optimized predicts pathogenicity; the SGM‑Consensus also indicates likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Based on the preponderance of pathogenic predictions and the high‑accuracy tools’ results, the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -14.187 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 2.14 | Destabilizing | 0.3 | 1.79 | Ambiguous | 1.97 | Ambiguous | 0.55 | Ambiguous | 0.465 | Likely Benign | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.929 | Probably Damaging | 3.01 | Benign | 0.05 | Affected | 0.1990 | 0.4784 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.2087T>G | L696R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L696R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: all available predictors except FATHMM (which flags it as benign) report pathogenicity. The benign group contains only FATHMM; the pathogenic group includes SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.390093 | Uncertain | 0.962 | 0.267 | 0.000 | -19.609 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.67 | Destabilizing | 0.0 | 5.36 | Destabilizing | 4.52 | Destabilizing | 2.44 | Destabilizing | 0.624 | Likely Pathogenic | -5.68 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.01 | Benign | 0.00 | Affected | 0.1200 | 0.0688 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2221C>G | P741A 2D AIThe SynGAP1 missense variant P741A 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, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” while 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 (none is available). 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 | -3.995 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -0.33 | Neutral | 0.425 | Benign | 0.136 | Benign | 3.01 | Benign | 0.98 | Tolerated | 0.2942 | 0.3883 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.1949A>T | N650I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N650I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, Rosetta, Foldetta, premPS, and FATHMM; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX reports an uncertain outcome. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the balance of evidence favors a pathogenic effect for the variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -15.940 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.50 | Ambiguous | 0.2 | 0.21 | Likely Benign | 0.36 | Likely Benign | 0.21 | Likely Benign | 0.485 | Likely Benign | -8.97 | Deleterious | 0.999 | Probably Damaging | 0.955 | Probably Damaging | 3.02 | Benign | 0.00 | Affected | 0.0907 | 0.4339 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.1950T>A | N650K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N650K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, Foldetta, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta and premPS. High‑accuracy assessments give a pathogenic verdict from AlphaMissense‑Optimized and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), while Foldetta predicts a benign effect on protein stability. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -13.078 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.33 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.17 | Likely Benign | 0.92 | Ambiguous | 0.269 | Likely Benign | -5.98 | Deleterious | 0.995 | Probably Damaging | 0.807 | Possibly Damaging | 3.02 | Benign | 0.03 | Affected | 3.37 | 30 | 0.3028 | 0.3360 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||
| c.1950T>G | N650K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650K is not reported in ClinVar and is present in gnomAD (ID 6‑33441209‑T‑G). Prediction tools that indicate a benign effect include REVEL, FoldX, FATHMM, and Foldetta, whereas a majority of tools predict pathogenicity: SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (premPS and Rosetta) give uncertain results. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of predictions lean toward pathogenicity, indicating the variant is most likely pathogenic, and this is consistent with the lack of a ClinVar entry; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | 6-33441209-T-G | -13.078 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.33 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.17 | Likely Benign | 0.92 | Ambiguous | 0.269 | Likely Benign | -5.98 | Deleterious | 0.995 | Probably Damaging | 0.807 | Possibly Damaging | 3.02 | Benign | 0.03 | Affected | 3.37 | 30 | 0.3028 | 0.3360 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||
| c.1987T>G | F663V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all indicate pathogenicity, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the change as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. No predictions are missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.056825 | Structured | 0.093963 | Uncertain | 0.944 | 0.355 | 0.000 | -14.196 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 3.04 | Destabilizing | 0.1 | 3.31 | Destabilizing | 3.18 | Destabilizing | 1.75 | Destabilizing | 0.655 | Likely Pathogenic | -6.98 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 3.02 | Benign | 0.00 | Affected | 0.1844 | 0.1983 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.3994A>G | T1332A 2D AIThe SynGAP1 missense variant T1332A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized 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 results are unavailable. Overall, the majority of available predictions (five pathogenic vs. three benign) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.948427 | Binding | 0.442 | 0.754 | 0.875 | -3.521 | Likely Benign | 0.887 | Likely Pathogenic | Ambiguous | 0.150 | Likely Benign | -2.85 | Deleterious | 0.953 | Possibly Damaging | 0.935 | Probably Damaging | 3.02 | Benign | 0.00 | Affected | 0.4042 | 0.4766 | 1 | 0 | 2.5 | -30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.1250A>T | Y417F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 Y417F variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM. Those that predict a pathogenic impact are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results come from AlphaMissense‑Optimized and premPS. High‑accuracy assessments show SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, Foldetta (combining FoldX‑MD and Rosetta) as Benign, and AlphaMissense‑Optimized as Uncertain. Overall, the majority of tools and the SGM‑Consensus score suggest a pathogenic effect, while Foldetta indicates a benign effect; the variant’s status is not contradicted by ClinVar (no entry). Thus, based on the available predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.346865 | Uncertain | 0.958 | 0.250 | 0.000 | -11.368 | Likely Pathogenic | 0.852 | Likely Pathogenic | Ambiguous | 0.47 | Likely Benign | 0.1 | -0.09 | Likely Benign | 0.19 | Likely Benign | 0.97 | Ambiguous | 0.367 | Likely Benign | -3.82 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 3.03 | Benign | 0.06 | Tolerated | 0.2617 | 0.3098 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||
| c.1877T>A | I626N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I626N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods further support this: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the unanimous agreement of the majority of tools and the corroborating high‑accuracy 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 | 0.109221 | Structured | 0.040732 | Uncertain | 0.970 | 0.223 | 0.000 | -15.240 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.49 | Destabilizing | 0.1 | 3.56 | Destabilizing | 3.53 | Destabilizing | 2.36 | Destabilizing | 0.621 | Likely Pathogenic | -6.41 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.03 | Benign | 0.00 | Affected | 0.0880 | 0.0270 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.1948A>T | N650Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX, Rosetta, and Foldetta are inconclusive. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, and Foldetta remains uncertain. Overall, the evidence strongly favors a pathogenic classification for the variant, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this mutation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -16.923 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.56 | Ambiguous | 0.3 | 1.32 | Ambiguous | 1.44 | Ambiguous | 0.16 | Likely Benign | 0.587 | Likely Pathogenic | -7.98 | Deleterious | 1.000 | Probably Damaging | 0.984 | Probably Damaging | 3.03 | Benign | 0.03 | Affected | 0.0852 | 0.3865 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.2257G>T | A753S 2D AIThe SynGAP1 missense variant A753S is reported as “Likely Benign” in ClinVar and is not present in gnomAD. 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 classify the change as benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. Foldetta results are unavailable. Overall, the variant is most likely benign, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.722781 | Binding | 0.381 | 0.873 | 0.625 | -3.656 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.105 | Likely Benign | 0.25 | Neutral | 0.062 | Benign | 0.015 | Benign | 3.03 | Benign | 0.59 | Tolerated | 0.2905 | 0.5899 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.2341A>G | M781V 2D AIThe SynGAP1 missense variant M781V is catalogued in gnomAD (ID 6‑33442893‑A‑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, was not available for this variant. Overall, the evidence overwhelmingly supports a benign effect, and this conclusion does not contradict any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.580690 | Disordered | 0.792850 | Binding | 0.342 | 0.889 | 0.625 | 6-33442893-A-G | 4 | 2.48e-6 | -2.624 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.174 | Likely Benign | 0.00 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.03 | Benign | 0.90 | Tolerated | 3.64 | 6 | 0.3081 | 0.2705 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||||||
| c.2791C>G | L931V 2D AIThe SynGAP1 missense variant L931V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for the L931V variant, and this conclusion does not contradict any ClinVar annotation, as none exists for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.989212 | Binding | 0.335 | 0.856 | 0.375 | -1.512 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.182 | Likely Benign | 0.71 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 3.03 | Benign | 0.70 | Tolerated | 0.1690 | 0.3164 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2800A>C | M934L 2D AIThe SynGAP1 missense variant M934L 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. Overall, the consensus of all available predictions points to a benign impact, and this is consistent with the lack of a ClinVar classification—there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.984677 | Binding | 0.290 | 0.867 | 0.625 | -2.482 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -0.73 | Neutral | 0.002 | Benign | 0.002 | Benign | 3.03 | Benign | 0.68 | Tolerated | 0.2004 | 0.4051 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2800A>T | M934L 2D AIThe SynGAP1 missense variant M934L 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 | 0.762850 | Disordered | 0.984677 | Binding | 0.290 | 0.867 | 0.625 | -2.482 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -0.73 | Neutral | 0.002 | Benign | 0.002 | Benign | 3.03 | Benign | 0.68 | Tolerated | 0.2004 | 0.4051 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3758C>A | A1253E 2D  AIThe SynGAP1 missense variant A1253E 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 predicts pathogenicity. High‑accuracy assessments corroborate this benign classification: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.661982 | Disordered | 0.391377 | Uncertain | 0.881 | 0.550 | 0.750 | -1.744 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.059 | Likely Benign | 2.03 | Neutral | 0.301 | Benign | 0.209 | Benign | 3.03 | Benign | 0.98 | Tolerated | 0.0948 | 0.1704 | 0 | -1 | -5.3 | 58.04 | ||||||||||||||||||||||||||||||||||||||
| c.3910C>T | P1304S 2D AIThe SynGAP1 missense variant P1304S is reported in gnomAD (ID 6‑33451784‑C‑T) 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 predict a benign effect. No tool in the dataset indicates 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 collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is provided). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | 6-33451784-C-T | 1 | 6.20e-7 | -4.103 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.039 | Likely Benign | 0.36 | Neutral | 0.059 | Benign | 0.041 | Benign | 3.03 | Benign | 0.58 | Tolerated | 3.77 | 5 | 0.2900 | 0.4442 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.1291C>G | L431V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L431V 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, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are FoldX, premPS, PROVEAN, and polyPhen‑2 HumDiv. Four tools (Rosetta, Foldetta, ESM1b, AlphaMissense‑Default) give uncertain or inconclusive results. 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 1‑to‑1 split between benign and pathogenic signals, and Foldetta also yields an uncertain outcome. Overall, the balance of evidence—including the higher number of benign predictions and the benign call from the most accurate tool—suggests that the variant is most likely benign. 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. | GAP | 0.094817 | Structured | 0.374755 | Uncertain | 0.959 | 0.300 | 0.000 | -7.949 | In-Between | 0.505 | Ambiguous | Likely Benign | 2.17 | Destabilizing | 0.0 | 1.50 | Ambiguous | 1.84 | Ambiguous | 1.32 | Destabilizing | 0.093 | Likely Benign | -2.58 | Deleterious | 0.861 | Possibly Damaging | 0.332 | Benign | 3.04 | Benign | 0.20 | Tolerated | 0.1377 | 0.3198 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||
| c.1777C>G | L593V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L593V 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Uncertain or inconclusive results come from Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments: AlphaMissense‑Optimized classifies the variant as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic prediction; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. Overall, the majority of evidence (six pathogenic vs. four benign) points to a pathogenic effect. 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 | 0.009728 | Structured | 0.110534 | Uncertain | 0.941 | 0.151 | 0.000 | -10.327 | Likely Pathogenic | 0.551 | Ambiguous | Likely Benign | 2.81 | Destabilizing | 0.2 | 1.10 | Ambiguous | 1.96 | Ambiguous | 1.39 | Destabilizing | 0.268 | Likely Benign | -2.59 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 3.04 | Benign | 0.12 | Tolerated | 0.1599 | 0.3577 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||
| c.1877T>C | I626T 2D AISynGAP1 missense variant I626T is listed in ClinVar with an uncertain significance (ClinVar ID 3359331.0) and is not reported in gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions are returned by REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a benign outcome, while AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Overall, the consensus of the majority of tools points to a pathogenic effect, contradicting the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.109221 | Structured | 0.040732 | Uncertain | 0.970 | 0.223 | 0.000 | Uncertain | 1 | -10.420 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 2.94 | Destabilizing | 0.1 | 2.70 | Destabilizing | 2.82 | Destabilizing | 2.23 | Destabilizing | 0.640 | Likely Pathogenic | -4.18 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.04 | Benign | 0.00 | Affected | 0.1000 | 0.0840 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||
| c.1877T>G | I626S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I626S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) 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 because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.109221 | Structured | 0.040732 | Uncertain | 0.970 | 0.223 | 0.000 | -14.449 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 3.80 | Destabilizing | 0.0 | 4.54 | Destabilizing | 4.17 | Destabilizing | 2.16 | Destabilizing | 0.706 | Likely Pathogenic | -5.41 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.04 | Benign | 0.00 | Affected | 0.2308 | 0.0858 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1949A>C | N650T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650T is not 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, and FATHMM, whereas a larger group predicts pathogenicity: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results come from Foldetta, premPS, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -13.626 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.31 | Likely Benign | 0.1 | 0.73 | Ambiguous | 0.52 | Ambiguous | 0.69 | Ambiguous | 0.471 | Likely Benign | -5.98 | Deleterious | 0.986 | Probably Damaging | 0.710 | Possibly Damaging | 3.04 | Benign | 0.01 | Affected | 0.1700 | 0.4843 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| 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 | 0.84 | Neutral | 0.983 | Probably Damaging | 0.828 | Possibly Damaging | 3.04 | Benign | 1.00 | Tolerated | 0.2033 | 0.5022 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3986T>C | L1329P 2D AIThe SynGAP1 missense variant L1329P is listed in gnomAD (ID 6‑33451860‑T‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and FATHMM, while pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a tie and is therefore inconclusive. No Foldetta stability assessment is available. Overall, the majority of high‑confidence predictors (five pathogenic vs three benign) lean toward a pathogenic effect. Because ClinVar contains no classification, there is no conflict with existing clinical annotation. Thus, based on current in silico evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.924905 | Binding | 0.336 | 0.748 | 0.875 | 6-33451860-T-C | -2.903 | Likely Benign | 0.951 | Likely Pathogenic | Ambiguous | 0.165 | Likely Benign | -3.74 | Deleterious | 0.994 | Probably Damaging | 0.993 | Probably Damaging | 3.04 | Benign | 0.00 | Affected | 3.77 | 5 | 0.3396 | 0.1794 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||
| 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 | -0.04 | Likely Benign | 0.5 | 1.15 | Ambiguous | 0.56 | Ambiguous | 0.31 | Likely Benign | 0.686 | Likely Pathogenic | -5.78 | Deleterious | 0.998 | Probably Damaging | 0.948 | Probably Damaging | 3.05 | Benign | 0.02 | Affected | 0.0975 | 0.5025 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||
| c.1916T>G | F639C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F639C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, and ESM1b all indicate pathogenicity, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the change as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. No predictions are missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.117665 | Uncertain | 0.942 | 0.284 | 0.000 | -12.532 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 4.02 | Destabilizing | 0.2 | 2.80 | Destabilizing | 3.41 | Destabilizing | 1.38 | Destabilizing | 0.615 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 0.935 | Probably Damaging | 3.05 | Benign | 0.01 | Affected | 0.2451 | 0.0783 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1954T>G | F652V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F652V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, whereas only FATHMM predicts a benign outcome. The high‑accuracy subset confirms this trend: AlphaMissense‑Optimized is pathogenic; SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic, 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 | GAP | 0.098513 | Structured | 0.356594 | Uncertain | 0.966 | 0.338 | 0.000 | -11.576 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 2.66 | Destabilizing | 0.1 | 3.21 | Destabilizing | 2.94 | Destabilizing | 1.49 | Destabilizing | 0.595 | Likely Pathogenic | -6.71 | Deleterious | 0.995 | Probably Damaging | 0.885 | Possibly Damaging | 3.05 | Benign | 0.00 | Affected | 0.1656 | 0.1783 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.1955T>C | F652S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F652S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) 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 because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.098513 | Structured | 0.356594 | Uncertain | 0.966 | 0.338 | 0.000 | -13.679 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.16 | Destabilizing | 0.2 | 4.92 | Destabilizing | 4.04 | Destabilizing | 2.16 | Destabilizing | 0.665 | Likely Pathogenic | -7.78 | Deleterious | 1.000 | Probably Damaging | 0.948 | Probably Damaging | 3.05 | Benign | 0.00 | Affected | 0.3777 | 0.0200 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1992G>C | L664F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664F resides in the GAP domain. ClinVar lists no entry for this variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Those that predict a pathogenic effect include SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are uncertain (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the majority of available predictions support a pathogenic impact. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.089318 | Uncertain | 0.937 | 0.339 | 0.000 | -12.834 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 1.98 | Ambiguous | 0.3 | 1.03 | Ambiguous | 1.51 | Ambiguous | 0.55 | Ambiguous | 0.355 | Likely Benign | -3.99 | Deleterious | 0.999 | Probably Damaging | 0.895 | Possibly Damaging | 3.05 | Benign | 0.03 | Affected | 0.0537 | 0.2311 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1992G>T | L664F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664F resides in the GAP domain. ClinVar lists no entry for this variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Those that predict a pathogenic effect include SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are uncertain (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the majority of available predictions support a pathogenic impact. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.089318 | Uncertain | 0.937 | 0.339 | 0.000 | -12.834 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 1.98 | Ambiguous | 0.3 | 1.03 | Ambiguous | 1.51 | Ambiguous | 0.55 | Ambiguous | 0.355 | Likely Benign | -3.99 | Deleterious | 0.999 | Probably Damaging | 0.895 | Possibly Damaging | 3.05 | Benign | 0.03 | Affected | 0.0537 | 0.2311 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.2086C>T | L696F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L696F has no ClinVar entry and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. 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 | 0.200174 | Structured | 0.390093 | Uncertain | 0.962 | 0.267 | 0.000 | -9.651 | Likely Pathogenic | 0.897 | Likely Pathogenic | Ambiguous | 0.14 | Likely Benign | 0.1 | 0.74 | Ambiguous | 0.44 | Likely Benign | 0.55 | Ambiguous | 0.422 | Likely Benign | -3.79 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.05 | Benign | 0.00 | Affected | 0.0667 | 0.2008 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.2500A>C | M834L 2D AIThe SynGAP1 missense variant M834L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -1.926 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -0.97 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.05 | Benign | 0.00 | Affected | 0.1087 | 0.3331 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2500A>T | M834L 2D AIThe SynGAP1 missense variant M834L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.585406 | Disordered | 0.640801 | Binding | 0.258 | 0.863 | 0.375 | -1.926 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -0.97 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.05 | Benign | 0.00 | Affected | 0.1087 | 0.3331 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.2821C>T | P941S 2D AIThe SynGAP1 missense variant P941S is reported in gnomAD (ID 6‑33443373‑C‑T) 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 return benign scores. 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, which evaluates protein‑folding stability via FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of all available predictions indicates that P941S 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 | 0.874069 | Disordered | 0.900790 | Binding | 0.403 | 0.906 | 0.625 | 6-33443373-C-T | 1 | 6.20e-7 | -5.099 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.039 | Likely Benign | 0.58 | Neutral | 0.036 | Benign | 0.039 | Benign | 3.05 | Benign | 0.95 | Tolerated | 4.32 | 4 | 0.2759 | 0.5576 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3901C>G | P1301A 2D AIThe SynGAP1 missense variant P1301A is catalogued in gnomAD (ID 6‑33451775‑C‑G) 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 tolerated or benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely benign. Foldetta, a protein‑folding stability predictor, was not available for this residue. Overall, the consensus of all available predictions is benign, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | 6-33451775-C-G | 1 | 6.20e-7 | -4.290 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.088 | Likely Benign | 0.66 | Neutral | 0.003 | Benign | 0.012 | Benign | 3.05 | Benign | 0.88 | Tolerated | 3.77 | 5 | 0.2850 | 0.3087 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.3986T>A | L1329Q 2D AIThe SynGAP1 missense variant L1329Q is reported in gnomAD (ID 6‑33451860‑T‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, 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, PROVEAN) is inconclusive, and Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a deleterious effect, indicating that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.924905 | Binding | 0.336 | 0.748 | 0.875 | 6-33451860-T-A | -4.106 | Likely Benign | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.157 | Likely Benign | -3.31 | Deleterious | 0.994 | Probably Damaging | 0.993 | Probably Damaging | 3.05 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1382 | 0.1505 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||
| c.3986T>G | L1329R 2D AIThe SynGAP1 missense variant L1329R is catalogued in gnomAD (ID 6‑33451860‑T‑G) but has no ClinVar submission. Functional prediction tools cluster into two groups: benign predictions from REVEL, ESM1b, and FATHMM; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized returns an uncertain result. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive due to a 2‑to‑2 split. No Foldetta stability assessment is available. Overall, the majority of high‑confidence predictors (five pathogenic vs three benign) lean toward a pathogenic effect. Because ClinVar contains no classification, there is no conflict with existing clinical annotations. Thus, based on current in silico evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.930790 | Disordered | 0.924905 | Binding | 0.336 | 0.748 | 0.875 | 6-33451860-T-G | -3.636 | Likely Benign | 0.923 | Likely Pathogenic | Ambiguous | 0.141 | Likely Benign | -3.16 | Deleterious | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 3.05 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1594 | 0.1547 | -2 | -3 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||
| 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 | 2.44 | Destabilizing | 0.1 | 0.90 | Ambiguous | 1.67 | Ambiguous | 0.72 | Ambiguous | 0.469 | Likely Benign | -5.63 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 3.06 | Benign | 0.01 | Affected | 0.3529 | 0.5161 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1873C>A | L625I 2D  AIThe SynGAP1 missense variant L625I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas a majority of tools (premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Tools with uncertain or inconclusive results—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Consequently, the overall evidence leans toward pathogenicity, 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. | GAP | 0.229226 | Structured | 0.045896 | Uncertain | 0.966 | 0.215 | 0.000 | -11.713 | Likely Pathogenic | 0.866 | Likely Pathogenic | Ambiguous | 0.75 | Ambiguous | 0.6 | 0.72 | Ambiguous | 0.74 | Ambiguous | 1.09 | Destabilizing | 0.412 | Likely Benign | -1.96 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.06 | Benign | 0.01 | Affected | 0.0864 | 0.3588 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1878T>G | I626M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I626M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and premPS give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic; Foldetta’s stability prediction is uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.109221 | Structured | 0.040732 | Uncertain | 0.970 | 0.223 | 0.000 | -11.407 | Likely Pathogenic | 0.618 | Likely Pathogenic | Likely Benign | 0.72 | Ambiguous | 0.1 | 1.78 | Ambiguous | 1.25 | Ambiguous | 0.92 | Ambiguous | 0.405 | Likely Benign | -2.76 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.06 | Benign | 0.02 | Affected | 0.0661 | 0.1959 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.1886T>A | V629D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V629D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all return pathogenic or likely pathogenic calls, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized indicates pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) predicts pathogenic. No predictions are 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 | 0.040537 | Structured | 0.034796 | Uncertain | 0.970 | 0.236 | 0.000 | -17.143 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 3.85 | Destabilizing | 0.1 | 3.82 | Destabilizing | 3.84 | Destabilizing | 2.17 | Destabilizing | 0.713 | Likely Pathogenic | -6.37 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.06 | Benign | 0.00 | Affected | 0.1284 | 0.0541 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||
| c.1904A>G | N635S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N635S is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6-33440956-A-G). Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and ESM1b. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Overall, the majority of available predictions lean toward a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | Conflicting | 4 | 6-33440956-A-G | 10 | 6.20e-6 | -9.002 | Likely Pathogenic | 0.101 | Likely Benign | Likely Benign | 0.80 | Ambiguous | 0.1 | 0.67 | Ambiguous | 0.74 | Ambiguous | 0.95 | Ambiguous | 0.104 | Likely Benign | -4.45 | Deleterious | 0.261 | Benign | 0.044 | Benign | 3.06 | Benign | 0.05 | Affected | 3.37 | 34 | 0.2816 | 0.4279 | 1 | 1 | 2.7 | -27.03 | 196.0 | 30.9 | 0.1 | 0.0 | -0.3 | 0.2 | X | Uncertain | In the WT simulations, the carboxamide side chain of Asn635, located on the outer surface of an α helix (res. Glu617-Asn635), forms hydrogen bonds with Gln631 on the same α helix and with the hydroxyl side chain of Ser590 on an opposing α helix (res. Glu582-Met603).In the variant simulations, the side chain of Ser635 is shorter than asparagine and thus prefers to hydrogen bond with the carbonyl group of Gln631 on the same helix and, to a lesser extent, with Ser590 compared to Asn635 in the WT. Ser635 forms hydrogen bonds with the backbone atoms of the same helix, which may destabilize the helix, although this is not clearly evident in the simulations. The weakening of the hydrogen bond between Ser635 and Ser590 in the variant may also weaken the tertiary structure assembly between the helices.Additionally, Asn635 is at the GTPase interface. However, the implication of the residue swap on the complex formation with the GTPase cannot be investigated using solvent-only simulations. | ||||||||||||||
| c.1916T>A | F639Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F639Y is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions are returned by SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments give a mixed signal: AlphaMissense‑Optimized classifies the change as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the balance of evidence leans toward pathogenicity, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.117665 | Uncertain | 0.942 | 0.284 | 0.000 | -11.762 | Likely Pathogenic | 0.670 | Likely Pathogenic | Likely Benign | 1.92 | Ambiguous | 0.1 | 0.99 | Ambiguous | 1.46 | Ambiguous | 1.20 | Destabilizing | 0.330 | Likely Benign | -2.99 | Deleterious | 0.930 | Possibly Damaging | 0.263 | Benign | 3.06 | Benign | 0.03 | Affected | 0.1530 | 0.1635 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.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 | 0.79 | Ambiguous | 0.2 | 1.43 | Ambiguous | 1.11 | Ambiguous | 0.77 | Ambiguous | 0.395 | Likely Benign | -4.98 | Deleterious | 0.996 | Probably Damaging | 0.606 | Possibly Damaging | 3.06 | Benign | 0.02 | Affected | 0.3791 | 0.5090 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||
| c.1954T>A | F652I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F652I 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 give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No prediction or stability assessment is missing or inconclusive. Based on the consensus of the available tools, 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 | 0.098513 | Structured | 0.356594 | Uncertain | 0.966 | 0.338 | 0.000 | -12.085 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 2.15 | Destabilizing | 0.1 | 3.40 | Destabilizing | 2.78 | Destabilizing | 1.40 | Destabilizing | 0.574 | Likely Pathogenic | -5.71 | Deleterious | 0.996 | Probably Damaging | 0.776 | Possibly Damaging | 3.06 | Benign | 0.00 | Affected | 0.1553 | 0.1955 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1987T>A | F663I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is 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 no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.056825 | Structured | 0.093963 | Uncertain | 0.944 | 0.355 | 0.000 | -15.006 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 2.63 | Destabilizing | 0.1 | 4.51 | Destabilizing | 3.57 | Destabilizing | 1.60 | Destabilizing | 0.641 | Likely Pathogenic | -5.99 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.06 | Benign | 0.00 | Affected | 0.1740 | 0.1955 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.2075T>A | L692Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L692Q is listed in ClinVar as Pathogenic (ClinVar ID 2714634.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; 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 pathogenic. No prediction or stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.295225 | Uncertain | 0.966 | 0.243 | 0.000 | Pathogenic | 1 | -13.873 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.24 | Destabilizing | 0.1 | 3.27 | Destabilizing | 3.26 | Destabilizing | 2.76 | Destabilizing | 0.596 | Likely Pathogenic | -5.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.06 | Benign | 0.00 | Affected | 3.42 | 17 | 0.1079 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.2075T>C | L692P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L692P is listed in ClinVar with an “Uncertain” status (ClinVar ID 847082.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining tools (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 assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.295225 | Uncertain | 0.966 | 0.243 | 0.000 | Uncertain | 1 | -16.447 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 9.19 | Destabilizing | 0.1 | 13.20 | Destabilizing | 11.20 | Destabilizing | 1.69 | Destabilizing | 0.668 | Likely Pathogenic | -6.98 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.06 | Benign | 0.00 | Affected | 3.42 | 17 | 0.3642 | 0.1025 | -3 | -3 | -5.4 | -16.04 | 186.2 | 62.8 | -0.2 | 0.1 | -0.7 | 0.3 | X | Potentially Pathogenic | The isobutyl side chain of Leu692, located in the middle of an α-helix (res. Leu685-Gln702), engages in hydrophobic packing with nearby residues (e.g., Leu441, Leu431, Leu696) in the inter-helix space. Prolines lack a free amide group necessary for hydrogen bonding with the carbonyl group of Glu688 in the same manner as Leu692 in the WT. Consequently, the residue swap with proline disrupts the continuity of the secondary structure element in the variant simulations. Additionally, the side chain of Pro692 is not as optimal as Leu692 for hydrophobic packing in the inter-helix space. | ||||||||||||||||
| 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 | -0.35 | Neutral | 0.011 | Benign | 0.017 | Benign | 3.06 | Benign | 1.00 | Tolerated | 0.1487 | 0.5474 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.1376G>A | G459D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G459D is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate benign effects include REVEL and FATHMM, while the majority of tools predict pathogenicity: FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as inconclusive. Overall, the evidence points to a pathogenic effect for G459D, and this conclusion does not conflict with the current ClinVar status. 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 | -11.258 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 2.21 | Destabilizing | 0.1 | 0.56 | Ambiguous | 1.39 | Ambiguous | 0.93 | Ambiguous | 0.454 | Likely Benign | -6.18 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.07 | Benign | 0.05 | Affected | 0.1466 | 0.1905 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.1811C>G | S604W 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant S604W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Benign predictions are provided by Rosetta, premPS, and FATHMM. Stability‑based methods give mixed results: FoldX is uncertain, while Foldetta is also uncertain. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors pathogenic. Foldetta remains inconclusive. Overall, the consensus of the majority of tools indicates a pathogenic 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. | Likely Pathogenic | GAP | 0.010926 | Structured | 0.192527 | Uncertain | 0.911 | 0.195 | 0.000 | -19.117 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -1.23 | Ambiguous | 0.1 | -2.05 | Stabilizing | -1.64 | Ambiguous | -0.19 | Likely Benign | 0.645 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.07 | Benign | 0.00 | Affected | 0.0818 | 0.4602 | -2 | -3 | -0.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1873C>G | L625V 2D AISynGAP1 missense variant L625V is listed in ClinVar with an uncertain significance (ClinVar ID 3392716.0) 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 premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic effect, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.045896 | Uncertain | 0.966 | 0.215 | 0.000 | Uncertain | 1 | -11.319 | Likely Pathogenic | 0.833 | Likely Pathogenic | Ambiguous | 1.80 | Ambiguous | 0.7 | 1.69 | Ambiguous | 1.75 | Ambiguous | 1.42 | Destabilizing | 0.480 | Likely Benign | -2.96 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 3.07 | Benign | 0.01 | Affected | 0.1306 | 0.3427 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||
| c.1876A>T | I626F 2D 3DClick to see structure in 3D Viewer AISynGAP1 I626F is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM‑Consensus (derived from a majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Taken together, the overwhelming majority of evidence indicates that I626F is 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 | 0.109221 | Structured | 0.040732 | Uncertain | 0.970 | 0.223 | 0.000 | -14.483 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 4.37 | Destabilizing | 0.3 | 2.12 | Destabilizing | 3.25 | Destabilizing | 0.66 | Ambiguous | 0.631 | Likely Pathogenic | -3.78 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.07 | Benign | 0.00 | Affected | 0.0481 | 0.1964 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.1885G>T | V629F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V629F is 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 is not counted as evidence. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta is pathogenic. No prediction is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions and the absence of any ClinVar annotation, the variant is most likely pathogenic, with no contradiction from ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.034796 | Uncertain | 0.970 | 0.236 | 0.000 | -13.484 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 3.41 | Destabilizing | 0.5 | 4.40 | Destabilizing | 3.91 | Destabilizing | 0.64 | Ambiguous | 0.642 | Likely Pathogenic | -4.68 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.07 | Benign | 0.00 | Affected | 0.0560 | 0.2915 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||
| c.1886T>G | V629G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 V629G 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 only FATHMM, whereas the remaining eleven tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) uniformly predict a pathogenic outcome; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support pathogenicity: 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. Taken together, the overwhelming majority of evidence indicates that V629G is likely pathogenic, 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. | GAP | 0.040537 | Structured | 0.034796 | Uncertain | 0.970 | 0.236 | 0.000 | -13.150 | Likely Pathogenic | 0.871 | Likely Pathogenic | Ambiguous | 3.81 | Destabilizing | 0.0 | 4.52 | Destabilizing | 4.17 | Destabilizing | 1.94 | Destabilizing | 0.678 | Likely Pathogenic | -6.47 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.07 | Benign | 0.00 | Affected | 0.1903 | 0.2240 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1987T>C | F663L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663L is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, which scores the variant as benign. All other evaluated algorithms—SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenicity, while Foldetta’s stability analysis is inconclusive and therefore unavailable. FoldX and Foldetta are treated as unavailable due to uncertain outputs. Based on the overwhelming agreement among pathogenic predictors and the lack of benign evidence, the variant is most likely pathogenic, 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 Pathogenic | GAP | 0.056825 | Structured | 0.093963 | Uncertain | 0.944 | 0.355 | 0.000 | -11.996 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.91 | Ambiguous | 0.1 | 2.01 | Destabilizing | 1.46 | Ambiguous | 1.51 | Destabilizing | 0.540 | Likely Pathogenic | -5.99 | Deleterious | 0.999 | Probably Damaging | 0.976 | Probably Damaging | 3.07 | Benign | 0.01 | Affected | 0.1973 | 0.2936 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1989T>A | F663L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors (PolyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM Consensus, premPS, and Rosetta) indicate a pathogenic impact. FoldX‑MD and Rosetta‑based stability calculations are inconclusive, yielding an uncertain Foldetta result. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence from consensus and high‑accuracy tools points to a pathogenic effect for F663L. 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 | GAP | 0.056825 | Structured | 0.093963 | Uncertain | 0.944 | 0.355 | 0.000 | -11.996 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.91 | Ambiguous | 0.1 | 2.01 | Destabilizing | 1.46 | Ambiguous | 1.51 | Destabilizing | 0.423 | Likely Benign | -5.99 | Deleterious | 0.999 | Probably Damaging | 0.976 | Probably Damaging | 3.07 | Benign | 0.01 | Affected | 0.1973 | 0.2936 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1989T>G | F663L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors (PolyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, premPS, and the SGM Consensus) indicate a pathogenic impact. FoldX‑MD and Rosetta give conflicting stability results, with FoldX uncertain and Rosetta pathogenic; Foldetta, which integrates both, is also uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for F663L. 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 | GAP | 0.056825 | Structured | 0.093963 | Uncertain | 0.944 | 0.355 | 0.000 | -11.996 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.91 | Ambiguous | 0.1 | 2.01 | Destabilizing | 1.46 | Ambiguous | 1.51 | Destabilizing | 0.423 | Likely Benign | -5.99 | Deleterious | 0.999 | Probably Damaging | 0.976 | Probably Damaging | 3.07 | Benign | 0.01 | Affected | 0.1973 | 0.2936 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.2074C>A | L692M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L692M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, 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 (2 vs 2) and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Thus, the overall evidence slightly favors pathogenicity, with a majority of standard tools predicting a deleterious impact. The variant is most likely pathogenic based on current predictions, and this assessment does not contradict the ClinVar status, which has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.064632 | Structured | 0.295225 | Uncertain | 0.966 | 0.243 | 0.000 | -9.659 | Likely Pathogenic | 0.746 | Likely Pathogenic | Likely Benign | 0.49 | Likely Benign | 0.0 | 1.81 | Ambiguous | 1.15 | Ambiguous | 1.01 | Destabilizing | 0.302 | Likely Benign | -1.99 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.07 | Benign | 0.01 | Affected | 0.0754 | 0.2585 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.2075T>G | L692R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L692R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.295225 | Uncertain | 0.966 | 0.243 | 0.000 | -16.656 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.34 | Destabilizing | 0.0 | 5.51 | Destabilizing | 4.93 | Destabilizing | 1.96 | Destabilizing | 0.611 | Likely Pathogenic | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.895 | Possibly Damaging | 3.07 | Benign | 0.00 | Affected | 0.1204 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.320G>A | R107K 2D AIThe SynGAP1 missense variant R107K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for R107K, 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 | 0.666105 | Disordered | 0.663448 | Binding | 0.331 | 0.863 | 0.875 | -3.941 | Likely Benign | 0.758 | Likely Pathogenic | Likely Benign | 0.153 | Likely Benign | -1.33 | Neutral | 0.004 | Benign | 0.001 | Benign | 3.07 | Benign | 0.00 | Affected | 0.5618 | 0.4185 | Weaken | 3 | 2 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||||||||||
| 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 | 0.20 | Neutral | 0.386 | Benign | 0.266 | Benign | 3.07 | Benign | 0.60 | Tolerated | 0.1732 | 0.5436 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.628C>T | H210Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 H210Y 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, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is “Likely Pathogenic.” 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) as Benign. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar classification because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -12.828 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.27 | Likely Benign | 0.8 | 0.38 | Likely Benign | 0.33 | Likely Benign | 0.39 | Likely Benign | 0.427 | Likely Benign | -5.12 | Deleterious | 0.963 | Probably Damaging | 0.628 | Possibly Damaging | 3.07 | Benign | 0.00 | Affected | 0.0497 | 0.3662 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||
| 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 | -0.09 | Likely Benign | 0.1 | 0.35 | Likely Benign | 0.13 | Likely Benign | 0.56 | Ambiguous | 0.631 | Likely Pathogenic | -4.48 | Deleterious | 1.000 | Probably Damaging | 0.968 | Probably Damaging | 3.08 | Benign | 0.07 | Tolerated | 0.1094 | 0.5332 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.1915T>A | F639I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F639I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FATHMM and Rosetta, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, premPS, 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 is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.117665 | Uncertain | 0.942 | 0.284 | 0.000 | -12.548 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 4.32 | Destabilizing | 0.3 | 0.47 | Likely Benign | 2.40 | Destabilizing | 1.44 | Destabilizing | 0.545 | Likely Pathogenic | -5.98 | Deleterious | 0.994 | Probably Damaging | 0.659 | Possibly Damaging | 3.08 | Benign | 0.01 | Affected | 0.2070 | 0.1755 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1915T>G | F639V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F639V is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining 12 tools (SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity; Rosetta is uncertain and is therefore not counted. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.117665 | Uncertain | 0.942 | 0.284 | 0.000 | -12.910 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 4.17 | Destabilizing | 0.1 | 1.18 | Ambiguous | 2.68 | Destabilizing | 1.47 | Destabilizing | 0.560 | Likely Pathogenic | -6.97 | Deleterious | 0.992 | Probably Damaging | 0.756 | Possibly Damaging | 3.08 | Benign | 0.02 | Affected | 0.2074 | 0.1583 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.2141T>C | L714P 2D AIThe SynGAP1 missense variant L714P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the preponderance of evidence from these tools, 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 | GAP | 0.314870 | Structured | 0.402311 | Uncertain | 0.961 | 0.369 | 0.000 | -12.562 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 7.48 | Destabilizing | 1.9 | 13.54 | Destabilizing | 10.51 | Destabilizing | 2.26 | Destabilizing | 0.441 | Likely Benign | -6.44 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.08 | Benign | 0.00 | Affected | 0.3572 | 0.1253 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.2464A>T | T822S 2D AIThe SynGAP1 missense variant T822S is not reported 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 T822S, 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 | 0.724957 | Disordered | 0.651624 | Binding | 0.295 | 0.881 | 0.750 | -1.710 | Likely Benign | 0.655 | Likely Pathogenic | Likely Benign | 0.107 | Likely Benign | -0.54 | Neutral | 0.998 | Probably Damaging | 0.949 | Probably Damaging | 3.08 | Benign | 0.74 | Tolerated | 0.3794 | 0.4547 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1259T>A | F420Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420Y is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show mixed results. Benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions are reported by premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. Predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments indicate that the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta remain uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | -12.138 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 1.18 | Ambiguous | 0.1 | 0.96 | Ambiguous | 1.07 | Ambiguous | 1.31 | Destabilizing | 0.228 | Likely Benign | -2.80 | Deleterious | 0.306 | Benign | 0.100 | Benign | 3.09 | Benign | 0.03 | Affected | 0.1609 | 0.1498 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1259T>C | F420S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420S (ClinVar ID 981441.0) is reported as Pathogenic in ClinVar and is not present in gnomAD. Prediction tools largely agree on a deleterious effect: all listed predictors except FATHMM return a pathogenic or likely pathogenic call. The single benign prediction comes from FATHMM. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts Pathogenic. No predictions or folding‑stability results are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | Likely Pathogenic | 1 | -13.231 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.34 | Destabilizing | 0.1 | 5.73 | Destabilizing | 5.54 | Destabilizing | 2.14 | Destabilizing | 0.544 | Likely Pathogenic | -7.43 | Deleterious | 0.998 | Probably Damaging | 0.938 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 3.37 | 29 | 0.4167 | 0.0200 | -3 | -2 | -3.6 | -60.10 | 213.3 | 57.8 | 0.0 | 0.0 | -0.4 | 0.1 | X | Potentially Pathogenic | In the WT, the phenyl ring of the Phe420 side chain, located on an α helix (res. Met414-Glu436), packs against hydrophobic residues in the interhelix area of the GAP domain (e.g., Leu689, Leu714, Leu717, Leu718). Although no large-scale adverse effects are seen in the variant simulations, the polar hydroxyl group of Ser420 is not suitable for the hydrophobic inter-helix space. Thus, the residue swap could affect protein folding. In theory, the introduced hydroxyl group could also lower the α helix integrity by H-bonding with the backbone atoms of neighboring residues in the same α helix. However, no such effect is seen in the variant simulations. | ||||||||||||||||
| c.1259T>G | F420C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420C is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. Only FATHMM predicts a benign outcome. When grouped by consensus, the benign prediction is singular (FATHMM), whereas the pathogenic predictions comprise the remaining eleven tools. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is 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, is 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 (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | -11.931 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.31 | Destabilizing | 0.1 | 5.11 | Destabilizing | 4.71 | Destabilizing | 2.49 | Destabilizing | 0.500 | Likely Pathogenic | -7.40 | Deleterious | 0.998 | Probably Damaging | 0.869 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.2458 | 0.0662 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| 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 | 2.34 | Destabilizing | 0.1 | 0.77 | Ambiguous | 1.56 | Ambiguous | 0.60 | Ambiguous | 0.414 | Likely Benign | -5.46 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.09 | Benign | 0.05 | Affected | 0.2340 | 0.5197 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.1375G>C | G459R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G459R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM Consensus score (Likely Pathogenic) all indicate a pathogenic impact. Stability‑based methods (FoldX, Rosetta, premPS) are inconclusive, and Foldetta likewise reports an uncertain effect. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as Likely Pathogenic, and Foldetta as unavailable. Taken together, the consensus of the majority of tools points to a pathogenic effect for G459R. This prediction 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 | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -12.958 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.84 | Ambiguous | 0.2 | 0.79 | Ambiguous | 1.32 | Ambiguous | 0.79 | Ambiguous | 0.486 | Likely Benign | -7.41 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 0.0903 | 0.4248 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1811C>T | S604L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S604L is listed in ClinVar with an “Uncertain” status (ClinVar ID 1055027.0) and is present in gnomAD (ID 6‑33440863‑C‑T). Prediction tools that agree on a benign effect are premPS and FATHMM. Tools that predict a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, 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 of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010926 | Structured | 0.192527 | Uncertain | 0.911 | 0.195 | 0.000 | Uncertain | 1 | 6-33440863-C-T | 6 | 3.72e-6 | -14.683 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | -0.94 | Ambiguous | 0.1 | -1.24 | Ambiguous | -1.09 | Ambiguous | -0.31 | Likely Benign | 0.639 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 3.37 | 35 | 0.1177 | 0.4518 | -3 | -2 | 4.6 | 26.08 | 234.0 | -49.6 | 0.0 | 0.1 | 0.3 | 0.5 | X | X | Potentially Pathogenic | Ser604 is located in a short turn between an α helix (res. Glu582-Met603) and a short α helical section (res. Ser606-Phe608). In the WT simulations, the hydroxyl side chain of Ser604 periodically hydrogen bonds with the backbone carbonyl groups of other α helix residues (e.g., Pro600, Met603). Serine weakens the α helix secondary structure, and thus, Ser604 along with Pro605 breaks the α helix, facilitating the turn in the WT structure.In contrast, in the variant simulations, Leu604 forms a few hydrophobic interactions (e.g., Leu607, Phe608). More importantly, the helix end is more stable than with Ser604 in the WT. The residue swap could have a more profound effect on the actual folding process, for example, by preventing the bending at the α helix end, than what the simulations suggest.Moreover, Ser604 directly hydrogen bonds with Ras residues Ser65 and Ala66 in the WT SynGAP-Ras complex. The hydrophobic leucine cannot maintain these interactions with Ras at the GAP-Ras interface. Thus, the effect of the residue swap on the complex formation with the GTPase cannot be fully explored in the solvent-only simulations. | ||||||||||||
| c.1954T>C | F652L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F652L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are made by REVEL and FATHMM, whereas the remaining evaluated algorithms (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all indicate pathogenicity. Stability‑based assessments from FoldX and Rosetta are inconclusive, and Foldetta likewise yields an uncertain result. High‑accuracy methods give a clearer picture: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels the variant as likely pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for F652L. This conclusion is consistent with the absence 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 | 0.098513 | Structured | 0.356594 | Uncertain | 0.966 | 0.338 | 0.000 | -9.026 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.31 | Ambiguous | 0.1 | 1.88 | Ambiguous | 1.60 | Ambiguous | 1.35 | Destabilizing | 0.467 | Likely Benign | -5.65 | Deleterious | 0.997 | Probably Damaging | 0.619 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.1750 | 0.2926 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1956T>A | F652L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F652L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are made by REVEL and FATHMM, whereas the remaining evaluated algorithms (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all indicate pathogenicity. Stability‑based assessments from FoldX and Rosetta are inconclusive, and Foldetta likewise yields an uncertain result. High‑accuracy methods give a clearer picture: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels the variant as likely pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for F652L. This conclusion is consistent with the absence 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 | 0.098513 | Structured | 0.356594 | Uncertain | 0.966 | 0.338 | 0.000 | -9.026 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.31 | Ambiguous | 0.1 | 1.88 | Ambiguous | 1.60 | Ambiguous | 1.35 | Destabilizing | 0.306 | Likely Benign | -5.65 | Deleterious | 0.997 | Probably Damaging | 0.619 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.1750 | 0.2926 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1956T>G | F652L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F652L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) indicate a pathogenic impact. FoldX and Rosetta give uncertain results, and Foldetta likewise reports an uncertain stability change. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it Likely Pathogenic, and Foldetta remaining uncertain. Overall, the preponderance of evidence from multiple pathogenic‑predicting tools and the high‑accuracy methods points to a likely pathogenic effect for F652L, with no conflict from ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.098513 | Structured | 0.356594 | Uncertain | 0.966 | 0.338 | 0.000 | -9.026 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.31 | Ambiguous | 0.1 | 1.88 | Ambiguous | 1.60 | Ambiguous | 1.35 | Destabilizing | 0.305 | Likely Benign | -5.65 | Deleterious | 0.997 | Probably Damaging | 0.619 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.1750 | 0.2926 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1958T>A | L653Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L653Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a deleterious effect. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic signal: 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 predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.335213 | Uncertain | 0.963 | 0.332 | 0.000 | -14.347 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 2.71 | Destabilizing | 0.1 | 3.26 | Destabilizing | 2.99 | Destabilizing | 1.98 | Destabilizing | 0.614 | Likely Pathogenic | -5.65 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.09 | Benign | 0.01 | Affected | 0.1195 | 0.1363 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1958T>C | L653P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L653P 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 only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods give the following 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. Based on the overwhelming agreement among these tools, 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 | 0.049374 | Structured | 0.335213 | Uncertain | 0.963 | 0.332 | 0.000 | -17.675 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 6.02 | Destabilizing | 0.8 | 9.20 | Destabilizing | 7.61 | Destabilizing | 2.56 | Destabilizing | 0.700 | Likely Pathogenic | -6.51 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 0.3251 | 0.1874 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1958T>G | L653R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L653R 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 limited to 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 reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.335213 | Uncertain | 0.963 | 0.332 | 0.000 | -16.078 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 6.92 | Destabilizing | 1.1 | 5.84 | Destabilizing | 6.38 | Destabilizing | 2.55 | Destabilizing | 0.649 | Likely Pathogenic | -5.75 | Deleterious | 0.997 | Probably Damaging | 0.806 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.1501 | 0.0805 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2077C>G | H693D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H693D is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity largely agree: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic signal: 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 predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.073402 | Structured | 0.323991 | Uncertain | 0.964 | 0.260 | 0.000 | -15.500 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.60 | Destabilizing | 0.1 | 2.03 | Destabilizing | 2.32 | Destabilizing | 1.62 | Destabilizing | 0.578 | Likely Pathogenic | -8.97 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.09 | Benign | 0.01 | Affected | 0.2166 | 0.1108 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.2078A>C | H693P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H693P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are limited to FATHMM, which classifies the variant as benign. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or 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 because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.073402 | Structured | 0.323991 | Uncertain | 0.964 | 0.260 | 0.000 | -16.281 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 5.54 | Destabilizing | 0.2 | 6.09 | Destabilizing | 5.82 | Destabilizing | 1.06 | Destabilizing | 0.600 | Likely Pathogenic | -9.97 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.09 | Benign | 0.01 | Affected | 0.2080 | 0.3210 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.2108T>A | L703H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from REVEL and FATHMM, whereas pathogenic predictions are made by FoldX, Rosetta, Foldetta, premPS, 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 reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM‑Consensus itself is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts Pathogenic. Taken together, the overwhelming majority of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.144935 | Structured | 0.388282 | Uncertain | 0.929 | 0.353 | 0.000 | -12.886 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 2.52 | Destabilizing | 0.0 | 2.29 | Destabilizing | 2.41 | Destabilizing | 1.75 | Destabilizing | 0.420 | Likely Benign | -5.71 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 0.1038 | 0.0288 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.2140C>A | L714M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L714M is not reported in ClinVar (no entry) and is absent from gnomAD. Benign predictions are provided by REVEL, FoldX, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (likely benign). Pathogenic predictions come from Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy tools give mixed results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign; Foldetta (combining FoldX‑MD and Rosetta) predicts pathogenic. Overall, the majority of 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 Benign | GAP | 0.314870 | Structured | 0.402311 | Uncertain | 0.961 | 0.369 | 0.000 | -0.989 | Likely Benign | 0.827 | Likely Pathogenic | Ambiguous | 0.45 | Likely Benign | 0.0 | 4.49 | Destabilizing | 2.47 | Destabilizing | 1.00 | Destabilizing | 0.249 | Likely Benign | -1.86 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 0.0687 | 0.2626 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.2141T>G | L714R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L714R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. 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, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely pathogenic, 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 Pathogenic | GAP | 0.314870 | Structured | 0.402311 | Uncertain | 0.961 | 0.369 | 0.000 | -12.763 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.38 | Destabilizing | 0.2 | 7.54 | Destabilizing | 5.96 | Destabilizing | 2.09 | Destabilizing | 0.402 | Likely Benign | -5.62 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 0.1186 | 0.0558 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.3749A>G | Q1250R 2D AIThe SynGAP1 missense variant Q1250R 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, 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 likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that 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 | 0.759478 | Disordered | 0.360484 | Uncertain | 0.881 | 0.554 | 0.750 | -5.183 | Likely Benign | 0.230 | Likely Benign | Likely Benign | 0.148 | Likely Benign | 0.76 | Neutral | 0.994 | Probably Damaging | 0.988 | Probably Damaging | 3.09 | Benign | 1.00 | Tolerated | 0.1330 | 0.0874 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||||||||||
| c.3865A>C | K1289Q 2D AIThe SynGAP1 missense variant K1289Q 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 | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -2.940 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 1.55 | Neutral | 0.004 | Benign | 0.004 | Benign | 3.09 | Benign | 1.00 | Tolerated | 0.4002 | 0.0590 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3869G>A | R1290K 2D AIThe SynGAP1 missense variant R1290K 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 predictions strongly suggest that the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.844138 | Binding | 0.567 | 0.795 | 0.625 | -3.749 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 0.037 | Likely Benign | 0.52 | Neutral | 0.004 | Benign | 0.006 | Benign | 3.09 | Benign | 1.00 | Tolerated | 0.3342 | 0.3113 | 3 | 2 | 0.6 | -28.01 | |||||||||||||||||||||||||||||||||||||||
| c.3910C>G | P1304A 2D AIThe SynGAP1 missense variant P1304A 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 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 | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | -4.072 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 1.35 | Neutral | 0.001 | Benign | 0.002 | Benign | 3.09 | Benign | 1.00 | Tolerated | 0.2923 | 0.4117 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3919C>T | P1307S 2D AIThe SynGAP1 missense variant P1307S 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 | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | -3.700 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.45 | Neutral | 0.239 | Benign | 0.157 | Benign | 3.09 | Benign | 0.48 | Tolerated | 0.3652 | 0.4846 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.629A>C | H210P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H210P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM; all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -14.634 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 2.26 | Destabilizing | 0.5 | 2.80 | Destabilizing | 2.53 | Destabilizing | 1.00 | Destabilizing | 0.512 | Likely Pathogenic | -8.55 | Deleterious | 0.989 | Probably Damaging | 0.795 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.1805 | 0.3175 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.629A>G | H210R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H210R missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and FoldX, whereas a majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The high‑accuracy AlphaMissense‑Optimized result is pathogenic; the SGM Consensus, based on the same set of predictors, is also pathogenic; Foldetta’s stability assessment is uncertain and therefore not considered evidence. Overall, the balance of evidence points to a pathogenic effect for H210R. This prediction does not contradict the ClinVar “Uncertain” classification, which remains unresolved. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | Uncertain | 1 | -14.254 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.4 | 3.05 | Destabilizing | 1.73 | Ambiguous | 1.12 | Destabilizing | 0.431 | Likely Benign | -6.74 | Deleterious | 0.808 | Possibly Damaging | 0.452 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.1427 | 0.1982 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||
| c.629A>T | H210L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H210L missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools cluster into two groups: benign predictions come from REVEL, Foldetta, premPS, and FATHMM, while pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Rosetta provide uncertain results. High‑accuracy assessments further highlight the discrepancy: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, whereas Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -14.516 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | -0.71 | Ambiguous | 0.1 | 1.35 | Ambiguous | 0.32 | Likely Benign | 0.49 | Likely Benign | 0.421 | Likely Benign | -9.41 | Deleterious | 0.895 | Possibly Damaging | 0.614 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.0617 | 0.4452 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||
| c.1793T>A | L598H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L598H is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized returns a pathogenic score; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.007259 | Structured | 0.147872 | Uncertain | 0.953 | 0.154 | 0.000 | -17.210 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 2.52 | Destabilizing | 0.2 | 2.37 | Destabilizing | 2.45 | Destabilizing | 2.24 | Destabilizing | 0.648 | Likely Pathogenic | -6.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.10 | Benign | 0.00 | Affected | 0.1060 | 0.0879 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.1793T>C | L598P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L598P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates it is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also classifies it as pathogenic. No prediction or stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, 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 | GAP | 0.007259 | Structured | 0.147872 | Uncertain | 0.953 | 0.154 | 0.000 | -12.621 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 8.31 | Destabilizing | 0.5 | 12.04 | Destabilizing | 10.18 | Destabilizing | 2.02 | Destabilizing | 0.705 | Likely Pathogenic | -6.87 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.10 | Benign | 0.00 | Affected | 0.2742 | 0.1192 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1793T>G | L598R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L598R is 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, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the overwhelming agreement among these tools, 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 | 0.007259 | Structured | 0.147872 | Uncertain | 0.953 | 0.154 | 0.000 | -17.392 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.70 | Destabilizing | 0.5 | 3.06 | Destabilizing | 2.88 | Destabilizing | 2.23 | Destabilizing | 0.682 | Likely Pathogenic | -5.87 | Deleterious | 0.999 | Probably Damaging | 0.973 | Probably Damaging | 3.10 | Benign | 0.00 | Affected | 0.1297 | 0.0679 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1810T>C | S604P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S604P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS and FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy methods give consistent results: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also labels the variant as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. Taken together, the overwhelming majority of computational evidence supports a pathogenic classification for S604P, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010926 | Structured | 0.192527 | Uncertain | 0.911 | 0.195 | 0.000 | -10.953 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.76 | Destabilizing | 0.3 | 8.40 | Destabilizing | 6.08 | Destabilizing | 0.04 | Likely Benign | 0.512 | Likely Pathogenic | -4.98 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 3.10 | Benign | 0.01 | Affected | 0.2524 | 0.4829 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.2077C>A | H693N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H693N is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL and FATHMM, whereas the majority of other in silico predictors—premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus—label it pathogenic. FoldX, Rosetta, and Foldetta provide uncertain results. High‑accuracy methods specifically give AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for H693N, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.073402 | Structured | 0.323991 | Uncertain | 0.964 | 0.260 | 0.000 | -12.275 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 1.74 | Ambiguous | 0.1 | 0.80 | Ambiguous | 1.27 | Ambiguous | 1.28 | Destabilizing | 0.436 | Likely Benign | -6.98 | Deleterious | 1.000 | Probably Damaging | 0.987 | Probably Damaging | 3.10 | Benign | 0.01 | Affected | 0.1380 | 0.1849 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||
| c.3985C>A | L1329M 2D AIThe SynGAP1 missense change L1329M is recorded in gnomAD (ID 6‑33451859‑C‑A) but has no ClinVar entry. Functional prediction tools split into two consensus groups: benign‑predicted by REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic‑predicted by polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus likewise indicates benign. Foldetta, a protein‑folding stability predictor 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 is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.924905 | Binding | 0.336 | 0.748 | 0.875 | 6-33451859-C-A | -5.493 | Likely Benign | 0.780 | Likely Pathogenic | Likely Benign | 0.087 | Likely Benign | -1.16 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 3.10 | Benign | 0.00 | Affected | 3.77 | 5 | 0.0914 | 0.4273 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||
| c.630C>A | H210Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H210Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign calls come from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar) and FATHMM, whereas pathogenic calls are made by premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN, favors a pathogenic outcome (3/4). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote) also predicts pathogenic. Foldetta, a protein‑folding stability predictor that integrates FoldX‑MD and Rosetta, is inconclusive and therefore not used as evidence. Overall, the majority of reliable predictors indicate a pathogenic effect for H210Q, and this conclusion does not conflict with any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -12.639 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.26 | Likely Benign | 0.3 | 1.96 | Ambiguous | 1.11 | Ambiguous | 1.20 | Destabilizing | 0.258 | Likely Benign | -6.84 | Deleterious | 0.141 | Benign | 0.064 | Benign | 3.10 | Benign | 0.00 | Affected | 0.1016 | 0.2852 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.630C>G | H210Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H210Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar) and FATHMM, whereas pathogenic calls come from premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized. When predictions are grouped, five tools favor a benign effect and six favor a pathogenic effect. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenic, and the Foldetta stability analysis is inconclusive. No evidence from ClinVar contradicts these findings. Therefore, the variant is most likely pathogenic based on the aggregate computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -12.639 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.26 | Likely Benign | 0.3 | 1.96 | Ambiguous | 1.11 | Ambiguous | 1.20 | Destabilizing | 0.258 | Likely Benign | -6.84 | Deleterious | 0.141 | Benign | 0.064 | Benign | 3.10 | Benign | 0.00 | Affected | 0.1016 | 0.2852 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.1768A>C | S590R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590R is not reported in ClinVar (status: None) and has no entries in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (likely pathogenic), REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions are inconclusive or missing. Based on the collective evidence, 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 | GAP | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | -18.228 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.69 | Ambiguous | 0.6 | 3.21 | Destabilizing | 2.45 | Destabilizing | 1.28 | Destabilizing | 0.640 | Likely Pathogenic | -4.88 | Deleterious | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.11 | Benign | 0.01 | Affected | 0.0983 | 0.3388 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1770C>A | S590R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, Rosetta, and Foldetta) all predict a pathogenic impact; FoldX is uncertain and therefore not counted. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | -18.228 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.69 | Ambiguous | 0.6 | 3.21 | Destabilizing | 2.45 | Destabilizing | 1.28 | Destabilizing | 0.391 | Likely Benign | -4.88 | Deleterious | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.11 | Benign | 0.01 | Affected | 0.0983 | 0.3388 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1770C>G | S590R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, Rosetta, and Foldetta) all predict a pathogenic impact; FoldX is uncertain and therefore not counted. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | -18.228 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.69 | Ambiguous | 0.6 | 3.21 | Destabilizing | 2.45 | Destabilizing | 1.28 | Destabilizing | 0.389 | Likely Benign | -4.88 | Deleterious | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.11 | Benign | 0.01 | Affected | 0.0983 | 0.3388 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1988T>A | F663Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663Y is not 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, and FATHMM. Those that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. 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 Benign. Overall, the majority of tools and the SGM‑Consensus lean toward pathogenicity, while a minority suggest benign impact. Thus, the variant is most likely pathogenic based on the available predictions, 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 | GAP | 0.056825 | Structured | 0.093963 | Uncertain | 0.944 | 0.355 | 0.000 | -12.749 | Likely Pathogenic | 0.853 | Likely Pathogenic | Ambiguous | 0.37 | Likely Benign | 0.1 | 0.19 | Likely Benign | 0.28 | Likely Benign | 1.03 | Destabilizing | 0.424 | Likely Benign | -2.99 | Deleterious | 0.984 | Probably Damaging | 0.913 | Probably Damaging | 3.11 | Benign | 0.05 | Affected | 0.1243 | 0.1584 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.2108T>C | L703P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic, while only FATHMM predicts it benign. The SGM‑Consensus, which is a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Pathogenic” result (3 pathogenic vs. 1 benign). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; SGM‑Consensus is likely pathogenic; and Foldetta, integrating FoldX‑MD and Rosetta outputs, is pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.144935 | Structured | 0.388282 | Uncertain | 0.929 | 0.353 | 0.000 | -13.766 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 4.44 | Destabilizing | 0.1 | 9.38 | Destabilizing | 6.91 | Destabilizing | 1.54 | Destabilizing | 0.559 | Likely Pathogenic | -5.70 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.11 | Benign | 0.00 | Affected | 0.3698 | 0.1186 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.2141T>A | L714Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L714Q is not reported in ClinVar (ClinVar: not reported) and is absent from gnomAD (gnomAD: not found). Prediction tools that agree on a benign effect are REVEL and FATHMM. All other evaluated tools—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.314870 | Structured | 0.402311 | Uncertain | 0.961 | 0.369 | 0.000 | -12.145 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.91 | Destabilizing | 0.0 | 5.23 | Destabilizing | 4.07 | Destabilizing | 2.13 | Destabilizing | 0.378 | Likely Benign | -5.56 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.11 | Benign | 0.00 | Affected | 0.1096 | 0.0558 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.3919C>G | P1307A 2D AIThe SynGAP1 missense variant P1307A is catalogued in gnomAD (ID 6‑33451793‑C‑G) 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 tolerated or benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely benign. Foldetta, a protein‑folding stability predictor, was not available for this variant. Overall, the consensus of all available predictions is benign, and this is consistent with the absence of a ClinVar pathogenic classification. Based on the consensus of all predictions, the variant is most likely benign, and this does not contradict ClinVar status, which has no pathogenic classification. 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 | 6-33451793-C-G | 1 | 6.20e-7 | -4.042 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.49 | Neutral | 0.003 | Benign | 0.006 | Benign | 3.11 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.3747 | 0.4451 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.3935C>A | A1312D 2D AIThe SynGAP1 missense variant A1312D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors a benign outcome (2 benign vs. 1 pathogenic, with one uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the balance of evidence, particularly from the high‑accuracy tools, 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. | 0.767246 | Disordered | 0.971112 | Binding | 0.392 | 0.902 | 0.750 | -4.419 | Likely Benign | 0.398 | Ambiguous | Likely Benign | 0.272 | Likely Benign | -2.74 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 3.11 | Benign | 0.00 | Affected | 0.2289 | 0.2993 | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.628C>A | H210N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H210N missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and FATHMM, while pathogenic predictions are made by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus score (Likely Pathogenic). Two tools give uncertain results: Foldetta (combining FoldX‑MD and Rosetta outputs) and Rosetta alone. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points toward a pathogenic effect for H210N. 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 | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -13.699 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.19 | Likely Benign | 0.3 | 1.24 | Ambiguous | 0.72 | Ambiguous | 1.12 | Destabilizing | 0.375 | Likely Benign | -6.01 | Deleterious | 0.895 | Possibly Damaging | 0.533 | Possibly Damaging | 3.11 | Benign | 0.00 | Affected | 0.1166 | 0.1839 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||
| c.1915T>C | F639L 2D AIThe SynGAP1 missense variant F639L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, polyPhen2_HumVar, and FATHMM, whereas pathogenic predictions are returned by SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen2_HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta and Foldetta provide uncertain results. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. Based on the majority of predictions, the variant is most likely pathogenic, which is consistent with the lack of ClinVar annotation and gnomAD absence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.117665 | Uncertain | 0.942 | 0.284 | 0.000 | -11.660 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.12 | Destabilizing | 0.7 | 1.15 | Ambiguous | 1.64 | Ambiguous | 1.43 | Destabilizing | 0.499 | Likely Benign | -5.98 | Deleterious | 0.994 | Probably Damaging | 0.380 | Benign | 3.12 | Benign | 0.03 | Affected | 0.2347 | 0.2726 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1916T>C | F639S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F639S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) 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 because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.117665 | Uncertain | 0.942 | 0.284 | 0.000 | -11.511 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 4.92 | Destabilizing | 0.3 | 3.08 | Destabilizing | 4.00 | Destabilizing | 1.87 | Destabilizing | 0.561 | Likely Pathogenic | -7.97 | Deleterious | 0.965 | Probably Damaging | 0.457 | Possibly Damaging | 3.12 | Benign | 0.04 | Affected | 0.3813 | 0.0200 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1917T>A | F639L 2D AIThe SynGAP1 missense variant F639L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, polyPhen2_HumVar, and FATHMM, whereas pathogenic predictions are returned by SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen2_HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta and Foldetta provide uncertain results. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. Based on the majority of predictions, the variant is most likely pathogenic, which is consistent with the lack of ClinVar annotation and gnomAD absence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.117665 | Uncertain | 0.942 | 0.284 | 0.000 | -11.660 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.12 | Destabilizing | 0.7 | 1.15 | Ambiguous | 1.64 | Ambiguous | 1.43 | Destabilizing | 0.336 | Likely Benign | -5.98 | Deleterious | 0.994 | Probably Damaging | 0.380 | Benign | 3.12 | Benign | 0.03 | Affected | 0.2347 | 0.2726 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1917T>G | F639L 2D AIThe SynGAP1 missense variant F639L is not reported in ClinVar or gnomAD. Prediction tools that indicate a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas a majority of tools predict pathogenicity: SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results come from Rosetta and Foldetta. High‑accuracy methods specifically show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Overall, the balance of evidence points to a pathogenic effect for F639L, and this assessment does not conflict with any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.117665 | Uncertain | 0.942 | 0.284 | 0.000 | -11.660 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.12 | Destabilizing | 0.7 | 1.15 | Ambiguous | 1.64 | Ambiguous | 1.43 | Destabilizing | 0.336 | Likely Benign | -5.98 | Deleterious | 0.994 | Probably Damaging | 0.380 | Benign | 3.12 | Benign | 0.03 | Affected | 0.2347 | 0.2726 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.2074C>G | L692V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L692V is not 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. All other evaluated tools—SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized indicates benign, but the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as pathogenic, and Foldetta also predicts pathogenic. No predictions are missing or inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for the variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.295225 | Uncertain | 0.966 | 0.243 | 0.000 | -11.441 | Likely Pathogenic | 0.733 | Likely Pathogenic | Likely Benign | 3.29 | Destabilizing | 0.1 | 2.91 | Destabilizing | 3.10 | Destabilizing | 1.57 | Destabilizing | 0.286 | Likely Benign | -2.99 | Deleterious | 0.978 | Probably Damaging | 0.606 | Possibly Damaging | 3.12 | Benign | 0.01 | Affected | 0.1395 | 0.2460 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.2107C>T | L703F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703F is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, premPS, FATHMM, and AlphaMissense‑Optimized, while those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta remains unavailable. Overall, the majority of reliable 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 | 0.144935 | Structured | 0.388282 | Uncertain | 0.929 | 0.353 | 0.000 | -10.929 | Likely Pathogenic | 0.768 | Likely Pathogenic | Likely Benign | 1.03 | Ambiguous | 0.1 | 0.59 | Ambiguous | 0.81 | Ambiguous | 0.50 | Likely Benign | 0.247 | Likely Benign | -3.25 | Deleterious | 0.994 | Probably Damaging | 0.806 | Possibly Damaging | 3.12 | Benign | 0.00 | Affected | 0.0600 | 0.2555 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.3934G>C | A1312P 2D  AIThe SynGAP1 missense variant A1312P 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 | 0.767246 | Disordered | 0.971112 | Binding | 0.392 | 0.902 | 0.750 | -2.488 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.222 | Likely Benign | -1.64 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 3.12 | Benign | 0.00 | Affected | 0.2208 | 0.5820 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.1244A>T | E415V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E415V missense variant is not reported in ClinVar or gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are reported by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) predicts benign. No evidence is missing or inconclusive. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -11.182 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.56 | Ambiguous | 0.2 | 0.14 | Likely Benign | 0.35 | Likely Benign | 0.40 | Likely Benign | 0.441 | Likely Benign | -6.52 | Deleterious | 0.998 | Probably Damaging | 0.983 | Probably Damaging | 3.13 | Benign | 0.02 | Affected | 0.0650 | 0.4218 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1342G>C | A448P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect, while only FATHMM predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized returns a pathogenic prediction; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a likely pathogenic result; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -13.706 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 5.42 | Destabilizing | 0.0 | 8.74 | Destabilizing | 7.08 | Destabilizing | 1.16 | Destabilizing | 0.650 | Likely Pathogenic | -4.94 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.13 | Benign | 0.01 | Affected | 0.1758 | 0.3626 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1343C>A | A448D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448D 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 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: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No prediction or folding result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -17.290 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 8.13 | Destabilizing | 0.2 | 4.35 | Destabilizing | 6.24 | Destabilizing | 1.40 | Destabilizing | 0.662 | Likely Pathogenic | -5.93 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.13 | Benign | 0.00 | Affected | 0.1541 | 0.1741 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1418T>A | V473E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a deleterious effect: all evaluated algorithms except FATHMM predict pathogenicity, while FATHMM alone predicts benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports a pathogenic effect. No predictions or stability results are missing or inconclusive. Based on the consensus of the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -15.296 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 3.20 | Destabilizing | 0.2 | 2.24 | Destabilizing | 2.72 | Destabilizing | 2.22 | Destabilizing | 0.664 | Likely Pathogenic | -5.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.13 | Benign | 0.00 | Affected | 0.0903 | 0.1396 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.1418T>G | V473G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473G has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the remaining eleven tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) uniformly predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) votes pathogenic, and Foldetta also predicts pathogenic. No predictions are missing or inconclusive. Consequently, the variant is most likely pathogenic based on the collective evidence, and this conclusion does not contradict any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -14.782 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 3.45 | Destabilizing | 0.0 | 3.40 | Destabilizing | 3.43 | Destabilizing | 2.69 | Destabilizing | 0.683 | Likely Pathogenic | -6.91 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.13 | Benign | 0.00 | Affected | 0.1885 | 0.2567 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1745A>G | E582G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E582G is not reported in ClinVar (ClinVar ID: None) and has no entry in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, and Foldetta give uncertain or inconclusive results. High‑accuracy methods give mixed signals: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic, and Foldetta’s stability assessment is uncertain. Overall, six tools predict pathogenicity while five predict benign, and the high‑accuracy consensus is split. Thus, the variant is most likely pathogenic based on the preponderance of evidence, and this assessment does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.033838 | Uncertain | 0.845 | 0.235 | 0.000 | -9.621 | Likely Pathogenic | 0.630 | Likely Pathogenic | Likely Benign | 1.35 | Ambiguous | 0.2 | 1.24 | Ambiguous | 1.30 | Ambiguous | 0.37 | Likely Benign | 0.224 | Likely Benign | -3.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.13 | Benign | 0.13 | Tolerated | 0.2835 | 0.3325 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1955T>A | F652Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F652Y is not 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, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that agree on a pathogenic effect are premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. Three tools (FoldX, Foldetta, AlphaMissense‑Optimized) give uncertain results. High‑accuracy methods provide no definitive verdict: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie (2 pathogenic, 2 benign) and thus inconclusive; Foldetta is uncertain. Consequently, the overall prediction landscape is balanced, with an equal number of benign and pathogenic calls and several uncertain results. The variant is therefore most likely **inconclusive** in terms of pathogenicity, and this lack of consensus does not contradict any ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.098513 | Structured | 0.356594 | Uncertain | 0.966 | 0.338 | 0.000 | -5.437 | Likely Benign | 0.890 | Likely Pathogenic | Ambiguous | 1.05 | Ambiguous | 0.2 | 0.27 | Likely Benign | 0.66 | Ambiguous | 1.24 | Destabilizing | 0.363 | Likely Benign | -2.92 | Deleterious | 0.957 | Probably Damaging | 0.390 | Benign | 3.13 | Benign | 0.00 | Affected | 0.1085 | 0.1584 | 7 | 3 | -4.1 | 16.00 | ||||||||||||||||||||||||||||||
| c.1957C>A | L653M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L653M has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Tools with uncertain or missing results (FoldX, Rosetta, Foldetta, premPS) are not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs. two benign votes), and Foldetta is also inconclusive. Overall, the majority of standard predictors lean toward pathogenicity, but the most reliable high‑accuracy tool indicates a benign effect, leaving the variant’s impact uncertain. No ClinVar entry exists, so there is no contradiction with clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.049374 | Structured | 0.335213 | Uncertain | 0.963 | 0.332 | 0.000 | -8.838 | Likely Pathogenic | 0.713 | Likely Pathogenic | Likely Benign | 0.99 | Ambiguous | 0.2 | 1.70 | Ambiguous | 1.35 | Ambiguous | 0.94 | Ambiguous | 0.259 | Likely Benign | -1.76 | Neutral | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.13 | Benign | 0.01 | Affected | 0.0935 | 0.3227 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.2077C>T | H693Y 2D AIThe SynGAP1 H693Y 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, premPS, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, 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 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. | GAP | 0.073402 | Structured | 0.323991 | Uncertain | 0.964 | 0.260 | 0.000 | -7.963 | In-Between | 0.984 | Likely Pathogenic | Likely Pathogenic | -0.16 | Likely Benign | 1.7 | -1.41 | Ambiguous | -0.79 | Ambiguous | 0.10 | Likely Benign | 0.513 | Likely Pathogenic | -5.98 | Deleterious | 0.553 | Possibly Damaging | 0.046 | Benign | 3.13 | Benign | 0.02 | Affected | 0.0819 | 0.3419 | 0 | 2 | 1.9 | 26.03 | ||||||||||||||||||||||||||||||
| c.2078A>G | H693R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H693R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the majority of algorithms (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX, Rosetta, and Foldetta are inconclusive. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect, and Foldetta’s stability analysis is unavailable. Based on the preponderance of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.073402 | Structured | 0.323991 | Uncertain | 0.964 | 0.260 | 0.000 | -14.326 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.39 | Ambiguous | 0.2 | 1.28 | Ambiguous | 1.34 | Ambiguous | 1.03 | Destabilizing | 0.593 | Likely Pathogenic | -7.97 | Deleterious | 0.998 | Probably Damaging | 0.646 | Possibly Damaging | 3.13 | Benign | 0.01 | Affected | 0.1839 | 0.1670 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||
| c.2108T>G | L703R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus) all classify the change as pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. The preponderance of pathogenic predictions, together with the high‑accuracy tools’ positive results, suggests that L703R is most likely pathogenic. 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 | GAP | 0.144935 | Structured | 0.388282 | Uncertain | 0.929 | 0.353 | 0.000 | -13.244 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 2.85 | Destabilizing | 0.0 | 3.74 | Destabilizing | 3.30 | Destabilizing | 1.79 | Destabilizing | 0.459 | Likely Benign | -4.92 | Deleterious | 0.994 | Probably Damaging | 0.806 | Possibly Damaging | 3.13 | Benign | 0.00 | Affected | 0.1223 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2795T>A | F932Y 2D AIThe SynGAP1 missense variant F932Y is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of other predictors (polyPhen‑2 HumDiv and HumVar) suggest pathogenic. When predictions are grouped by agreement, the benign‑predicating tools outnumber the pathogenic ones, and the single uncertain call from AlphaMissense‑Default does not alter this balance. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Benign. Foldetta data are unavailable. Overall, the computational evidence 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 | 0.675549 | Disordered | 0.989197 | Binding | 0.293 | 0.858 | 0.500 | -5.248 | Likely Benign | 0.540 | Ambiguous | Likely Benign | 0.180 | Likely Benign | 1.58 | Neutral | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 3.13 | Benign | 0.74 | Tolerated | 0.1473 | 0.2003 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.132G>C | W44C 2D  AIThe SynGAP1 missense variant W44C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of evaluated tools (seven pathogenic vs. three benign) indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar status because the variant has not yet been classified in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.301917 | Structured | 0.431379 | Uncertain | 0.377 | 0.748 | 0.375 | -6.216 | Likely Benign | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.321 | Likely Benign | -4.70 | Deleterious | 0.943 | Possibly Damaging | 0.941 | Probably Damaging | 3.14 | Benign | 0.00 | Affected | 0.3542 | 0.2370 | -8 | -2 | 3.4 | -83.07 | ||||||||||||||||||||||||||||||||||||||||
| c.132G>T | W44C 2D AIThe SynGAP1 missense variant W44C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, 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 (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 evaluated tools (seven pathogenic vs. three benign) indicate a pathogenic effect. This prediction 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. | 0.301917 | Structured | 0.431379 | Uncertain | 0.377 | 0.748 | 0.375 | -6.216 | Likely Benign | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.321 | Likely Benign | -4.70 | Deleterious | 0.943 | Possibly Damaging | 0.941 | Probably Damaging | 3.14 | Benign | 0.00 | Affected | 0.3542 | 0.2370 | -8 | -2 | 3.4 | -83.07 | ||||||||||||||||||||||||||||||||||||||||
| c.1448T>A | I483K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is 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 in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -18.260 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.53 | Destabilizing | 0.1 | 5.15 | Destabilizing | 4.34 | Destabilizing | 2.01 | Destabilizing | 0.585 | Likely Pathogenic | -6.50 | Deleterious | 0.962 | Probably Damaging | 0.991 | Probably Damaging | 3.14 | Benign | 0.00 | Affected | 0.0868 | 0.0670 | -2 | -3 | -8.4 | 15.01 | |||||||||||||||||||||||||||||
| c.1448T>G | I483R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) 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 because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -17.066 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 5.14 | Destabilizing | 0.4 | 4.09 | Destabilizing | 4.62 | Destabilizing | 1.97 | Destabilizing | 0.595 | Likely Pathogenic | -6.50 | Deleterious | 0.997 | Probably Damaging | 0.991 | Probably Damaging | 3.14 | Benign | 0.00 | Affected | 0.1120 | 0.0870 | -2 | -3 | -9.0 | 43.03 | |||||||||||||||||||||||||||||
| c.1769G>A | S590N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590N is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, while the majority of other in silico predictors (PolyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, PROVEAN, premPS, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) indicate a pathogenic or likely pathogenic impact. FoldX and Foldetta, which assess protein‑folding stability, return uncertain results and are therefore not considered evidence for either outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of pathogenic predictions strongly suggests that S590N is most likely pathogenic, a conclusion that is consistent with the absence of ClinVar annotation and gnomAD data. 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 | -15.149 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 1.27 | Ambiguous | 0.1 | 2.10 | Destabilizing | 1.69 | Ambiguous | 1.48 | Destabilizing | 0.411 | Likely Benign | -2.96 | Deleterious | 0.921 | Possibly Damaging | 0.598 | Possibly Damaging | 3.14 | Benign | 0.01 | Affected | 0.1254 | 0.4202 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||
| c.1777C>A | L593I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L593I missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Predictions that are uncertain are Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect. The variant’s predicted benign status does not contradict its ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.009728 | Structured | 0.110534 | Uncertain | 0.941 | 0.151 | 0.000 | -8.617 | Likely Pathogenic | 0.448 | Ambiguous | Likely Benign | 2.16 | Destabilizing | 0.3 | 0.76 | Ambiguous | 1.46 | Ambiguous | 0.39 | Likely Benign | 0.169 | Likely Benign | -1.59 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.14 | Benign | 0.17 | Tolerated | 0.1071 | 0.3582 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.2066T>A | L689H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L689H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods further support this: AlphaMissense‑Optimized 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. No prediction or folding stability result is 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 no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.227227 | Uncertain | 0.963 | 0.248 | 0.000 | -14.659 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.40 | Destabilizing | 0.1 | 2.50 | Destabilizing | 2.95 | Destabilizing | 2.21 | Destabilizing | 0.532 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.14 | Benign | 0.00 | Affected | 0.1013 | 0.0456 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.2079T>A | H693Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H693Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL and FATHMM, while the remaining evaluated algorithms (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all predict pathogenicity. FoldX and Rosetta give uncertain stability changes, and Foldetta likewise reports no definitive effect. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains inconclusive. Overall, the preponderance of evidence from multiple pathogenic‑oriented predictors and the high‑accuracy consensus indicates that H693Q is most likely pathogenic, a conclusion that aligns with the lack of ClinVar annotation and gnomAD data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.073402 | Structured | 0.323991 | Uncertain | 0.964 | 0.260 | 0.000 | -11.425 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 0.78 | Ambiguous | 0.85 | Ambiguous | 1.27 | Destabilizing | 0.386 | Likely Benign | -7.97 | Deleterious | 1.000 | Probably Damaging | 0.921 | Probably Damaging | 3.14 | Benign | 0.01 | Affected | 0.1274 | 0.2955 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.2079T>G | H693Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H693Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL and FATHMM, while the remaining evaluated algorithms (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all predict pathogenicity. FoldX and Rosetta give uncertain stability changes, and Foldetta likewise reports no definitive effect. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains inconclusive. Overall, the preponderance of evidence from multiple pathogenic‑oriented predictors and the high‑accuracy consensus indicates that H693Q is most likely pathogenic, a conclusion that aligns with the lack of ClinVar annotation and gnomAD data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.073402 | Structured | 0.323991 | Uncertain | 0.964 | 0.260 | 0.000 | -11.425 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 0.78 | Ambiguous | 0.85 | Ambiguous | 1.27 | Destabilizing | 0.386 | Likely Benign | -7.97 | Deleterious | 1.000 | Probably Damaging | 0.921 | Probably Damaging | 3.14 | Benign | 0.01 | Affected | 0.1274 | 0.2955 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.1304T>G | L435W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L435W is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM. The majority of other in silico predictors (REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as pathogenic, and the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. Overall, the computational evidence strongly favors a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | Uncertain | 1 | -14.889 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 2.11 | Destabilizing | 0.1 | 0.69 | Ambiguous | 1.40 | Ambiguous | 1.66 | Destabilizing | 0.572 | Likely Pathogenic | -5.63 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.15 | Benign | 0.00 | Affected | 3.37 | 29 | 0.0536 | 0.2496 | -2 | -2 | -4.7 | 73.05 | 242.2 | -25.2 | 0.0 | 0.0 | 0.3 | 0.1 | X | Potentially Pathogenic | The iso-butyl side chain of Leu435, located in an α helix (res. Met414-Glu436), packs against other hydrophobic residues in an interhelix space (e.g., Val699, Val447, Leu489, Leu439) in the WT simulations. In the variant simulations, the indole ring of Trp435 fits into the same niche despite its considerably bulkier size. Additionally, the side chain forms an H-bond with the backbone carbonyl of Leu696 in an α helix (res. Asp684-Gln702). Although no apparent negative changes are observed during the variant simulation, the size difference between the swapped residues could affect the protein folding process. | ||||||||||||||||
| c.1343C>G | A448G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448G resides in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas those that predict pathogenicity are Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default; FoldX is inconclusive. High‑accuracy assessments further clarify the impact: AlphaMissense‑Optimized reports a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a pathogenic effect. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. 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 | -9.984 | Likely Pathogenic | 0.640 | Likely Pathogenic | Likely Benign | 1.76 | Ambiguous | 0.0 | 2.45 | Destabilizing | 2.11 | Destabilizing | 1.00 | Destabilizing | 0.378 | Likely Benign | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.980 | Probably Damaging | 3.15 | Benign | 0.06 | Tolerated | 0.2135 | 0.2936 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1448T>C | I483T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts a pathogenic effect. Based on the preponderance of pathogenic predictions and the absence of any benign consensus, 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 | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -10.692 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 2.32 | Destabilizing | 0.0 | 2.05 | Destabilizing | 2.19 | Destabilizing | 1.77 | Destabilizing | 0.474 | Likely Benign | -4.24 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.15 | Benign | 0.05 | Affected | 0.0888 | 0.0840 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.1540A>G | I514V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514V is catalogued in gnomAD (variant ID 6‑33438783‑A‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are limited to polyPhen‑2 HumDiv and HumVar. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized reports benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence indicates that I514V is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | 6-33438783-A-G | 7 | 4.34e-6 | -5.187 | Likely Benign | 0.245 | Likely Benign | Likely Benign | 1.39 | Ambiguous | 0.0 | 0.44 | Likely Benign | 0.92 | Ambiguous | 0.89 | Ambiguous | 0.173 | Likely Benign | -0.79 | Neutral | 0.914 | Possibly Damaging | 0.960 | Probably Damaging | 3.15 | Benign | 0.13 | Tolerated | 3.37 | 35 | 0.0939 | 0.2130 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||||||
| c.1745A>T | E582V 2D 3DClick to see structure in 3D Viewer AISynGAP1 E582V is not reported in ClinVar and is absent from gnomAD. Computational predictors show a split: benign calls from REVEL, Rosetta, premPS, SIFT, and FATHMM; pathogenic calls from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default; and two uncertain calls from FoldX and AlphaMissense‑Optimized. High‑accuracy methods give a pathogenic consensus: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is uncertain due to conflicting inputs. Overall, the computational evidence leans toward pathogenicity, and this assessment does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.033838 | Uncertain | 0.845 | 0.235 | 0.000 | -10.737 | Likely Pathogenic | 0.842 | Likely Pathogenic | Ambiguous | 0.87 | Ambiguous | 0.1 | -0.13 | Likely Benign | 0.37 | Likely Benign | 0.24 | Likely Benign | 0.251 | Likely Benign | -3.92 | Deleterious | 0.995 | Probably Damaging | 0.996 | Probably Damaging | 3.15 | Benign | 0.10 | Tolerated | 0.0564 | 0.4186 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1769G>C | S590T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590T is not 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, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and ESM1b. Two tools (premPS 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) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. 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. | GAP | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | -12.472 | Likely Pathogenic | 0.458 | Ambiguous | Likely Benign | 0.23 | Likely Benign | 0.1 | 0.42 | Likely Benign | 0.33 | Likely Benign | 0.64 | Ambiguous | 0.459 | Likely Benign | -2.89 | Deleterious | 0.183 | Benign | 0.050 | Benign | 3.15 | Benign | 0.08 | Tolerated | 0.1420 | 0.5723 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.2066T>G | L689R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L689R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. No predictions are missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.227227 | Uncertain | 0.963 | 0.248 | 0.000 | -17.776 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 5.91 | Destabilizing | 0.6 | 5.61 | Destabilizing | 5.76 | Destabilizing | 2.14 | Destabilizing | 0.609 | Likely Pathogenic | -5.98 | Deleterious | 1.000 | Probably Damaging | 0.932 | Probably Damaging | 3.15 | Benign | 0.00 | Affected | 0.1208 | 0.0530 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2086C>A | L696I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L696I missense change is not reported in ClinVar and has no entry in gnomAD. 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, SIFT, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and premPS 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, and Foldetta is unavailable. Overall, the majority of conventional tools lean toward pathogenicity, and the high‑accuracy prediction that is available (AlphaMissense‑Optimized) indicates benign, leaving the evidence mixed. Thus, the variant is most likely pathogenic based on the preponderance of predictions, and this does not contradict the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.200174 | Structured | 0.390093 | Uncertain | 0.962 | 0.267 | 0.000 | -10.652 | Likely Pathogenic | 0.698 | Likely Pathogenic | Likely Benign | 1.01 | Ambiguous | 0.1 | 0.58 | Ambiguous | 0.80 | Ambiguous | 0.85 | Ambiguous | 0.250 | Likely Benign | -1.86 | Neutral | 0.996 | Probably Damaging | 0.989 | Probably Damaging | 3.15 | Benign | 0.00 | Affected | 0.0921 | 0.2542 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.3464T>C | V1155A 2D AIThe SynGAP1 missense variant V1155A is not reported 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 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 Uncertain, SGM‑Consensus as Likely Benign, and 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. | Likely Benign | 0.750527 | Disordered | 0.855718 | Binding | 0.335 | 0.857 | 0.500 | -2.019 | Likely Benign | 0.941 | Likely Pathogenic | Ambiguous | 0.224 | Likely Benign | 0.77 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 3.15 | Benign | 1.00 | Tolerated | 0.3070 | 0.1859 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.3832C>G | P1278A 2D AIThe SynGAP1 missense variant P1278A 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 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, 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 status (none reported). 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 | -4.187 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.100 | Likely Benign | 0.89 | Neutral | 0.001 | Benign | 0.002 | Benign | 3.15 | Benign | 1.00 | Tolerated | 0.3597 | 0.3353 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3893A>G | Q1298R 2D AIThe SynGAP1 missense variant Q1298R 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, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -2.643 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 0.112 | Likely Benign | 1.38 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.15 | Benign | 1.00 | Tolerated | 0.1142 | 0.1628 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| 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 | -2.25 | Neutral | 0.978 | Probably Damaging | 0.983 | Probably Damaging | 3.15 | Benign | 0.00 | Affected | 0.2241 | 0.5058 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3935C>T | A1312V 2D AIThe SynGAP1 missense variant A1312V is reported in gnomAD (ID 6‑33451809‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: six methods (REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score all predict a benign effect, while three tools (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT) predict pathogenicity. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns “Benign” and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” No Foldetta stability data are available, so it does not influence the conclusion. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar status (none is listed). 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 | 6-33451809-C-T | 4 | 2.48e-6 | -4.585 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.231 | Likely Benign | -1.74 | Neutral | 0.991 | Probably Damaging | 0.983 | Probably Damaging | 3.15 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1495 | 0.6343 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||
| c.1238C>A | P413H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P413H 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 only FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact; Rosetta is uncertain. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among pathogenic predictors and the high‑accuracy tools, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.332472 | Uncertain | 0.927 | 0.201 | 0.000 | -13.376 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.89 | Destabilizing | 1.0 | 1.85 | Ambiguous | 3.37 | Destabilizing | 1.07 | Destabilizing | 0.546 | Likely Pathogenic | -8.29 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.16 | Benign | 0.00 | Affected | 0.1745 | 0.3480 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||
| c.1258T>G | F420V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420V is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic outcome: FoldX, Rosetta, Foldetta, premPS, 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, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts Pathogenic; the SGM‑Consensus itself is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts Pathogenic. Based on the preponderance of pathogenic predictions and the high‑accuracy tool consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | -11.849 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 3.42 | Destabilizing | 0.1 | 3.35 | Destabilizing | 3.39 | Destabilizing | 1.58 | Destabilizing | 0.402 | Likely Benign | -6.41 | Deleterious | 0.495 | Possibly Damaging | 0.191 | Benign | 3.16 | Benign | 0.01 | Affected | 0.2038 | 0.2022 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.130T>A | W44R 2D  AIThe SynGAP1 W44R 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, whereas 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‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of tools (seven pathogenic vs. three benign) indicate a pathogenic impact. 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. | 0.301917 | Structured | 0.431379 | Uncertain | 0.377 | 0.748 | 0.375 | -4.850 | Likely Benign | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.291 | Likely Benign | -5.06 | Deleterious | 0.943 | Possibly Damaging | 0.888 | Possibly Damaging | 3.16 | Benign | 0.00 | Affected | 0.4268 | 0.0749 | 2 | -3 | -3.6 | -30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.130T>C | W44R 2D AISynGAP1 W44R is not reported in ClinVar and is absent from gnomAD. Consensus from standard predictors shows a split: benign calls come from REVEL, ESM1b, and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessment focuses on AlphaMissense‑Optimized, which predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic effect, 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. | 0.301917 | Structured | 0.431379 | Uncertain | 0.377 | 0.748 | 0.375 | -4.850 | Likely Benign | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.291 | Likely Benign | -5.06 | Deleterious | 0.943 | Possibly Damaging | 0.888 | Possibly Damaging | 3.16 | Benign | 0.00 | Affected | 0.4268 | 0.0749 | 2 | -3 | -3.6 | -30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.130T>G | W44G 2D  AIThe SynGAP1 missense variant W44G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: 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 benign (3), and no ClinVar evidence contradicts this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.301917 | Structured | 0.431379 | Uncertain | 0.377 | 0.748 | 0.375 | -4.658 | Likely Benign | 0.850 | Likely Pathogenic | Ambiguous | 0.323 | Likely Benign | -4.80 | Deleterious | 0.659 | Possibly Damaging | 0.693 | Possibly Damaging | 3.16 | Benign | 0.00 | Affected | 0.4198 | 0.2164 | -7 | -2 | 0.5 | -129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.131G>C | W44S 2D  AIThe SynGAP1 missense variant W44S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.301917 | Structured | 0.431379 | Uncertain | 0.377 | 0.748 | 0.375 | -5.113 | Likely Benign | 0.921 | Likely Pathogenic | Ambiguous | 0.275 | Likely Benign | -4.68 | Deleterious | 0.824 | Possibly Damaging | 0.775 | Possibly Damaging | 3.16 | Benign | 0.00 | Affected | 0.4139 | 0.2371 | -2 | -3 | 0.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.1355T>A | V452D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V452D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, while all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy predictors, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | -15.793 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.92 | Destabilizing | 0.1 | 3.37 | Destabilizing | 3.65 | Destabilizing | 2.52 | Destabilizing | 0.630 | Likely Pathogenic | -6.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.16 | Benign | 0.00 | Affected | 0.1320 | 0.0610 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||
| c.1532G>T | G511V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511V 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 only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently has no classification for G511V. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | -11.738 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 3.47 | Destabilizing | 0.2 | 0.79 | Ambiguous | 2.13 | Destabilizing | 0.65 | Ambiguous | 0.540 | Likely Pathogenic | -8.71 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.16 | Benign | 0.01 | Affected | 0.1557 | 0.3019 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| 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 | 6.40 | Destabilizing | 1.1 | 10.90 | Destabilizing | 8.65 | Destabilizing | 0.61 | Ambiguous | 0.612 | Likely Pathogenic | -4.82 | Deleterious | 0.998 | Probably Damaging | 0.790 | Possibly Damaging | 3.16 | Benign | 0.02 | Affected | 0.1979 | 0.5137 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.2084T>C | L695P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L695P is 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, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods give the following 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) also predicts pathogenic. Based on the overwhelming agreement among these tools, 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 | 0.118441 | Structured | 0.373419 | Uncertain | 0.942 | 0.258 | 0.000 | -17.496 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.63 | Destabilizing | 0.2 | 4.73 | Destabilizing | 4.68 | Destabilizing | 2.11 | Destabilizing | 0.612 | Likely Pathogenic | -6.85 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.16 | Benign | 0.00 | Affected | 0.3044 | 0.0992 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.2086C>G | L696V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L696V variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas the majority of other in silico predictors (FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) report a pathogenic outcome; Rosetta remains inconclusive. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts benign, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for the variant, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.390093 | Uncertain | 0.962 | 0.267 | 0.000 | Uncertain | 1 | -11.909 | Likely Pathogenic | 0.745 | Likely Pathogenic | Likely Benign | 2.35 | Destabilizing | 0.1 | 1.85 | Ambiguous | 2.10 | Destabilizing | 1.46 | Destabilizing | 0.351 | Likely Benign | -2.79 | Deleterious | 0.992 | Probably Damaging | 0.970 | Probably Damaging | 3.16 | Benign | 0.00 | Affected | 3.46 | 13 | 0.1307 | 0.2830 | 1 | 2 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.2140C>G | L714V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L714V has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. 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 (2 pathogenic vs. 2 benign). Overall, the majority of predictions (10 pathogenic vs. 4 benign) indicate a likely pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no record for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.314870 | Structured | 0.402311 | Uncertain | 0.961 | 0.369 | 0.000 | -4.966 | Likely Benign | 0.781 | Likely Pathogenic | Likely Benign | 3.91 | Destabilizing | 0.1 | 6.19 | Destabilizing | 5.05 | Destabilizing | 1.21 | Destabilizing | 0.259 | Likely Benign | -2.76 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 3.16 | Benign | 0.00 | Affected | 0.1421 | 0.2689 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||
| c.1303T>A | L435M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L435M missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect; 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 | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -4.705 | Likely Benign | 0.534 | Ambiguous | Likely Benign | 0.24 | Likely Benign | 0.0 | 1.02 | Ambiguous | 0.63 | Ambiguous | 1.05 | Destabilizing | 0.233 | Likely Benign | -1.74 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.17 | Benign | 0.01 | Affected | 0.0675 | 0.2753 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1355T>G | V452G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V452G 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—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. AlphaMissense‑Optimized is uncertain, providing no definitive direction. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic verdict, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. AlphaMissense‑Optimized remains uncertain. Overall, the preponderance of evidence indicates that V452G is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | -13.410 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 3.70 | Destabilizing | 0.1 | 3.37 | Destabilizing | 3.54 | Destabilizing | 2.46 | Destabilizing | 0.570 | Likely Pathogenic | -6.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.17 | Benign | 0.00 | Affected | 0.1948 | 0.2567 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1937T>A | L646Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L646Q lies in the GAP domain. ClinVar has no entry for this variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect are REVEL, FATHMM, and AlphaMissense‑Optimized. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Taken together, the overwhelming majority of evidence indicates that 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 | 0.048328 | Structured | 0.303751 | Uncertain | 0.941 | 0.344 | 0.000 | -12.735 | Likely Pathogenic | 0.752 | Likely Pathogenic | Likely Benign | 3.23 | Destabilizing | 0.1 | 3.04 | Destabilizing | 3.14 | Destabilizing | 2.12 | Destabilizing | 0.462 | Likely Benign | -2.78 | Deleterious | 0.994 | Probably Damaging | 0.790 | Possibly Damaging | 3.17 | Benign | 0.00 | Affected | 0.2090 | 0.1963 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1937T>C | L646P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L646P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) 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 because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.303751 | Uncertain | 0.941 | 0.344 | 0.000 | -12.956 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 7.34 | Destabilizing | 0.5 | 12.08 | Destabilizing | 9.71 | Destabilizing | 2.72 | Destabilizing | 0.604 | Likely Pathogenic | -4.55 | Deleterious | 0.999 | Probably Damaging | 0.926 | Probably Damaging | 3.17 | Benign | 0.00 | Affected | 0.3481 | 0.1874 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1937T>G | L646R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L646R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic calls are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, SGM Consensus is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Overall, the preponderance of evidence points to a pathogenic effect for L646R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.303751 | Uncertain | 0.941 | 0.344 | 0.000 | -12.393 | Likely Pathogenic | 0.920 | Likely Pathogenic | Ambiguous | 4.44 | Destabilizing | 0.2 | 3.94 | Destabilizing | 4.19 | Destabilizing | 2.75 | Destabilizing | 0.455 | Likely Benign | -3.56 | Deleterious | 0.014 | Benign | 0.002 | Benign | 3.17 | Benign | 0.03 | Affected | 0.2304 | 0.1405 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2066T>C | L689P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L689P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) 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 because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.227227 | Uncertain | 0.963 | 0.248 | 0.000 | -17.900 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 6.76 | Destabilizing | 0.2 | 13.35 | Destabilizing | 10.06 | Destabilizing | 2.29 | Destabilizing | 0.631 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.17 | Benign | 0.00 | Affected | 0.3668 | 0.1353 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.2084T>A | L695Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L695Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). FoldX and Foldetta provide uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus, derived from a majority of high‑confidence predictors, indicates pathogenicity; Foldetta remains inconclusive. Overall, the majority of reliable tools predict a pathogenic effect, and this is consistent with the lack of ClinVar annotation (no contradiction). 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. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.373419 | Uncertain | 0.942 | 0.258 | 0.000 | -12.192 | Likely Pathogenic | 0.706 | Likely Pathogenic | Likely Benign | 1.88 | Ambiguous | 0.1 | 2.03 | Destabilizing | 1.96 | Ambiguous | 1.71 | Destabilizing | 0.554 | Likely Pathogenic | -5.92 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.17 | Benign | 0.08 | Tolerated | 0.0869 | 0.0688 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.2084T>G | L695R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L695R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, while the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all classify the variant as pathogenic. AlphaMissense‑Optimized returns an uncertain result. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also pathogenic. Overall, the evidence overwhelmingly 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 | GAP | 0.118441 | Structured | 0.373419 | Uncertain | 0.942 | 0.258 | 0.000 | -15.582 | Likely Pathogenic | 0.873 | Likely Pathogenic | Ambiguous | 2.05 | Destabilizing | 0.1 | 2.66 | Destabilizing | 2.36 | Destabilizing | 1.57 | Destabilizing | 0.605 | Likely Pathogenic | -5.92 | Deleterious | 0.993 | Probably Damaging | 0.588 | Possibly Damaging | 3.17 | Benign | 0.00 | Affected | 0.1220 | 0.0530 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.248G>T | R83I 2D  AIThe SynGAP1 missense variant R83I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, 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 (two pathogenic vs. two benign). Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the preponderance of evidence (seven pathogenic vs. three benign predictions) indicates that R83I 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. | 0.637480 | Disordered | 0.522784 | Binding | 0.275 | 0.895 | 0.250 | -4.021 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.183 | Likely Benign | -3.15 | Deleterious | 0.972 | Probably Damaging | 0.766 | Possibly Damaging | 3.17 | Benign | 0.00 | Affected | 0.1450 | 0.3219 | -2 | -3 | 9.0 | -43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3934G>A | A1312T 2D AISynGAP1 missense variant A1312T 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. 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 | 0.767246 | Disordered | 0.971112 | Binding | 0.392 | 0.902 | 0.750 | -4.137 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.155 | Likely Benign | -0.65 | Neutral | 0.991 | Probably Damaging | 0.989 | Probably Damaging | 3.17 | Benign | 0.00 | Affected | 0.1865 | 0.7600 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.1237C>A | P413T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P413T 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 limited to FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No predictions are inconclusive or missing. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.332472 | Uncertain | 0.927 | 0.201 | 0.000 | -12.851 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.22 | Destabilizing | 0.2 | 1.87 | Ambiguous | 2.55 | Destabilizing | 0.93 | Ambiguous | 0.554 | Likely Pathogenic | -7.37 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.18 | Benign | 0.01 | Affected | 0.1663 | 0.4670 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||
| c.1304T>C | L435S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L435S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity largely agree: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic signal: 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 predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -12.662 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 4.18 | Destabilizing | 0.0 | 4.09 | Destabilizing | 4.14 | Destabilizing | 1.83 | Destabilizing | 0.596 | Likely Pathogenic | -5.63 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.18 | Benign | 0.01 | Affected | 0.2705 | 0.0505 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||
| c.1418T>C | V473A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V473A missense variant is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are all uncertain or unavailable, providing no decisive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of available predictions support a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation (no contradiction). 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 | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -10.867 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 1.88 | Ambiguous | 0.0 | 1.76 | Ambiguous | 1.82 | Ambiguous | 2.17 | Destabilizing | 0.485 | Likely Benign | -3.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.18 | Benign | 0.00 | Affected | 0.2529 | 0.2521 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1886T>C | V629A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V629A 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, SIFT, and FATHMM. Those that predict a pathogenic effect comprise SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as Pathogenic (combining FoldX‑MD and Rosetta outputs). Overall, the majority of predictions (8 pathogenic vs. 3 benign) indicate that V629A is most likely pathogenic, 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 | 0.040537 | Structured | 0.034796 | Uncertain | 0.970 | 0.236 | 0.000 | -8.652 | Likely Pathogenic | 0.926 | Likely Pathogenic | Ambiguous | 2.24 | Destabilizing | 0.1 | 1.96 | Ambiguous | 2.10 | Destabilizing | 1.58 | Destabilizing | 0.492 | Likely Benign | -3.58 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.18 | Benign | 0.11 | Tolerated | 0.2518 | 0.2124 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.2003C>A | S668Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S668Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS and FATHMM, whereas the remaining 12 tools (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict it to be pathogenic or likely pathogenic. High‑accuracy methods give consistent results: AlphaMissense‑Optimized scores it as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No predictions are missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | -14.833 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 18.34 | Destabilizing | 6.2 | 12.69 | Destabilizing | 15.52 | Destabilizing | 0.06 | Likely Benign | 0.641 | Likely Pathogenic | -5.95 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.18 | Benign | 0.00 | Affected | 0.0647 | 0.5693 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.2003C>T | S668F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S668F is reported in ClinVar as Pathogenic (ClinVar ID 1309930.0) and is not found in gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from premPS and FATHMM, while the remaining 12 tools (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also Pathogenic. No predictions are inconclusive. Overall, the computational evidence strongly supports a pathogenic effect, consistent with the ClinVar classification. Therefore, the variant is most likely pathogenic based on the consensus of prediction tools, and this assessment aligns with its ClinVar status. 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 | Likely Pathogenic | 1 | -15.047 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 16.72 | Destabilizing | 5.0 | 11.07 | Destabilizing | 13.90 | Destabilizing | 0.00 | Likely Benign | 0.643 | Likely Pathogenic | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.18 | Benign | 0.00 | Affected | 3.38 | 28 | 0.0656 | 0.5849 | -3 | -2 | 3.6 | 60.10 | 250.9 | -59.6 | -0.1 | 0.1 | 0.0 | 0.1 | X | X | X | Potentially Pathogenic | In the WT simulations, the hydroxyl side chain of Ser668, located on an α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), forms hydrogen bonds with the backbone carbonyl groups of Leu664, Tyr665, and Glu666, as well as the guanidinium group of Arg573 on a nearby α-helix (res. Arg563-Glu578). In the variant simulations, the side chain of Phe668 cannot maintain the same hydrogen-bond network. Due to its larger size, it moves away to avoid steric hindrance. In the WT simulations, a network of hydrogen bonds between several residues (e.g., Asn669, Lys566, and Glu666) keeps both α-helices and the proceeding loop (res. Asn669-Asp684) tightly connected, but this setup is not present in the variant simulations. Additionally, in the variant simulations, the side chain of Arg573 shifts to form a more stable salt bridge with the carboxylate group of Glu582 instead of hydrogen bonding with Ser668 as in the WT simulations. | ||||||||||||||
| c.2065C>T | L689F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L689F is not 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. Two tools (Rosetta and premPS) yield uncertain results. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.227227 | Uncertain | 0.963 | 0.248 | 0.000 | -9.817 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 2.45 | Destabilizing | 0.2 | 1.95 | Ambiguous | 2.20 | Destabilizing | 0.67 | Ambiguous | 0.286 | Likely Benign | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.860 | Possibly Damaging | 3.18 | Benign | 0.00 | Affected | 0.0608 | 0.2891 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.2078A>T | H693L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H693L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from Foldetta, premPS, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain results are reported by FoldX and Rosetta. High‑accuracy assessments indicate AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also leans pathogenic, whereas Foldetta predicts benign stability. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.073402 | Structured | 0.323991 | Uncertain | 0.964 | 0.260 | 0.000 | -14.006 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | -0.53 | Ambiguous | 0.1 | 0.92 | Ambiguous | 0.20 | Likely Benign | -0.29 | Likely Benign | 0.573 | Likely Pathogenic | -10.96 | Deleterious | 0.979 | Probably Damaging | 0.390 | Benign | 3.18 | Benign | 0.01 | Affected | 0.0824 | 0.4675 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||
| c.247A>G | R83G 2D AIThe SynGAP1 R83G 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 and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign votes) and is therefore treated as unavailable. Foldetta stability analysis is not provided and is likewise unavailable. Overall, the preponderance of evidence (six pathogenic vs. three benign predictions) indicates that the variant is most likely pathogenic, with no contradiction to ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.637480 | Disordered | 0.522784 | Binding | 0.275 | 0.895 | 0.250 | -4.708 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.111 | Likely Benign | -2.60 | Deleterious | 0.909 | Possibly Damaging | 0.587 | Possibly Damaging | 3.18 | Benign | 0.00 | Affected | 0.3514 | 0.2537 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.248G>C | R83T 2D AIThe SynGAP1 missense variant R83T has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign calls (REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus “Likely Benign”) and pathogenic calls (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized). High‑accuracy assessments further split the verdict: AlphaMissense‑Optimized predicts pathogenic, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign; Foldetta results are unavailable. With five tools supporting benign and five supporting pathogenic, the evidence is evenly divided. Consequently, the variant’s clinical significance remains uncertain and is not contradicted by any ClinVar annotation, which has no classification. Overall, the variant is most likely pathogenic, and this does not contradict ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.522784 | Binding | 0.275 | 0.895 | 0.250 | -3.585 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.124 | Likely Benign | -2.15 | Neutral | 0.909 | Possibly Damaging | 0.587 | Possibly Damaging | 3.18 | Benign | 0.00 | Affected | 0.1671 | 0.3360 | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||||||||||||
| c.2510T>G | V837G 2D AIThe SynGAP1 missense variant V837G is not reported 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 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 | 0.525368 | Disordered | 0.626284 | Binding | 0.318 | 0.871 | 0.125 | -2.599 | Likely Benign | 0.315 | Likely Benign | Likely Benign | 0.187 | Likely Benign | 0.93 | Neutral | 0.997 | Probably Damaging | 0.999 | Probably Damaging | 3.18 | Benign | 1.00 | Tolerated | 0.2260 | 0.2422 | -1 | -3 | -4.6 | -42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3445C>T | P1149S 2D AIThe SynGAP1 missense variant P1149S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.786938 | Binding | 0.424 | 0.837 | 0.625 | -2.650 | Likely Benign | 0.184 | Likely Benign | Likely Benign | 0.067 | Likely Benign | 0.14 | Neutral | 0.068 | Benign | 0.065 | Benign | 3.18 | Benign | 0.48 | Tolerated | 0.3460 | 0.4826 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3706C>G | Q1236E 2D AIThe SynGAP1 missense variant Q1236E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence supports a benign classification for Q1236E, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.680603 | Disordered | 0.567914 | Binding | 0.883 | 0.537 | 0.125 | -0.371 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 0.263 | Likely Benign | 0.66 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 3.18 | Benign | 1.00 | Tolerated | 0.0985 | 0.1130 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||||||
| c.3985C>G | L1329V 2D AIThe SynGAP1 missense variant L1329V is catalogued in gnomAD (6‑33451859‑C‑G) but has no ClinVar entry. Functional prediction tools show mixed results: benign calls come from REVEL, PROVEAN, ESM1b, and FATHMM, whereas pathogenic calls are reported by polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. When predictions are grouped by consensus, the majority of standard algorithms (REVEL, PROVEAN, ESM1b, FATHMM) support a benign effect, while a minority (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default) suggest pathogenicity. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts a benign outcome, and the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect, and this conclusion is consistent with the lack of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.930790 | Disordered | 0.924905 | Binding | 0.336 | 0.748 | 0.875 | 6-33451859-C-G | 1 | 6.40e-7 | -4.209 | Likely Benign | 0.770 | Likely Pathogenic | Likely Benign | 0.077 | Likely Benign | -1.55 | Neutral | 0.980 | Probably Damaging | 0.952 | Probably Damaging | 3.18 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1571 | 0.3579 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.4007A>T | E1336V 2D AIThe SynGAP1 missense variant E1336V has no ClinVar record (ClinVar status: None) and is not present in gnomAD (gnomAD ID: None). 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. AlphaMissense‑Optimized is reported as uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a tie (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Consequently, the variant’s predicted impact is ambiguous, with an equal split between benign and pathogenic calls and no evidence from ClinVar to contradict this uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.865454 | Disordered | 0.973342 | Binding | 0.336 | 0.717 | 0.750 | -3.367 | Likely Benign | 0.932 | Likely Pathogenic | Ambiguous | 0.221 | Likely Benign | -4.46 | Deleterious | 0.789 | Possibly Damaging | 0.348 | Benign | 3.18 | Benign | 0.00 | Affected | 0.0991 | 0.7425 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||||
| c.628C>G | H210D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H210D is not 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, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain, and Rosetta alone is also uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for H210D, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -16.440 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.13 | Likely Benign | 0.4 | 1.23 | Ambiguous | 0.68 | Ambiguous | 1.23 | Destabilizing | 0.489 | Likely Benign | -7.73 | Deleterious | 0.895 | Possibly Damaging | 0.533 | Possibly Damaging | 3.18 | Benign | 0.00 | Affected | 0.2025 | 0.1255 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.1235T>G | L412W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L412W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) 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 because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -13.436 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 8.44 | Destabilizing | 0.4 | 9.91 | Destabilizing | 9.18 | Destabilizing | 1.65 | Destabilizing | 0.503 | Likely Pathogenic | -5.53 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | 0.0586 | 0.2664 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||
| c.1237C>G | P413A 2D 3DClick to see structure in 3D Viewer AISynGAP1 P413A is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the majority of algorithms—FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect for P413A, 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 | 0.113710 | Structured | 0.332472 | Uncertain | 0.927 | 0.201 | 0.000 | -12.686 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.38 | Destabilizing | 0.0 | 0.79 | Ambiguous | 1.59 | Ambiguous | 0.81 | Ambiguous | 0.392 | Likely Benign | -7.37 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.19 | Benign | 0.02 | Affected | 0.3350 | 0.3863 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1237C>T | P413S 2D 3DClick to see structure in 3D Viewer AISynGAP1 P413S is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta—indicate a pathogenic effect. High‑accuracy methods give a consistent pathogenic verdict: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic, and Foldetta (which integrates FoldX‑MD and Rosetta outputs) predicts pathogenic; FoldX alone supports pathogenicity while Rosetta remains uncertain. Taken together, the overwhelming majority of predictions support a pathogenic classification, and this is not contradicted by the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.332472 | Uncertain | 0.927 | 0.201 | 0.000 | -12.586 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.06 | Destabilizing | 0.1 | 1.72 | Ambiguous | 2.39 | Destabilizing | 0.93 | Ambiguous | 0.509 | Likely Pathogenic | -7.37 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.19 | Benign | 0.04 | Affected | 0.3454 | 0.3819 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| c.1238C>T | P413L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P413L 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, premPS, and FATHMM. Those that predict a pathogenic effect comprise SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence 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. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.332472 | Uncertain | 0.927 | 0.201 | 0.000 | -12.735 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.61 | Destabilizing | 0.4 | 1.34 | Ambiguous | 1.98 | Ambiguous | 0.30 | Likely Benign | 0.461 | Likely Benign | -9.21 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | 0.2056 | 0.5614 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.1244A>C | E415A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E415A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, Foldetta, and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are given by FoldX and premPS. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of tools lean toward pathogenicity, and the high‑accuracy predictions support this view. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -11.743 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.61 | Ambiguous | 0.2 | 0.05 | Likely Benign | 0.33 | Likely Benign | 0.53 | Ambiguous | 0.435 | Likely Benign | -5.56 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.19 | Benign | 0.03 | Affected | 0.2909 | 0.3432 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1337A>T | E446V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E446V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, premPS, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (8 pathogenic vs. 3 benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.276479 | Uncertain | 0.940 | 0.216 | 0.000 | -12.231 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 1.72 | Ambiguous | 0.7 | 0.34 | Likely Benign | 1.03 | Ambiguous | 0.37 | Likely Benign | 0.513 | Likely Pathogenic | -6.55 | Deleterious | 0.995 | Probably Damaging | 0.983 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | 0.0618 | 0.6433 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| 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 | 3.06 | Destabilizing | 0.2 | 2.40 | Destabilizing | 2.73 | Destabilizing | 0.63 | Ambiguous | 0.558 | Likely Pathogenic | -3.95 | Deleterious | 0.996 | Probably Damaging | 0.973 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | 0.1187 | 0.5050 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1745A>C | E582A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E582A 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, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Two tools (FoldX and ESM1b) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. 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. | GAP | 0.102787 | Structured | 0.033838 | Uncertain | 0.845 | 0.235 | 0.000 | -7.432 | In-Between | 0.661 | Likely Pathogenic | Likely Benign | 0.78 | Ambiguous | 0.2 | 0.15 | Likely Benign | 0.47 | Likely Benign | 0.27 | Likely Benign | 0.263 | Likely Benign | -2.99 | Deleterious | 0.998 | Probably Damaging | 0.999 | Probably Damaging | 3.19 | Benign | 0.26 | Tolerated | 0.3236 | 0.4000 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||
| c.1810T>A | S604T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S604T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, SIFT, and FATHMM, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive (FoldX, Rosetta, AlphaMissense‑Optimized) are treated as unavailable. 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 (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall pattern of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010926 | Structured | 0.192527 | Uncertain | 0.911 | 0.195 | 0.000 | -9.674 | Likely Pathogenic | 0.897 | Likely Pathogenic | Ambiguous | 0.64 | Ambiguous | 0.1 | -0.58 | Ambiguous | 0.03 | Likely Benign | -0.16 | Likely Benign | 0.337 | Likely Benign | -2.99 | Deleterious | 0.826 | Possibly Damaging | 0.872 | Possibly Damaging | 3.19 | Benign | 0.08 | Tolerated | 0.1687 | 0.4919 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.2063A>T | E688V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E688V missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Foldetta, premPS, and FATHMM, while pathogenic calls are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta is uncertain. High‑accuracy methods give divergent results: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of tools support a pathogenic effect, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.211124 | Uncertain | 0.947 | 0.223 | 0.000 | -14.642 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | -0.02 | Likely Benign | 0.6 | -0.63 | Ambiguous | -0.33 | Likely Benign | 0.37 | Likely Benign | 0.532 | Likely Pathogenic | -6.62 | Deleterious | 0.998 | Probably Damaging | 0.983 | Probably Damaging | 3.19 | Benign | 0.02 | Affected | 0.0681 | 0.5831 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.2107C>G | L703V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703V is 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Because the variant is not present in ClinVar or gnomAD, there is no existing clinical classification to contradict. Overall, the majority of predictions and the two high‑accuracy benign assessments suggest the variant is most likely benign, although the Foldetta result indicates a potential pathogenic effect that warrants further functional investigation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.144935 | Structured | 0.388282 | Uncertain | 0.929 | 0.353 | 0.000 | -10.086 | Likely Pathogenic | 0.301 | Likely Benign | Likely Benign | 2.32 | Destabilizing | 0.1 | 2.61 | Destabilizing | 2.47 | Destabilizing | 1.07 | Destabilizing | 0.080 | Likely Benign | -2.22 | Neutral | 0.789 | Possibly Damaging | 0.352 | Benign | 3.19 | Benign | 0.00 | Affected | 0.1383 | 0.2621 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.249A>C | R83S 2D AIThe SynGAP1 R83S missense variant has no ClinVar entry and is present in gnomAD (ID 6‑33425857‑A‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) remains Likely Benign. Foldetta results are unavailable. Overall, the predictions are split, but the consensus‑based high‑accuracy tools lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, 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 | 0.637480 | Disordered | 0.522784 | Binding | 0.275 | 0.895 | 0.250 | 6-33425857-A-C | 1 | 6.20e-7 | -2.550 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.094 | Likely Benign | -1.87 | Neutral | 0.909 | Possibly Damaging | 0.587 | Possibly Damaging | 3.19 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3161 | 0.2734 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||
| c.249A>T | R83S 2D AISynGAP1 R83S is listed in ClinVar (ID 537001.0) with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign; Foldetta results are unavailable. Overall, the predictions are split, with an equal number of benign and pathogenic calls, and the high‑accuracy tools are discordant. Thus, the variant is most likely pathogenic based on the predominance of pathogenic predictions, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.522784 | Binding | 0.275 | 0.895 | 0.250 | Uncertain | 1 | -2.550 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.094 | Likely Benign | -1.87 | Neutral | 0.909 | Possibly Damaging | 0.587 | Possibly Damaging | 3.19 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3161 | 0.2734 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||
| c.1244A>G | E415G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E415G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Stability‑based methods (FoldX, Rosetta, premPS) and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for E415G. This prediction is consistent with the lack of ClinVar annotation and does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -12.244 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 1.16 | Ambiguous | 0.2 | 0.88 | Ambiguous | 1.02 | Ambiguous | 0.65 | Ambiguous | 0.432 | Likely Benign | -6.45 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.20 | Benign | 0.01 | Affected | 0.2518 | 0.3158 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.131G>T | W44L 2D  AIThe SynGAP1 missense variant W44L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Consensus from standard predictors shows a split: benign calls come from REVEL, ESM1b, and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized returns an uncertain result. High‑accuracy assessment is inconclusive: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑vs‑2 tie, and Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a pathogenic interpretation, with no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.301917 | Structured | 0.431379 | Uncertain | 0.377 | 0.748 | 0.375 | -5.743 | Likely Benign | 0.869 | Likely Pathogenic | Ambiguous | 0.211 | Likely Benign | -4.37 | Deleterious | 0.659 | Possibly Damaging | 0.693 | Possibly Damaging | 3.20 | Benign | 0.00 | Affected | 0.2584 | 0.3413 | -2 | -2 | 4.7 | -73.05 | ||||||||||||||||||||||||||||||||||||||||
| c.1450T>C | F484L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN (3 pathogenic vs. 1 benign) and therefore also indicates pathogenicity. AlphaMissense‑Optimized independently predicts pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, seven tools predict pathogenicity versus four predicting benign, and the high‑accuracy consensus supports a pathogenic interpretation. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -11.052 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.52 | Ambiguous | 0.0 | 1.32 | Ambiguous | 1.42 | Ambiguous | 1.20 | Destabilizing | 0.275 | Likely Benign | -5.64 | Deleterious | 0.054 | Benign | 0.022 | Benign | 3.20 | Benign | 0.04 | Affected | 0.1737 | 0.2956 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1452C>A | F484L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN (3 pathogenic vs. 1 benign) and therefore also indicates pathogenicity. AlphaMissense‑Optimized independently predicts pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, seven tools predict pathogenicity versus four predicting benign, and the high‑accuracy consensus supports a pathogenic interpretation. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -11.052 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.52 | Ambiguous | 0.0 | 1.32 | Ambiguous | 1.42 | Ambiguous | 1.20 | Destabilizing | 0.214 | Likely Benign | -5.64 | Deleterious | 0.054 | Benign | 0.022 | Benign | 3.20 | Benign | 0.04 | Affected | 0.1737 | 0.2956 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1452C>G | F484L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, yields an uncertain result. Overall, seven tools predict pathogenicity versus four predicting benign, and the high‑accuracy methods reinforce the pathogenic signal. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -11.052 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.52 | Ambiguous | 0.0 | 1.32 | Ambiguous | 1.42 | Ambiguous | 1.20 | Destabilizing | 0.214 | Likely Benign | -5.64 | Deleterious | 0.054 | Benign | 0.022 | Benign | 3.20 | Benign | 0.04 | Affected | 0.1737 | 0.2956 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1556A>T | E519V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519V missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further highlight the discord: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates benign stability. Overall, the preponderance of evidence points to a pathogenic effect for E519V. This conclusion does not conflict with 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 | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | -10.513 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.59 | Ambiguous | 0.0 | -0.40 | Likely Benign | 0.10 | Likely Benign | 0.16 | Likely Benign | 0.400 | Likely Benign | -6.33 | Deleterious | 0.996 | Probably Damaging | 0.991 | Probably Damaging | 3.20 | Benign | 0.00 | Affected | 0.0825 | 0.4369 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.2083C>G | L695V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L695V is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. 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 is also unavailable. Overall, the majority of available predictions (six pathogenic vs. four benign) indicate that the variant is most likely pathogenic, and this assessment 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. | GAP | 0.118441 | Structured | 0.373419 | Uncertain | 0.942 | 0.258 | 0.000 | -10.605 | Likely Pathogenic | 0.317 | Likely Benign | Likely Benign | 1.61 | Ambiguous | 0.0 | 1.57 | Ambiguous | 1.59 | Ambiguous | 1.19 | Destabilizing | 0.274 | Likely Benign | -2.99 | Deleterious | 0.993 | Probably Damaging | 0.694 | Possibly Damaging | 3.20 | Benign | 0.02 | Affected | 0.1158 | 0.2828 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||
| c.2854G>C | G952R 2D AIThe SynGAP1 missense variant G952R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that G952R is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.910621 | Binding | 0.341 | 0.926 | 0.750 | -5.974 | Likely Benign | 0.295 | Likely Benign | Likely Benign | 0.139 | Likely Benign | -0.93 | Neutral | 0.077 | Benign | 0.011 | Benign | 3.20 | Benign | 0.02 | Affected | 0.1145 | 0.4933 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2854G>T | G952C 2D AIThe SynGAP1 missense variant G952C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.910621 | Binding | 0.341 | 0.926 | 0.750 | -8.599 | Likely Pathogenic | 0.088 | Likely Benign | Likely Benign | 0.272 | Likely Benign | -0.18 | Neutral | 0.371 | Benign | 0.169 | Benign | 3.20 | Benign | 0.01 | Affected | 0.1458 | 0.4439 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.2855G>A | G952D 2D AIThe SynGAP1 missense variant G952D is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools overwhelmingly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Benign. Only SIFT predicts a pathogenic outcome, and ESM1b remains uncertain. High‑accuracy assessments corroborate the benign trend: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.910621 | Binding | 0.341 | 0.926 | 0.750 | -7.299 | In-Between | 0.274 | Likely Benign | Likely Benign | 0.241 | Likely Benign | -0.75 | Neutral | 0.033 | Benign | 0.015 | Benign | 3.20 | Benign | 0.05 | Affected | 0.1928 | 0.2826 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2855G>T | G952V 2D AIThe SynGAP1 missense variant G952V is listed in ClinVar (ID 2055482.0) with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that G952V is most likely benign, and this conclusion does not contradict the current ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.910621 | Binding | 0.341 | 0.926 | 0.750 | Uncertain | 1 | -7.074 | In-Between | 0.078 | Likely Benign | Likely Benign | 0.231 | Likely Benign | -0.33 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.20 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1538 | 0.3507 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| c.3895C>A | L1299I 2D AIThe SynGAP1 missense variant L1299I 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.896323 | Binding | 0.398 | 0.832 | 0.750 | -5.264 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.396 | Likely Benign | 0.71 | Neutral | 0.003 | Benign | 0.004 | Benign | 3.20 | Benign | 1.00 | Tolerated | 0.1014 | 0.3893 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.4007A>G | E1336G 2D AIThe SynGAP1 missense variant E1336G is not 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. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2). Foldetta, which would assess protein‑folding stability, has no available result for this variant. Overall, the balance of evidence (five benign vs three pathogenic predictions) suggests the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.865454 | Disordered | 0.973342 | Binding | 0.336 | 0.717 | 0.750 | -3.574 | Likely Benign | 0.932 | Likely Pathogenic | Ambiguous | 0.211 | Likely Benign | -4.36 | Deleterious | 0.345 | Benign | 0.109 | Benign | 3.20 | Benign | 0.00 | Affected | 0.3092 | 0.6170 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.1316T>A | L439Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L439Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) 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 because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.281542 | Uncertain | 0.942 | 0.265 | 0.000 | -11.162 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 2.50 | Destabilizing | 0.1 | 2.06 | Destabilizing | 2.28 | Destabilizing | 1.35 | Destabilizing | 0.575 | Likely Pathogenic | -5.15 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.21 | Benign | 0.01 | Affected | 0.1065 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1316T>C | L439P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L439P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic view: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.281542 | Uncertain | 0.942 | 0.265 | 0.000 | -9.929 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 6.30 | Destabilizing | 0.2 | 7.62 | Destabilizing | 6.96 | Destabilizing | 1.28 | Destabilizing | 0.539 | Likely Pathogenic | -5.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.21 | Benign | 0.02 | Affected | 0.3426 | 0.1192 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1355T>C | V452A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V452A is not reported in ClinVar and has no entry in gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta remains inconclusive. Overall, the consensus of the available tools points to a pathogenic effect for V452A, 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 | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | -10.423 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 2.21 | Destabilizing | 0.0 | 1.51 | Ambiguous | 1.86 | Ambiguous | 2.18 | Destabilizing | 0.505 | Likely Pathogenic | -3.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.21 | Benign | 0.00 | Affected | 0.2642 | 0.2521 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1463C>T | T488M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T488M is listed in ClinVar with an uncertain significance (ClinVar ID 2824521.0) and is present in gnomAD (ID 6‑33438495‑C‑T). Prediction tools that indicate a benign effect include premPS and FATHMM, whereas the majority of algorithms predict a pathogenic outcome: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as inconclusive. No other tools provide definitive evidence. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, 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 | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | Uncertain | 1 | 6-33438495-C-T | 2 | 1.24e-6 | -12.459 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.66 | Ambiguous | 0.3 | 1.62 | Ambiguous | 1.14 | Ambiguous | 0.46 | Likely Benign | 0.746 | Likely Pathogenic | -5.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.21 | Benign | 0.00 | Affected | 3.37 | 35 | 0.1027 | 0.4857 | -1 | -1 | 2.6 | 30.09 | ||||||||||||||||||||||
| c.1556A>G | E519G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519G missense variant is not reported in ClinVar (ClinVar status: None) and has no entry in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, and premPS. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain predictions come from Foldetta, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments: AlphaMissense‑Optimized is uncertain; SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; Foldetta is uncertain. Overall, the majority of available predictions (7 pathogenic vs. 4 benign) lean toward a pathogenic 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 Pathogenic | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | -10.835 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 0.22 | Likely Benign | 0.1 | 0.92 | Ambiguous | 0.57 | Ambiguous | 0.22 | Likely Benign | 0.458 | Likely Benign | -6.12 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.21 | Benign | 0.01 | Affected | 0.2729 | 0.3471 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1661T>A | V554E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V554E is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: all evaluated algorithms except FATHMM classify the variant as pathogenic (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default). FATHMM is the sole benign prediction. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.020522 | Structured | 0.007349 | Uncertain | 0.955 | 0.226 | 0.000 | -12.813 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 2.51 | Destabilizing | 0.1 | 2.05 | Destabilizing | 2.28 | Destabilizing | 2.42 | Destabilizing | 0.590 | Likely Pathogenic | -5.96 | Deleterious | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 3.21 | Benign | 0.00 | Affected | 0.0862 | 0.1180 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.1661T>G | V554G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V554G 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, while the remaining eleven tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as pathogenic. No predictions are missing or inconclusive. Overall, the variant is most likely pathogenic based on the collective evidence, 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. | GAP | 0.020522 | Structured | 0.007349 | Uncertain | 0.955 | 0.226 | 0.000 | -13.879 | Likely Pathogenic | 0.942 | Likely Pathogenic | Ambiguous | 3.31 | Destabilizing | 0.1 | 4.13 | Destabilizing | 3.72 | Destabilizing | 2.40 | Destabilizing | 0.594 | Likely Pathogenic | -6.96 | Deleterious | 0.997 | Probably Damaging | 1.000 | Probably Damaging | 3.21 | Benign | 0.00 | Affected | 0.1619 | 0.1548 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1792C>G | L598V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L598V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as inconclusive. Overall, the majority of evidence points to a pathogenic impact, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.007259 | Structured | 0.147872 | Uncertain | 0.953 | 0.154 | 0.000 | Uncertain | 1 | -10.002 | Likely Pathogenic | 0.578 | Likely Pathogenic | Likely Benign | 1.89 | Ambiguous | 0.1 | 1.58 | Ambiguous | 1.74 | Ambiguous | 1.01 | Destabilizing | 0.221 | Likely Benign | -2.92 | Deleterious | 0.944 | Possibly Damaging | 0.786 | Possibly Damaging | 3.21 | Benign | 0.02 | Affected | 3.37 | 35 | 0.1082 | 0.1795 | 2 | 1 | 0.4 | -14.03 | 218.4 | 29.6 | 0.0 | 0.0 | 0.8 | 0.0 | X | Potentially Benign | The iso-butyl side chain of Leu598, located on an α helix (res. Glu582-Met603), packs hydrophobically with other hydrophobic residues in the inter-helix space (e.g., Ile602, Phe594, Ile510).In the variant simulations, Val598, which has similar size and physicochemical properties to leucine, resides in the inter-helix hydrophobic space in a similar manner to Leu598 in the WT. This causes no negative effects on the protein structure. | ||||||||||||||||
| c.1936C>G | L646V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L646V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and FATHMM, whereas pathogenic predictions arise from FoldX, Rosetta, premPS, SIFT, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “Likely Benign” (3 benign vs 1 pathogenic votes). High‑accuracy assessments further indicate AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of tools, including the high‑accuracy methods, lean toward a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.048328 | Structured | 0.303751 | Uncertain | 0.941 | 0.344 | 0.000 | -8.995 | Likely Pathogenic | 0.332 | Likely Benign | Likely Benign | 3.82 | Destabilizing | 0.2 | 2.01 | Destabilizing | 2.92 | Destabilizing | 1.41 | Destabilizing | 0.125 | Likely Benign | -1.40 | Neutral | 0.040 | Benign | 0.021 | Benign | 3.21 | Benign | 0.03 | Affected | 0.2200 | 0.3767 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.3934G>T | A1312S 2D AIThe SynGAP1 missense variant A1312S is reported in gnomAD (variant ID 6‑33451808‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: six methods (REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score all predict a benign effect, while three tools (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT) predict pathogenicity. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns “Benign” and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” No Foldetta stability data are available, so it does not influence the conclusion. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar status (none is listed). 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 | 6-33451808-G-T | 1 | 6.21e-7 | -3.906 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -1.03 | Neutral | 0.978 | Probably Damaging | 0.983 | Probably Damaging | 3.21 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2850 | 0.6211 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||
| c.4006G>C | E1336Q 2D AIThe SynGAP1 missense change E1336Q 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‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar 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 | 0.865454 | Disordered | 0.973342 | Binding | 0.336 | 0.717 | 0.750 | -4.113 | Likely Benign | 0.769 | Likely Pathogenic | Likely Benign | 0.159 | Likely Benign | -1.88 | Neutral | 0.731 | Possibly Damaging | 0.301 | Benign | 3.21 | Benign | 0.00 | Affected | 0.1432 | 0.7427 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.1235T>C | L412S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L412S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all return pathogenic or likely pathogenic scores, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized indicates pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) also predicts pathogenic. No prediction is inconclusive or missing. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -13.884 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.03 | Destabilizing | 0.2 | 4.20 | Destabilizing | 4.12 | Destabilizing | 2.01 | Destabilizing | 0.557 | Likely Pathogenic | -5.53 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.22 | Benign | 0.00 | Affected | 0.2821 | 0.0505 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||
| c.1243G>A | E415K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E415K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus shows AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall balance of predictions—particularly the two high‑accuracy pathogenic calls versus one benign—the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -11.433 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | -0.07 | Likely Benign | 0.3 | -0.13 | Likely Benign | -0.10 | Likely Benign | 0.46 | Likely Benign | 0.326 | Likely Benign | -3.69 | Deleterious | 0.998 | Probably Damaging | 0.975 | Probably Damaging | 3.22 | Benign | 0.03 | Affected | 0.2174 | 0.3860 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1245G>C | E415D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E415D 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, premPS, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Predictions that are inconclusive or uncertain are FoldX, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, while Foldetta predicts a benign effect. Overall, the balance of evidence leans toward a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -7.766 | In-Between | 0.952 | Likely Pathogenic | Ambiguous | 0.75 | Ambiguous | 0.1 | 0.21 | Likely Benign | 0.48 | Likely Benign | 0.49 | Likely Benign | 0.220 | Likely Benign | -2.60 | Deleterious | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.22 | Benign | 0.04 | Affected | 0.1777 | 0.2075 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1245G>T | E415D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E415D 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, premPS, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are FoldX, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta indicates a benign effect. Overall, the majority of standard tools lean toward pathogenicity, and the high‑accuracy consensus also supports a pathogenic classification. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -7.766 | In-Between | 0.952 | Likely Pathogenic | Ambiguous | 0.75 | Ambiguous | 0.1 | 0.21 | Likely Benign | 0.48 | Likely Benign | 0.49 | Likely Benign | 0.220 | Likely Benign | -2.60 | Deleterious | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.22 | Benign | 0.04 | Affected | 0.1777 | 0.2075 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1258T>A | F420I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign calls come from REVEL, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | -12.567 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.88 | Destabilizing | 0.0 | 3.64 | Destabilizing | 3.26 | Destabilizing | 1.25 | Destabilizing | 0.330 | Likely Benign | -5.46 | Deleterious | 0.575 | Possibly Damaging | 0.059 | Benign | 3.22 | Benign | 0.02 | Affected | 0.1864 | 0.2113 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1316T>G | L439R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L439R 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 limited to FATHMM, while the remaining evaluated algorithms (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic or likely pathogenic impact; FoldX is uncertain and is treated as unavailable. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.281542 | Uncertain | 0.942 | 0.265 | 0.000 | -12.870 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 1.90 | Ambiguous | 0.5 | 2.62 | Destabilizing | 2.26 | Destabilizing | 1.40 | Destabilizing | 0.554 | Likely Pathogenic | -5.25 | Deleterious | 0.996 | Probably Damaging | 0.983 | Probably Damaging | 3.22 | Benign | 0.01 | Affected | 0.1217 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1463C>G | T488R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T488R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only FATHMM, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. 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 for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | -14.353 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 1.29 | Ambiguous | 0.3 | 1.55 | Ambiguous | 1.42 | Ambiguous | 0.85 | Ambiguous | 0.726 | Likely Pathogenic | -5.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.22 | Benign | 0.00 | Affected | 0.0711 | 0.2048 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||
| c.1660G>A | V554M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V554M is not reported in ClinVar but is present in gnomAD (ID 6‑33438903‑G‑A). Functional prediction tools show a split opinion: benign calls come from REVEL, Rosetta, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default; FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessment focuses on AlphaMissense‑Optimized, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. AlphaMissense‑Optimized predicts benign, the SGM Consensus is a tie and thus unavailable, and Foldetta is uncertain, so it is treated as unavailable. Overall, the available evidence leans toward a benign effect, and this does not contradict ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.020522 | Structured | 0.007349 | Uncertain | 0.955 | 0.226 | 0.000 | 6-33438903-G-A | 1 | 6.20e-7 | -8.118 | Likely Pathogenic | 0.671 | Likely Pathogenic | Likely Benign | -1.11 | Ambiguous | 0.0 | -0.20 | Likely Benign | -0.66 | Ambiguous | 0.73 | Ambiguous | 0.217 | Likely Benign | -2.26 | Neutral | 0.994 | Probably Damaging | 0.867 | Possibly Damaging | 3.22 | Benign | 0.00 | Affected | 3.37 | 35 | 0.0743 | 0.2810 | 1 | 2 | -2.3 | 32.06 | |||||||||||||||||||||||||
| c.1661T>C | V554A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V554A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and FATHMM. All other evaluated predictors—SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.020522 | Structured | 0.007349 | Uncertain | 0.955 | 0.226 | 0.000 | -9.730 | Likely Pathogenic | 0.870 | Likely Pathogenic | Ambiguous | 2.07 | Destabilizing | 0.1 | 2.34 | Destabilizing | 2.21 | Destabilizing | 2.00 | Destabilizing | 0.419 | Likely Benign | -3.97 | Deleterious | 0.998 | Probably Damaging | 0.981 | Probably Damaging | 3.22 | Benign | 0.02 | Affected | 0.2131 | 0.1633 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1744G>C | E582Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E582Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome 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, reports the variant as Likely Benign. High‑accuracy assessments—AlphaMissense‑Optimized, SGM‑Consensus, and Foldetta—all predict a benign impact, with Foldetta combining FoldX‑MD and Rosetta stability outputs. In contrast, the two polyPhen‑2 scores and AlphaMissense‑Default suggest pathogenicity, but these are outnumbered by benign predictions. 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 status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.102787 | Structured | 0.033838 | Uncertain | 0.845 | 0.235 | 0.000 | -3.700 | Likely Benign | 0.605 | Likely Pathogenic | Likely Benign | 0.17 | Likely Benign | 0.1 | 0.21 | Likely Benign | 0.19 | Likely Benign | -0.24 | Likely Benign | 0.138 | Likely Benign | -0.61 | Neutral | 0.992 | Probably Damaging | 0.993 | Probably Damaging | 3.22 | Benign | 0.57 | Tolerated | 0.0979 | 0.3402 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1746G>C | E582D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E582D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: a benign group comprising REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, and a pathogenic group containing polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Remaining tools (FoldX, Rosetta, ESM1b, AlphaMissense‑Default) yield uncertain results and are treated as unavailable. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leans toward benign, and Foldetta indicates no significant destabilization. Consequently, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.102787 | Structured | 0.033838 | Uncertain | 0.845 | 0.235 | 0.000 | -7.974 | In-Between | 0.520 | Ambiguous | Likely Benign | 0.57 | Ambiguous | 0.2 | 0.95 | Ambiguous | 0.76 | Ambiguous | 0.40 | Likely Benign | 0.093 | Likely Benign | -1.63 | Neutral | 0.986 | Probably Damaging | 0.989 | Probably Damaging | 3.22 | Benign | 0.27 | Tolerated | 0.1481 | 0.2236 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1746G>T | E582D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E582D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: a benign group comprising REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, and a pathogenic group consisting of polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Remaining tools (FoldX, Rosetta, ESM1b, AlphaMissense‑Default) yield uncertain results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because two of the four inputs are uncertain; Foldetta, which integrates FoldX‑MD and Rosetta outputs, also reports an uncertain stability change. Consequently, the preponderance of evidence points to a benign effect. This conclusion aligns with the absence of a ClinVar assertion, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.102787 | Structured | 0.033838 | Uncertain | 0.845 | 0.235 | 0.000 | -7.974 | In-Between | 0.520 | Ambiguous | Likely Benign | 0.57 | Ambiguous | 0.2 | 0.95 | Ambiguous | 0.76 | Ambiguous | 0.40 | Likely Benign | 0.093 | Likely Benign | -1.63 | Neutral | 0.986 | Probably Damaging | 0.989 | Probably Damaging | 3.22 | Benign | 0.27 | Tolerated | 0.1481 | 0.2236 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1885G>C | V629L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V629L has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, and FATHMM, whereas the majority of algorithms predict a pathogenic outcome: Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools report uncertainty: Foldetta and premPS. 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: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates likely pathogenic, while Foldetta remains uncertain. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.034796 | Uncertain | 0.970 | 0.236 | 0.000 | -12.785 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.06 | Likely Benign | 0.2 | 2.26 | Destabilizing | 1.16 | Ambiguous | 0.54 | Ambiguous | 0.391 | Likely Benign | -2.79 | Deleterious | 0.975 | Probably Damaging | 0.958 | Probably Damaging | 3.22 | Benign | 0.02 | Affected | 0.0805 | 0.3336 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.3908G>A | G1303D 2D AIThe SynGAP1 missense variant G1303D 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, 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 | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -3.825 | Likely Benign | 0.329 | Likely Benign | Likely Benign | 0.103 | Likely Benign | 2.64 | Neutral | 0.002 | Benign | 0.008 | Benign | 3.22 | Benign | 1.00 | Tolerated | 0.1784 | 0.1452 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.4007A>C | E1336A 2D AIThe SynGAP1 missense variant E1336A is not 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: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the majority of evidence (five benign vs. three pathogenic) supports a benign classification. This prediction does not contradict any ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.865454 | Disordered | 0.973342 | Binding | 0.336 | 0.717 | 0.750 | -3.545 | Likely Benign | 0.879 | Likely Pathogenic | Ambiguous | 0.191 | Likely Benign | -3.78 | Deleterious | 0.345 | Benign | 0.099 | Benign | 3.22 | Benign | 0.00 | Affected | 0.4000 | 0.7385 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.1303T>G | L435V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L435V has no ClinVar assertion and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and AlphaMissense‑Default. ESM1b is uncertain. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized predicts benign, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—favors pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. With the preponderance of pathogenic calls from both general and high‑accuracy tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -7.134 | In-Between | 0.571 | Likely Pathogenic | Likely Benign | 2.97 | Destabilizing | 0.1 | 2.33 | Destabilizing | 2.65 | Destabilizing | 1.36 | Destabilizing | 0.217 | Likely Benign | -2.80 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 3.23 | Benign | 0.06 | Tolerated | 0.1216 | 0.2628 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||
| c.1364T>A | L455Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455Q 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 only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta (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 conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -13.075 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.84 | Destabilizing | 0.0 | 3.42 | Destabilizing | 3.13 | Destabilizing | 2.24 | Destabilizing | 0.655 | Likely Pathogenic | -5.66 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.23 | Benign | 0.00 | Affected | 0.0871 | 0.0958 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1364T>C | L455P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455P 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 only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -14.150 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 7.45 | Destabilizing | 0.2 | 11.99 | Destabilizing | 9.72 | Destabilizing | 2.19 | Destabilizing | 0.695 | Likely Pathogenic | -6.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.23 | Benign | 0.00 | Affected | 0.3211 | 0.1221 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1447A>G | I483V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions are reported by premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Predictions marked as uncertain include FoldX, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, whereas Foldetta remains uncertain. Overall, the balance of evidence from both general and high‑accuracy tools leans toward a benign effect, which does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | Conflicting | 2 | -10.121 | Likely Pathogenic | 0.523 | Ambiguous | Likely Benign | 1.00 | Ambiguous | 0.0 | 0.27 | Likely Benign | 0.64 | Ambiguous | 1.02 | Destabilizing | 0.228 | Likely Benign | -0.86 | Neutral | 0.914 | Possibly Damaging | 0.921 | Probably Damaging | 3.23 | Benign | 0.03 | Affected | 3.37 | 32 | 0.0876 | 0.2691 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||||||||
| c.1532G>C | G511A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. 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 remains uncertain. Overall, the balance of evidence (seven pathogenic versus three benign predictions) indicates that 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 | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | -9.621 | Likely Pathogenic | 0.844 | Likely Pathogenic | Ambiguous | 0.80 | Ambiguous | 0.2 | 0.25 | Likely Benign | 0.53 | Ambiguous | 0.55 | Ambiguous | 0.275 | Likely Benign | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.23 | Benign | 0.02 | Affected | 0.3793 | 0.2778 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1535A>T | E512V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E512V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification; this conclusion does not contradict ClinVar status, which has no entry 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 | -14.011 | Likely Pathogenic | 0.933 | Likely Pathogenic | Ambiguous | 0.72 | Ambiguous | 0.1 | 1.00 | Ambiguous | 0.86 | Ambiguous | 0.14 | Likely Benign | 0.439 | Likely Benign | -6.71 | Deleterious | 0.989 | Probably Damaging | 0.854 | Possibly Damaging | 3.23 | Benign | 0.01 | Affected | 0.0994 | 0.4884 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.2054T>G | L685W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the majority of tools (REVEL, premPS, 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 results and are not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -15.885 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.53 | Ambiguous | 0.2 | 1.14 | Ambiguous | 1.34 | Ambiguous | 1.14 | Destabilizing | 0.509 | Likely Pathogenic | -5.99 | Deleterious | 1.000 | Probably Damaging | 0.984 | Probably Damaging | 3.23 | Benign | 0.00 | Affected | 0.0700 | 0.2328 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||
| c.3874C>A | L1292I 2D AIThe SynGAP1 missense variant L1292I 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 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 | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | -5.480 | Likely Benign | 0.135 | Likely Benign | Likely Benign | 0.050 | Likely Benign | 0.71 | Neutral | 0.002 | Benign | 0.006 | Benign | 3.23 | Benign | 1.00 | Tolerated | 0.1101 | 0.3323 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3898C>G | P1300A 2D AIThe SynGAP1 missense variant P1300A is reported in gnomAD (ID 6‑33451772‑C‑G) and has no ClinVar entry. Across the evaluated in‑silico tools, every predictor classifies the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity, so the pathogenic‑prediction group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates a benign effect, and the SGM Consensus (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, was not available for this variant. Based on the unanimous benign predictions and the absence of any pathogenic signal, the variant 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 | 0.788093 | Disordered | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | 6-33451772-C-G | 2 | 1.24e-6 | -3.802 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.065 | Likely Benign | 0.55 | Neutral | 0.008 | Benign | 0.006 | Benign | 3.23 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.3342 | 0.3744 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.4006G>A | E1336K 2D AIThe SynGAP1 missense variant E1336K is listed in ClinVar (ID 984837) with an “Uncertain” status and is present in gnomAD (6‑33451880‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM. Those that predict a pathogenic impact are polyPhen‑2 HumDiv, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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 pathogenic, while the SGM‑Consensus remains likely benign; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign effect, and this conclusion does not contradict the ClinVar designation, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.865454 | Disordered | 0.973342 | Binding | 0.336 | 0.717 | 0.750 | Conflicting | 3 | 6-33451880-G-A | 6 | 4.20e-6 | -4.697 | Likely Benign | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.272 | Likely Benign | -2.44 | Neutral | 0.748 | Possibly Damaging | 0.079 | Benign | 3.23 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2630 | 0.7501 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||
| c.1315C>A | L439M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L439M is reported in gnomAD (variant ID 6‑33438220‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on benign impact include REVEL, FoldX, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from premPS, polyPhen‑2 (HumDiv and HumVar) and SIFT. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Default. 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 inconclusive. Overall, the majority of evidence points to a benign effect; 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 | GAP | 0.222385 | Structured | 0.281542 | Uncertain | 0.942 | 0.265 | 0.000 | 6-33438220-C-A | 1 | 6.20e-7 | -5.840 | Likely Benign | 0.363 | Ambiguous | Likely Benign | -0.33 | Likely Benign | 0.1 | 1.34 | Ambiguous | 0.51 | Ambiguous | 1.01 | Destabilizing | 0.187 | Likely Benign | -1.43 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.24 | Benign | 0.02 | Affected | 3.38 | 25 | 0.0720 | 0.2753 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||||||
| c.1336G>C | E446Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E446Q missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other folding‑stability predictions are available. Overall, the balance of evidence from the consensus of multiple in silico predictors points to a pathogenic classification for E446Q. 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 | GAP | 0.271506 | Structured | 0.276479 | Uncertain | 0.940 | 0.216 | 0.000 | -11.107 | Likely Pathogenic | 0.752 | Likely Pathogenic | Likely Benign | 0.92 | Ambiguous | 0.5 | 0.54 | Ambiguous | 0.73 | Ambiguous | 0.84 | Ambiguous | 0.337 | Likely Benign | -2.80 | Deleterious | 0.992 | Probably Damaging | 0.973 | Probably Damaging | 3.24 | Benign | 0.04 | Affected | 0.1049 | 0.6218 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| 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 | 2.62 | Destabilizing | 0.7 | 1.63 | Ambiguous | 2.13 | Destabilizing | 0.83 | Ambiguous | 0.510 | Likely Pathogenic | -6.42 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.24 | Benign | 0.00 | Affected | 0.2665 | 0.5202 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1364T>G | L455R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455R resides 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 include only FATHMM; all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -16.347 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 6.36 | Destabilizing | 0.2 | 4.96 | Destabilizing | 5.66 | Destabilizing | 2.08 | Destabilizing | 0.648 | Likely Pathogenic | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.24 | Benign | 0.00 | Affected | 0.1126 | 0.0600 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1462A>C | T488P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T488P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining twelve tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity; premPS is uncertain and therefore not counted. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Based on the overwhelming consensus of these 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 | GAP | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | -13.432 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 4.40 | Destabilizing | 0.7 | 5.68 | Destabilizing | 5.04 | Destabilizing | 0.68 | Ambiguous | 0.505 | Likely Pathogenic | -5.70 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.24 | Benign | 0.00 | Affected | 0.1518 | 0.3557 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.1462A>G | T488A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T488A is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, while the majority of tools (FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) predict pathogenicity; Rosetta and premPS are uncertain. 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 likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the preponderance of evidence indicates that T488A 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 | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | -11.341 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 2.12 | Destabilizing | 0.2 | 1.99 | Ambiguous | 2.06 | Destabilizing | 0.57 | Ambiguous | 0.497 | Likely Benign | -4.64 | Deleterious | 0.996 | Probably Damaging | 0.989 | Probably Damaging | 3.24 | Benign | 0.01 | Affected | 0.2871 | 0.2872 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1463C>A | T488K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T488K is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining eleven tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all classify the variant as pathogenic. The high‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta outputs)—all predict pathogenicity. No prediction or folding‑stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | -14.391 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.09 | Destabilizing | 0.2 | 2.33 | Destabilizing | 2.21 | Destabilizing | 0.90 | Ambiguous | 0.692 | Likely Pathogenic | -5.64 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.24 | Benign | 0.00 | Affected | 0.0871 | 0.2104 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||
| c.1532G>A | G511E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. 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 | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | -12.263 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 2.17 | Destabilizing | 0.2 | 2.62 | Destabilizing | 2.40 | Destabilizing | 1.15 | Destabilizing | 0.479 | Likely Benign | -7.69 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.24 | Benign | 0.02 | Affected | 0.1882 | 0.4240 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||
| c.1643A>T | E548V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E548V missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that indicate a benign effect include FoldX, Rosetta, Foldetta, premPS, and FATHMM. In contrast, tools predicting a pathogenic impact are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of predictions (10 pathogenic vs. 5 benign) support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.008632 | Uncertain | 0.965 | 0.288 | 0.000 | -15.029 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.29 | Likely Benign | 0.0 | -0.18 | Likely Benign | 0.06 | Likely Benign | 0.36 | Likely Benign | 0.578 | Likely Pathogenic | -6.83 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.24 | Benign | 0.02 | Affected | 0.0569 | 0.4714 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.2002T>A | S668T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S668T is not reported in ClinVar (ClinVar ID: None) and has no entries in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, premPS, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No evidence from FoldX or Rosetta alone is conclusive. Overall, the balance of predictions leans toward pathogenicity, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | -11.860 | Likely Pathogenic | 0.703 | Likely Pathogenic | Likely Benign | 1.73 | Ambiguous | 0.7 | 0.89 | Ambiguous | 1.31 | Ambiguous | 0.27 | Likely Benign | 0.238 | Likely Benign | -2.99 | Deleterious | 0.844 | Possibly Damaging | 0.198 | Benign | 3.24 | Benign | 0.02 | Affected | 0.1212 | 0.5918 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.2083C>A | L695I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L695I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and ESM1b predict a pathogenic outcome. The remaining tools—AlphaMissense‑Default, Foldetta, premPS, and Rosetta—return uncertain results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, whereas Foldetta remains uncertain. Overall, the majority of reliable predictions support a benign classification, 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. | GAP | 0.118441 | Structured | 0.373419 | Uncertain | 0.942 | 0.258 | 0.000 | -12.096 | Likely Pathogenic | 0.395 | Ambiguous | Likely Benign | 0.47 | Likely Benign | 0.1 | 0.63 | Ambiguous | 0.55 | Ambiguous | 0.93 | Ambiguous | 0.251 | Likely Benign | -2.00 | Neutral | 0.996 | Probably Damaging | 0.905 | Possibly Damaging | 3.24 | Benign | 0.08 | Tolerated | 0.0815 | 0.2759 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.3913A>G | T1305A 2D AIThe SynGAP1 missense variant T1305A is listed in ClinVar (ID 411587.0) with an “Uncertain” clinical significance and is present in the gnomAD database (variant ID 6‑33451787‑A‑G). 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 reports a pathogenic or likely pathogenic outcome. High‑accuracy assessments reinforce 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. Overall, the computational evidence overwhelmingly supports a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.894658 | Binding | 0.390 | 0.873 | 0.875 | Conflicting | 4 | 6-33451787-A-G | 30 | 1.86e-5 | -2.692 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 1.74 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.24 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.4533 | 0.4746 | 1 | 0 | 2.5 | -30.03 | ||||||||||||||||||||||||||||||||
| c.1234T>A | L412M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L412M has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and FATHMM, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Five tools give uncertain or inconclusive results (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized). High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑vs‑2 tie; and Foldetta is uncertain. Consequently, the overall evidence leans toward a pathogenic effect, with no ClinVar record to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -9.342 | Likely Pathogenic | 0.944 | Likely Pathogenic | Ambiguous | 0.75 | Ambiguous | 0.0 | 1.99 | Ambiguous | 1.37 | Ambiguous | 0.86 | Ambiguous | 0.246 | Likely Benign | -1.84 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.25 | Benign | 0.05 | Affected | 0.0746 | 0.3482 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.1234T>G | L412V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L412V is not 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—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely pathogenic, 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 Pathogenic | GAP | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -11.726 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 3.65 | Destabilizing | 0.0 | 3.52 | Destabilizing | 3.59 | Destabilizing | 1.54 | Destabilizing | 0.231 | Likely Benign | -2.76 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 3.25 | Benign | 0.01 | Affected | 0.1275 | 0.3378 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1361T>A | I454N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454N resides in the GAP domain. ClinVar has no entry for this variant, and it is absent from gnomAD. Prediction tools that agree on benign impact are REVEL and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict pathogenicity. High‑accuracy methods further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta predicts a destabilizing, pathogenic change. Overall, the evidence strongly favors a pathogenic classification, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -14.246 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.24 | Destabilizing | 0.1 | 3.56 | Destabilizing | 3.90 | Destabilizing | 2.44 | Destabilizing | 0.497 | Likely Benign | -6.82 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.25 | Benign | 0.00 | Affected | 0.0750 | 0.0412 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.1363C>A | L455M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L455M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and Foldetta is uncertain. No folding‑stability method provides a definitive result. Consequently, the computational evidence does not favor either benign or pathogenic classification. The variant’s status is therefore inconclusive, and this lack of consensus does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -10.086 | Likely Pathogenic | 0.802 | Likely Pathogenic | Ambiguous | 0.88 | Ambiguous | 0.0 | 1.27 | Ambiguous | 1.08 | Ambiguous | 0.59 | Ambiguous | 0.147 | Likely Benign | -1.64 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.25 | Benign | 0.11 | Tolerated | 0.0606 | 0.3362 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.1475A>G | K492R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K492R is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of tools (seven pathogenic vs. six benign) lean toward a pathogenic interpretation, and this 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 | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -11.290 | Likely Pathogenic | 0.599 | Likely Pathogenic | Likely Benign | -0.20 | Likely Benign | 0.1 | 0.45 | Likely Benign | 0.13 | Likely Benign | 0.84 | Ambiguous | 0.487 | Likely Benign | -2.98 | Deleterious | 0.997 | Probably Damaging | 0.990 | Probably Damaging | 3.25 | Benign | 0.05 | Affected | 0.3911 | 0.0835 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||
| c.1601C>G | S534C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, FoldX, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is uncertain, so both are treated as unavailable. No other high‑accuracy predictions are available. Overall, the evidence is evenly split between benign and pathogenic predictions, leaving the variant’s clinical significance inconclusive. There is no ClinVar status to contradict this balanced prediction. 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 | -8.077 | Likely Pathogenic | 0.247 | Likely Benign | Likely Benign | 0.18 | Likely Benign | 0.1 | 0.90 | Ambiguous | 0.54 | Ambiguous | 0.56 | Ambiguous | 0.308 | Likely Benign | -4.05 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | 3.25 | Benign | 0.00 | Affected | 0.0984 | 0.4861 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||
| c.176T>C | L59P 2D AIThe SynGAP1 missense variant L59P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. ESM1b is 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 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. | 0.212910 | Structured | 0.484882 | Uncertain | 0.510 | 0.668 | 0.000 | -7.076 | In-Between | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.362 | Likely Benign | -2.74 | Deleterious | 0.943 | Possibly Damaging | 0.944 | Probably Damaging | 3.25 | Benign | 0.00 | Affected | 0.3787 | 0.1382 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.1810T>G | S604A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S604A has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Rosetta is uncertain and does not contribute to a consensus. 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. With two of the three high‑accuracy tools indicating benign and no ClinVar evidence to contradict, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010926 | Structured | 0.192527 | Uncertain | 0.911 | 0.195 | 0.000 | -10.017 | Likely Pathogenic | 0.608 | Likely Pathogenic | Likely Benign | 0.02 | Likely Benign | 0.1 | -0.60 | Ambiguous | -0.29 | Likely Benign | 0.11 | Likely Benign | 0.378 | Likely Benign | -2.99 | Deleterious | 0.944 | Possibly Damaging | 0.987 | Probably Damaging | 3.25 | Benign | 0.08 | Tolerated | 0.5198 | 0.3530 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||
| c.2029A>T | S677C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677C is reported in ClinVar as Benign (ClinVar ID 2825814.0) and is not present in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 HumDiv, SIFT, and ESM1b predict a pathogenic impact. High‑accuracy predictors all support a benign outcome: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote from 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 preponderance of evidence, the variant is most likely benign, and this assessment aligns with its ClinVar status. 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 | Benign | 1 | -8.496 | Likely Pathogenic | 0.076 | Likely Benign | Likely Benign | -0.51 | Ambiguous | 0.3 | -0.30 | Likely Benign | -0.41 | Likely Benign | 0.15 | Likely Benign | 0.153 | Likely Benign | -2.41 | Neutral | 0.932 | Possibly Damaging | 0.222 | Benign | 3.25 | Benign | 0.04 | Affected | 3.41 | 23 | 0.1375 | 0.6697 | -1 | 0 | 3.3 | 16.06 | |||||||||||||||||||||||||
| c.2123T>A | L708H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L708H is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default; the SGM Consensus score is also labeled Likely Pathogenic. Stability‑based methods FoldX and Rosetta return uncertain results, and Foldetta likewise is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of conventional predictors lean toward pathogenicity, whereas a few high‑accuracy tools suggest benign or are inconclusive. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.250310 | Structured | 0.365875 | Uncertain | 0.931 | 0.378 | 0.000 | -8.059 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 1.84 | Ambiguous | 0.1 | 1.55 | Ambiguous | 1.70 | Ambiguous | 1.44 | Destabilizing | 0.243 | Likely Benign | -4.68 | Deleterious | 1.000 | Probably Damaging | 0.981 | Probably Damaging | 3.25 | Benign | 0.02 | Affected | 0.0824 | 0.0288 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.3418A>T | T1140S 2D AIThe SynGAP1 missense variant T1140S 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 | 0.926919 | Disordered | 0.708094 | Binding | 0.293 | 0.854 | 1.000 | -2.805 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -0.27 | Neutral | 0.025 | Benign | 0.010 | Benign | 3.25 | Benign | 0.91 | Tolerated | 0.3401 | 0.3504 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3629A>G | H1210R 2D AIThe SynGAP1 missense variant H1210R is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. 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 predict a benign effect. No tool in the dataset indicates pathogenicity, so the pathogenic‑prediction group is empty. High‑accuracy assessments corroborate this benign consensus: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields “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 | Coiled-coil | 0.599170 | Disordered | 0.587579 | Binding | 0.900 | 0.567 | 0.375 | 0.860 | Likely Benign | 0.173 | Likely Benign | Likely Benign | 0.088 | Likely Benign | 0.89 | Neutral | 0.178 | Benign | 0.089 | Benign | 3.25 | Benign | 1.00 | Tolerated | 0.1535 | 0.2384 | 2 | 0 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||||||||||
| c.1243G>C | E415Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E415Q 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, Rosetta, premPS, SIFT, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, seven tools predict pathogenicity versus six predicting benignity, and the two most reliable predictors (AlphaMissense‑Optimized and SGM‑Consensus) both favor pathogenicity. Therefore, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -9.085 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.29 | Likely Benign | 0.2 | 0.22 | Likely Benign | 0.26 | Likely Benign | 0.01 | Likely Benign | 0.236 | Likely Benign | -2.63 | Deleterious | 0.997 | Probably Damaging | 0.973 | Probably Damaging | 3.26 | Benign | 0.08 | Tolerated | 0.1084 | 0.3474 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1305G>C | L435F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L435F is not 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: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote). High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain, providing no definitive evidence for either outcome. Given the preponderance of pathogenic predictions and the lack of any ClinVar annotation to contradict this assessment, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -11.871 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 0.51 | Ambiguous | 0.1 | 0.95 | Ambiguous | 0.73 | Ambiguous | 0.69 | Ambiguous | 0.222 | Likely Benign | -3.75 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0.0587 | 0.2723 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1305G>T | L435F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L435F is not 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: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (Likely Pathogenic). High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain, providing no definitive evidence for either outcome. Given the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -11.871 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 0.51 | Ambiguous | 0.1 | 0.95 | Ambiguous | 0.73 | Ambiguous | 0.69 | Ambiguous | 0.222 | Likely Benign | -3.75 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0.0587 | 0.2723 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| 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 | 3.31 | Destabilizing | 0.2 | 1.80 | Ambiguous | 2.56 | Destabilizing | 0.66 | Ambiguous | 0.487 | Likely Benign | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.955 | Probably Damaging | 3.26 | Benign | 0.02 | Affected | 0.0950 | 0.4955 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.1354G>A | V452I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V452I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and SIFT, while ESM1b also predicts pathogenicity. Uncertain predictions come from Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Taken together, the majority of evidence points to a benign impact. This conclusion does not contradict the ClinVar “Uncertain” classification, which remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | Uncertain | 1 | -8.985 | Likely Pathogenic | 0.361 | Ambiguous | Likely Benign | -0.08 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.22 | Likely Benign | 0.25 | Likely Benign | 0.218 | Likely Benign | -0.99 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.26 | Benign | 0.05 | Affected | 0.0630 | 0.3476 | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||||||||
| c.1361T>C | I454T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is 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 no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -9.045 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.20 | Destabilizing | 0.0 | 2.83 | Destabilizing | 3.02 | Destabilizing | 2.02 | Destabilizing | 0.502 | Likely Pathogenic | -4.74 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.0877 | 0.0708 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.1361T>G | I454S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy predictors, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -13.025 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.50 | Destabilizing | 0.1 | 4.45 | Destabilizing | 4.48 | Destabilizing | 2.20 | Destabilizing | 0.574 | Likely Pathogenic | -5.83 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.2116 | 0.0800 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1391T>G | F464C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) 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 because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -13.011 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.18 | Destabilizing | 0.0 | 4.31 | Destabilizing | 4.25 | Destabilizing | 2.20 | Destabilizing | 0.740 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.2298 | 0.1219 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1449A>G | I483M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I483M missense variant is not reported in ClinVar (ClinVar status: not present) but is catalogued in gnomAD (gnomAD ID: 6‑33438481‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta as benign. No conclusive folding‑stability result is available from Rosetta. Overall, the majority of high‑accuracy tools (two benign, one pathogenic) lean toward a benign interpretation, and this assessment is not contradicted by any 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. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | 6-33438481-A-G | 1 | 6.20e-7 | -8.839 | Likely Pathogenic | 0.777 | Likely Pathogenic | Likely Benign | 0.02 | Likely Benign | 0.0 | 0.73 | Ambiguous | 0.38 | Likely Benign | 1.06 | Destabilizing | 0.261 | Likely Benign | -2.78 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.05 | Affected | 3.37 | 32 | 0.0607 | 0.1959 | 1 | 2 | -2.6 | 18.03 | ||||||||||||||||||||||||
| 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 | 0.15 | Likely Benign | 0.4 | 0.97 | Ambiguous | 0.56 | Ambiguous | -0.14 | Likely Benign | 0.336 | Likely Benign | -6.38 | Deleterious | 0.998 | Probably Damaging | 0.919 | Probably Damaging | 3.26 | Benign | 0.06 | Tolerated | 0.1804 | 0.5096 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1522G>T | D508Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D508Y missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. FoldX and Rosetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labeling it likely pathogenic, and Foldetta predicting a benign outcome. Overall, the majority of evidence (seven pathogenic vs. five benign) 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. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -12.917 | Likely Pathogenic | 0.739 | Likely Pathogenic | Likely Benign | -0.53 | Ambiguous | 0.2 | 0.72 | Ambiguous | 0.10 | Likely Benign | 0.06 | Likely Benign | 0.363 | Likely Benign | -8.37 | Deleterious | 1.000 | Probably Damaging | 0.965 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0.0908 | 0.4736 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.1531G>A | G511R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G511R is listed in ClinVar as Pathogenic (ClinVar ID 1774641.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Stability calculations from FoldX and Rosetta are uncertain, and premPS is unavailable. Overall, the majority of evidence points to a pathogenic impact, aligning with the ClinVar classification and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | Likely Pathogenic | 1 | -11.327 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.94 | Ambiguous | 0.3 | 1.32 | Ambiguous | 1.63 | Ambiguous | 0.94 | Ambiguous | 0.416 | Likely Benign | -7.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.06 | Tolerated | 3.37 | 35 | 0.1307 | 0.4104 | -3 | -2 | -4.1 | 99.14 | 279.4 | -159.9 | 0.0 | 0.0 | 0.7 | 0.1 | X | X | Potentially Pathogenic | Gly511 is located in an α-helix (res. Gly502-Tyr518), facing hydrophobic residues in an inter-helix space (e.g., Leu610, Ile514) in the WT simulations. In contrast, in the variant simulations, the bulkier and positively charged guanidinium side chain of Arg511 forms a salt bridge with the carboxylate group of Glu217 or hydrogen bonds with the backbone carbonyl group of Leu610. Although the residue swap introduces a third positively charged residue in close vicinity (Arg511, Lys507, Arg515), the protein structure seems to remain stable in the variant simulations. Importantly, according to ClinVar, the residue swap alters the last nucleotide of an exon and is predicted to destroy the splice donor site, resulting in aberrant splicing and pathogenic status. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||
| c.1531G>C | G511R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511R is listed in ClinVar (ID 452818.0) as Pathogenic and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain, which is treated as unavailable evidence. Overall, the majority of available predictions support a pathogenic impact, aligning with the ClinVar classification. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | Pathogenic | 1 | -11.327 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.94 | Ambiguous | 0.3 | 1.32 | Ambiguous | 1.63 | Ambiguous | 0.94 | Ambiguous | 0.415 | Likely Benign | -7.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.06 | Tolerated | 3.37 | 35 | 0.1307 | 0.4104 | -3 | -2 | -4.1 | 99.14 | 279.4 | -159.9 | 0.0 | 0.0 | 0.7 | 0.1 | X | X | Potentially Pathogenic | Gly511 is located in an α-helix (res. Gly502-Tyr518), facing hydrophobic residues in an inter-helix space (e.g., Leu610, Ile514) in the WT simulations. In contrast, in the variant simulations, the bulkier and positively charged guanidinium side chain of Arg511 forms a salt bridge with the carboxylate group of Glu217 or hydrogen bonds with the backbone carbonyl group of Leu610. Although the residue swap introduces a third positively charged residue in close vicinity (Arg511, Lys507, Arg515), the protein structure seems to remain stable in the variant simulations. Importantly, according to ClinVar, the residue swap alters the last nucleotide of an exon and is predicted to destroy the splice donor site, resulting in aberrant splicing and pathogenic status. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||
| c.1562A>T | E521V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E521V missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy AlphaMissense‑Optimized score is pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign outcome. Overall, the majority of evidence points to a pathogenic impact for E521V, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -10.297 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.31 | Likely Benign | 0.1 | 0.49 | Likely Benign | 0.40 | Likely Benign | 0.21 | Likely Benign | 0.413 | Likely Benign | -5.15 | Deleterious | 0.995 | Probably Damaging | 0.996 | Probably Damaging | 3.26 | Benign | 0.05 | Affected | 0.0913 | 0.7104 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| 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 | -0.03 | Likely Benign | 0.1 | 0.88 | Ambiguous | 0.43 | Likely Benign | 0.43 | Likely Benign | 0.313 | Likely Benign | -5.09 | Deleterious | 0.998 | Probably Damaging | 0.998 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.0621 | 0.5379 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||
| c.176T>A | L59Q 2D AIThe SynGAP1 missense variant L59Q is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools are mixed: benign calls come from SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, and FATHMM, whereas pathogenic calls are made by polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further highlight this discordance: AlphaMissense‑Optimized predicts a pathogenic effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. No Foldetta stability analysis is available for this residue. Overall, the majority of high‑confidence tools lean toward a pathogenic interpretation, but the presence of several strong benign predictions and the lack of ClinVar evidence suggest uncertainty. The variant is most likely pathogenic based on the prevailing predictions, and this does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.212910 | Structured | 0.484882 | Uncertain | 0.510 | 0.668 | 0.000 | -3.841 | Likely Benign | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.287 | Likely Benign | -2.21 | Neutral | 0.943 | Possibly Damaging | 0.944 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.1103 | 0.0758 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.176T>G | L59R 2D AISynGAP1 missense variant L59R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. The predictions are therefore split, with an equal number of benign and pathogenic calls, and the high‑accuracy tools provide contradictory signals. Consequently, the variant is most likely pathogenic based on the presence of multiple pathogenic predictions and the high‑accuracy AlphaMissense‑Optimized result, 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 | 0.212910 | Structured | 0.484882 | Uncertain | 0.510 | 0.668 | 0.000 | -4.037 | Likely Benign | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.266 | Likely Benign | -2.09 | Neutral | 0.943 | Possibly Damaging | 0.944 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.1298 | 0.0600 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.1847A>T | D616V 2D  3DClick to see structure in 3D Viewer AISynGAP1 D616V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, and FATHMM, while pathogenic calls are made by FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. Uncertain results are reported by Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments give a pathogenic signal: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Overall, the majority of evidence, including the high‑accuracy tools, supports a pathogenic effect for D616V. This conclusion is not contradicted by ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | -13.992 | Likely Pathogenic | 0.919 | Likely Pathogenic | Ambiguous | 2.41 | Destabilizing | 0.2 | 1.95 | Ambiguous | 2.18 | Destabilizing | 0.36 | Likely Benign | 0.268 | Likely Benign | -7.36 | Deleterious | 0.972 | Probably Damaging | 0.682 | Possibly Damaging | 3.26 | Benign | 0.00 | Affected | 0.0699 | 0.4393 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.1885G>A | V629I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V629I is not 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, AlphaMissense‑Optimized, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and SIFT, with ESM1b also indicating pathogenicity. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta also predicts a benign outcome. Taken together, the preponderance of evidence supports a benign classification for V629I, 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. | GAP | 0.040537 | Structured | 0.034796 | Uncertain | 0.970 | 0.236 | 0.000 | -9.876 | Likely Pathogenic | 0.462 | Ambiguous | Likely Benign | -0.22 | Likely Benign | 0.1 | 0.37 | Likely Benign | 0.08 | Likely Benign | 0.21 | Likely Benign | 0.305 | Likely Benign | -1.00 | Neutral | 0.975 | Probably Damaging | 0.958 | Probably Damaging | 3.26 | Benign | 0.04 | Affected | 0.0650 | 0.2919 | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||
| c.1961A>G | E654G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E654G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign impact are premPS and FATHMM, while the majority (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict pathogenicity. 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 E654G. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.026892 | Structured | 0.303029 | Uncertain | 0.957 | 0.311 | 0.000 | -12.487 | Likely Pathogenic | 0.898 | Likely Pathogenic | Ambiguous | 1.29 | Ambiguous | 0.2 | 1.62 | Ambiguous | 1.46 | Ambiguous | 0.34 | Likely Benign | 0.547 | Likely Pathogenic | -6.73 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0.2818 | 0.3109 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.2048T>A | I683N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict pathogenicity, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized returns a pathogenic score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) also indicates pathogenicity. No predictions are missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -12.120 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 2.18 | Destabilizing | 0.1 | 2.08 | Destabilizing | 2.13 | Destabilizing | 1.46 | Destabilizing | 0.546 | Likely Pathogenic | -6.87 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0.0978 | 0.1133 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| 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 | 0.55 | Ambiguous | 0.5 | -0.53 | Ambiguous | 0.01 | Likely Benign | 0.68 | Ambiguous | 0.495 | Likely Benign | -5.55 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0.3806 | 0.5296 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.2114A>T | K705M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K705M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, FoldX, Foldetta, premPS, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by Rosetta and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM‑Consensus) aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and yields a pathogenic verdict (3/4 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of evidence points toward a pathogenic impact, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.379324 | Uncertain | 0.922 | 0.364 | 0.000 | -9.595 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | -0.13 | Likely Benign | 0.0 | 0.53 | Ambiguous | 0.20 | Likely Benign | 0.17 | Likely Benign | 0.306 | Likely Benign | -3.65 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.0724 | 0.3057 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.2186A>T | N729I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729I is listed in gnomAD (ID 6‑33441651‑A‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, premPS, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicting benign, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points to a benign impact. There is no ClinVar status to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | 6-33441651-A-T | 1 | 6.20e-7 | -3.308 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.54 | Ambiguous | 0.6 | 0.79 | Ambiguous | 0.67 | Ambiguous | 0.29 | Likely Benign | 0.043 | Likely Benign | -2.96 | Deleterious | 0.506 | Possibly Damaging | 0.243 | Benign | 3.26 | Benign | 0.13 | Tolerated | 3.59 | 7 | 0.0625 | 0.4698 | -3 | -2 | 8.0 | -0.94 | |||||||||||||||||||||||||
| 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 | -0.20 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.26 | Benign | 0.08 | Tolerated | 0.3309 | 0.4957 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1236G>C | L412F 2D AIThe SynGAP1 missense variant L412F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas the majority of tools (SGM‑Consensus, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Taken together, the consensus of the majority of evidence points to a pathogenic effect for L412F, 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 | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -8.710 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 7.00 | Destabilizing | 3.5 | 3.61 | Destabilizing | 5.31 | Destabilizing | 0.48 | Likely Benign | 0.286 | Likely Benign | -3.69 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.27 | Benign | 0.04 | Affected | 0.0602 | 0.2891 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1236G>T | L412F 2D AIThe SynGAP1 missense variant L412F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas the majority of tools (SGM‑Consensus, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Taken together, the consensus of the majority of evidence points to a pathogenic effect for L412F, 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 | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -8.710 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 7.00 | Destabilizing | 3.5 | 3.61 | Destabilizing | 5.31 | Destabilizing | 0.48 | Likely Benign | 0.283 | Likely Benign | -3.69 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.27 | Benign | 0.04 | Affected | 0.0602 | 0.2891 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1342G>T | A448S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A448S missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that indicate a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict any ClinVar annotation because none exists. 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 | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -9.213 | Likely Pathogenic | 0.590 | Likely Pathogenic | Likely Benign | 1.18 | Ambiguous | 0.1 | 1.97 | Ambiguous | 1.58 | Ambiguous | 0.55 | Ambiguous | 0.310 | Likely Benign | -2.96 | Deleterious | 0.965 | Probably Damaging | 0.972 | Probably Damaging | 3.27 | Benign | 0.06 | Tolerated | 0.2420 | 0.3471 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1362C>G | I454M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools (SGM‑Consensus, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. Tools with inconclusive results are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for I454M. This conclusion is not contradicted by ClinVar, 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 | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -8.437 | Likely Pathogenic | 0.871 | Likely Pathogenic | Ambiguous | 1.06 | Ambiguous | 0.1 | 2.32 | Destabilizing | 1.69 | Ambiguous | 1.08 | Destabilizing | 0.292 | Likely Benign | -2.86 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.27 | Benign | 0.01 | Affected | 0.0566 | 0.2524 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.1391T>C | F464S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) 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 because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -13.361 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 4.84 | Destabilizing | 0.0 | 4.90 | Destabilizing | 4.87 | Destabilizing | 2.52 | Destabilizing | 0.748 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.27 | Benign | 0.00 | Affected | 0.3700 | 0.0358 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1523A>T | D508V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D508V missense change is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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 (a folding‑stability method combining FoldX‑MD and Rosetta outputs) as benign. With seven benign versus six pathogenic calls and two of the three high‑accuracy tools supporting benign, the variant is most likely benign. 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 | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -13.529 | Likely Pathogenic | 0.691 | Likely Pathogenic | Likely Benign | 0.07 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.37 | Likely Benign | 0.07 | Likely Benign | 0.381 | Likely Benign | -8.37 | Deleterious | 0.985 | Probably Damaging | 0.895 | Possibly Damaging | 3.27 | Benign | 0.08 | Tolerated | 0.1050 | 0.4604 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| 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 | -0.01 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.33 | Likely Benign | 0.46 | Likely Benign | 0.314 | Likely Benign | -5.02 | Deleterious | 0.998 | Probably Damaging | 0.998 | Probably Damaging | 3.27 | Benign | 0.00 | Affected | 0.0629 | 0.5073 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.1643A>C | E548A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E548A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, FATHMM, premPS, and Foldetta, whereas pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a pathogenic call from AlphaMissense‑Optimized, a likely pathogenic verdict from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and a benign result from Foldetta. Overall, the majority of evidence points to a pathogenic effect, so the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.008632 | Uncertain | 0.965 | 0.288 | 0.000 | -13.543 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.18 | Likely Benign | 0.1 | 0.56 | Ambiguous | 0.37 | Likely Benign | 0.48 | Likely Benign | 0.499 | Likely Benign | -5.83 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.27 | Benign | 0.05 | Affected | 0.3035 | 0.4328 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1952A>T | E651V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E651V missense change is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools split in their assessment: benign‑predicted scores include REVEL, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic‑predicted scores come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized and FoldX give uncertain results. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, leans pathogenic (3 pathogenic vs. 1 benign); Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the majority of tools (including the high‑accuracy SGM Consensus) suggest a pathogenic impact, whereas Foldetta and several other predictors indicate benign. The variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.365409 | Uncertain | 0.955 | 0.340 | 0.000 | -10.025 | Likely Pathogenic | 0.865 | Likely Pathogenic | Ambiguous | 0.63 | Ambiguous | 0.1 | 0.25 | Likely Benign | 0.44 | Likely Benign | 0.21 | Likely Benign | 0.467 | Likely Benign | -5.53 | Deleterious | 0.988 | Probably Damaging | 0.734 | Possibly Damaging | 3.27 | Benign | 0.05 | Affected | 0.0824 | 0.6136 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.2003C>G | S668C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S668C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from premPS, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions are returned by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) supports a pathogenic outcome; Foldetta remains inconclusive. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | -12.815 | Likely Pathogenic | 0.758 | Likely Pathogenic | Likely Benign | 1.31 | Ambiguous | 0.6 | 1.36 | Ambiguous | 1.34 | Ambiguous | 0.18 | Likely Benign | 0.503 | Likely Pathogenic | -4.99 | Deleterious | 0.999 | Probably Damaging | 0.944 | Probably Damaging | 3.27 | Benign | 0.02 | Affected | 0.0962 | 0.5528 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.2047A>T | I683F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, 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. High‑accuracy assessments show the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, while AlphaMissense‑Optimized and Foldetta are inconclusive and thus treated as unavailable evidence. Overall, the balance of evidence favors a pathogenic classification for I683F, and this assessment does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -12.781 | Likely Pathogenic | 0.828 | Likely Pathogenic | Ambiguous | 1.38 | Ambiguous | 0.1 | -0.23 | Likely Benign | 0.58 | Ambiguous | 0.59 | Ambiguous | 0.481 | Likely Benign | -3.99 | Deleterious | 0.971 | Probably Damaging | 0.499 | Possibly Damaging | 3.27 | Benign | 0.01 | Affected | 0.0770 | 0.2307 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.2054T>C | L685S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685S is 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, 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: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any existing 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 | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -12.303 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.08 | Destabilizing | 0.2 | 2.95 | Destabilizing | 3.02 | Destabilizing | 1.24 | Destabilizing | 0.520 | Likely Pathogenic | -5.99 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.27 | Benign | 0.01 | Affected | 0.2844 | 0.0505 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||
| c.2062G>A | E688K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E688K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, FATHMM, and Foldetta, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta and premPS. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign stability. Overall, the majority of conventional predictors and the SGM Consensus lean toward pathogenicity, and there is no conflict with ClinVar status because the variant is not yet catalogued. Thus, based on current computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.211124 | Uncertain | 0.947 | 0.223 | 0.000 | -15.177 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.44 | Likely Benign | 0.6 | -0.60 | Ambiguous | -0.08 | Likely Benign | 0.77 | Ambiguous | 0.469 | Likely Benign | -3.49 | Deleterious | 0.998 | Probably Damaging | 0.975 | Probably Damaging | 3.27 | Benign | 0.01 | Affected | 0.2458 | 0.5518 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| 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 | 0.17 | Likely Benign | 0.9 | 0.15 | Likely Benign | 0.16 | Likely Benign | 0.59 | Ambiguous | 0.302 | Likely Benign | -2.53 | Deleterious | 0.997 | Probably Damaging | 0.973 | Probably Damaging | 3.27 | Benign | 0.15 | Tolerated | 0.1154 | 0.5387 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.2063A>G | E688G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E688G has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Those that predict a pathogenic effect include FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive predictions come from Foldetta, premPS, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain (treated as unavailable). Overall, the majority of reliable tools predict a deleterious effect. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.211124 | Uncertain | 0.947 | 0.223 | 0.000 | -14.338 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 2.17 | Destabilizing | 0.5 | 1.44 | Ambiguous | 1.81 | Ambiguous | 0.86 | Ambiguous | 0.486 | Likely Benign | -6.55 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.27 | Benign | 0.00 | Affected | 0.3059 | 0.4433 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.2065C>G | L689V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L689V is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) and the SGM Consensus (Likely Pathogenic) predict a pathogenic impact. The high‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; SGM Consensus is Likely Pathogenic; Foldetta predicts a pathogenic effect. Taken together, the preponderance of evidence points to a pathogenic effect for L689V. This conclusion is not contradicted by ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.227227 | Uncertain | 0.963 | 0.248 | 0.000 | -11.387 | Likely Pathogenic | 0.862 | Likely Pathogenic | Ambiguous | 2.98 | Destabilizing | 0.1 | 2.25 | Destabilizing | 2.62 | Destabilizing | 1.32 | Destabilizing | 0.234 | Likely Benign | -2.97 | Deleterious | 0.926 | Possibly Damaging | 0.481 | Possibly Damaging | 3.27 | Benign | 0.00 | Affected | 0.1393 | 0.3189 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.2123T>G | L708R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L708R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as Likely Pathogenic. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of tools (six pathogenic vs. four benign) and the SGM Consensus support a pathogenic classification, whereas AlphaMissense‑Optimized suggests benign. The variant is most likely pathogenic based on the collective predictions, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.250310 | Structured | 0.365875 | Uncertain | 0.931 | 0.378 | 0.000 | -9.154 | Likely Pathogenic | 0.638 | Likely Pathogenic | Likely Benign | 0.87 | Ambiguous | 0.0 | 0.90 | Ambiguous | 0.89 | Ambiguous | 1.24 | Destabilizing | 0.249 | Likely Benign | -4.18 | Deleterious | 0.988 | Probably Damaging | 0.598 | Possibly Damaging | 3.27 | Benign | 0.19 | Tolerated | 0.1091 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2185A>T | N729Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta remains uncertain. The high‑accuracy consensus methods give a consistent benign signal: 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. Taken together, the overwhelming majority of evidence points to a benign effect. Thus, 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 | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | -2.284 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.00 | Likely Benign | 0.1 | 0.82 | Ambiguous | 0.41 | Likely Benign | 0.08 | Likely Benign | 0.060 | Likely Benign | -2.35 | Neutral | 0.575 | Possibly Damaging | 0.053 | Benign | 3.27 | Benign | 0.14 | Tolerated | 0.0570 | 0.4073 | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||||||
| c.1337A>C | E446A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E446A is not reported in ClinVar and is absent from gnomAD. In silico predictors that classify the variant as benign include REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized. Predictors that classify it as pathogenic comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, yielded an inconclusive result and is treated as unavailable. Overall, the majority of predictions lean toward pathogenicity, and this conclusion is not contradicted by the absence of a ClinVar entry. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.276479 | Uncertain | 0.940 | 0.216 | 0.000 | -9.868 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 1.66 | Ambiguous | 0.7 | 0.39 | Likely Benign | 1.03 | Ambiguous | 0.67 | Ambiguous | 0.443 | Likely Benign | -5.60 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 3.28 | Benign | 0.01 | Affected | 0.3195 | 0.5877 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| 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 | 0.19 | Likely Benign | 0.0 | -0.22 | Likely Benign | -0.02 | Likely Benign | 0.67 | Ambiguous | 0.241 | Likely Benign | -2.76 | Deleterious | 0.940 | Possibly Damaging | 0.843 | Possibly Damaging | 3.28 | Benign | 0.06 | Tolerated | 0.1015 | 0.4980 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||
| c.1391T>A | F464Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464Y is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, while AlphaMissense‑Optimized and Foldetta provide uncertain results and are treated as unavailable evidence. Overall, the balance of evidence points to a pathogenic effect for F464Y, 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 | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -10.056 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 1.35 | Ambiguous | 0.1 | 0.24 | Likely Benign | 0.80 | Ambiguous | 1.31 | Destabilizing | 0.387 | Likely Benign | -2.98 | Deleterious | 0.979 | Probably Damaging | 0.953 | Probably Damaging | 3.28 | Benign | 0.01 | Affected | 0.1081 | 0.1523 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1555G>A | E519K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519K missense variant is listed in gnomAD (ID 6‑33438798‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E519K, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | 6-33438798-G-A | 1 | 6.20e-7 | -13.532 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | -0.55 | Ambiguous | 0.0 | -0.60 | Ambiguous | -0.58 | Ambiguous | 0.06 | Likely Benign | 0.328 | Likely Benign | -3.48 | Deleterious | 0.996 | Probably Damaging | 0.987 | Probably Damaging | 3.28 | Benign | 0.03 | Affected | 3.37 | 35 | 0.2545 | 0.3379 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||
| c.1555G>C | E519Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519Q 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, FoldX, Rosetta, premPS, PROVEAN, SIFT, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. 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 benign effect on protein stability. Overall, the majority of evidence points to a benign impact, 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. | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | -8.693 | Likely Pathogenic | 0.792 | Likely Pathogenic | Ambiguous | -0.35 | Likely Benign | 0.1 | -0.14 | Likely Benign | -0.25 | Likely Benign | -0.21 | Likely Benign | 0.195 | Likely Benign | -2.48 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 3.28 | Benign | 0.14 | Tolerated | 0.1394 | 0.3418 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.1562A>C | E521A 2D 3DClick to see structure in 3D Viewer AISynGAP1 E521A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign calls (REVEL, FoldX, Rosetta, premPS, SIFT, FATHMM) and pathogenic calls (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). AlphaMissense‑Optimized is uncertain. High‑accuracy assessments give conflicting results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. No prediction or stability result is missing. Overall, the evidence is evenly split, with six benign and six pathogenic calls, and the two high‑accuracy tools disagree. Therefore, the variant’s impact remains uncertain; it is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -8.997 | Likely Pathogenic | 0.892 | Likely Pathogenic | Ambiguous | 0.18 | Likely Benign | 0.1 | 0.40 | Likely Benign | 0.29 | Likely Benign | 0.11 | Likely Benign | 0.395 | Likely Benign | -4.12 | Deleterious | 0.998 | Probably Damaging | 0.999 | Probably Damaging | 3.28 | Benign | 0.13 | Tolerated | 0.4041 | 0.5918 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1846G>T | D616Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D616Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools predict a pathogenic outcome: SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, 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 balance of evidence favors a pathogenic interpretation, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | -12.638 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 1.70 | Ambiguous | 0.3 | 1.32 | Ambiguous | 1.51 | Ambiguous | 0.35 | Likely Benign | 0.374 | Likely Benign | -7.43 | Deleterious | 0.999 | Probably Damaging | 0.970 | Probably Damaging | 3.28 | Benign | 0.01 | Affected | 0.0465 | 0.4069 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.1957C>G | L653V 2D AIThe SynGAP1 missense variant L653V is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, and premPS, while ESM1b is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of evidence points to a benign impact, and this does not contradict the ClinVar “Uncertain” classification. Thus, based on current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.049374 | Structured | 0.335213 | Uncertain | 0.963 | 0.332 | 0.000 | Uncertain | 1 | -7.050 | In-Between | 0.301 | Likely Benign | Likely Benign | 3.28 | Destabilizing | 0.3 | 2.18 | Destabilizing | 2.73 | Destabilizing | 1.32 | Destabilizing | 0.146 | Likely Benign | -2.25 | Neutral | 0.227 | Benign | 0.039 | Benign | 3.28 | Benign | 0.08 | Tolerated | 0.1436 | 0.3557 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||
| c.2002T>G | S668A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S668A 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, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools—AlphaMissense‑Default and FoldX—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Taking all evidence together, the majority of predictions (seven benign versus four pathogenic) and the two high‑accuracy benign calls suggest 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. | GAP | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | -12.011 | Likely Pathogenic | 0.506 | Ambiguous | Likely Benign | 0.73 | Ambiguous | 0.3 | -0.44 | Likely Benign | 0.15 | Likely Benign | 0.48 | Likely Benign | 0.399 | Likely Benign | -2.99 | Deleterious | 0.887 | Possibly Damaging | 0.738 | Possibly Damaging | 3.28 | Benign | 0.19 | Tolerated | 0.4866 | 0.3967 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||
| c.2030G>A | S677N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677N is catalogued in gnomAD (6‑33441289‑G‑A) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while premPS and ESM1b are uncertain. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: 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. Thus, all available evidence supports a benign classification, and there is no conflict with ClinVar status (which is absent). The variant is most likely benign. 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 | 6-33441289-G-A | 1 | 6.20e-7 | -7.955 | In-Between | 0.111 | Likely Benign | Likely Benign | 0.17 | Likely Benign | 0.5 | -0.15 | Likely Benign | 0.01 | Likely Benign | 0.89 | Ambiguous | 0.079 | Likely Benign | -2.05 | Neutral | 0.038 | Benign | 0.007 | Benign | 3.28 | Benign | 0.15 | Tolerated | 3.41 | 23 | 0.1763 | 0.5688 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||
| c.2132T>C | L711P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L711P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and FATHMM; all other evaluated algorithms—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.377436 | Uncertain | 0.950 | 0.364 | 0.000 | -12.128 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 5.70 | Destabilizing | 0.1 | 8.15 | Destabilizing | 6.93 | Destabilizing | 2.09 | Destabilizing | 0.375 | Likely Benign | -6.59 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.28 | Benign | 0.00 | Affected | 0.3300 | 0.0986 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.2150T>C | L717P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L717P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from REVEL and FATHMM, while the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) all classify the variant as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts a pathogenic effect. No predictions are missing or inconclusive. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.429342 | Uncertain | 0.969 | 0.397 | 0.000 | -10.214 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.96 | Destabilizing | 0.2 | 6.56 | Destabilizing | 5.26 | Destabilizing | 1.66 | Destabilizing | 0.447 | Likely Benign | -5.32 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.28 | Benign | 0.00 | Affected | 0.3065 | 0.1053 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.2150T>G | L717R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L717R is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, while the remaining 13 tools (SGM‑Consensus, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the majority‑vote SGM Consensus) predict pathogenicity; FoldX is uncertain. High‑accuracy methods reinforce a pathogenic verdict: AlphaMissense‑Optimized scores it as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta also predicts pathogenic. No prediction is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.429342 | Uncertain | 0.969 | 0.397 | 0.000 | -11.352 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 1.66 | Ambiguous | 0.1 | 3.78 | Destabilizing | 2.72 | Destabilizing | 1.57 | Destabilizing | 0.353 | Likely Benign | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.28 | Benign | 0.00 | Affected | 0.1169 | 0.0558 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2185A>C | N729H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729H is not reported in ClinVar and is absent from gnomAD. 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; the only inconclusive results come from Rosetta (uncertain) and Foldetta (uncertain). High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign, while Foldetta remains uncertain. Overall, the evidence overwhelmingly supports a benign classification, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | -0.670 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.27 | Likely Benign | 0.0 | 0.84 | Ambiguous | 0.56 | Ambiguous | 0.00 | Likely Benign | 0.080 | Likely Benign | -0.92 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.28 | Benign | 0.17 | Tolerated | 0.1197 | 0.4602 | 2 | 1 | 0.3 | 23.04 | ||||||||||||||||||||||||||||||
| c.248G>A | R83K 2D AIThe SynGAP1 missense variant R83K is not reported 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 “Likely Benign,” while AlphaMissense‑Optimized is “Uncertain.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, 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 | 0.637480 | Disordered | 0.522784 | Binding | 0.275 | 0.895 | 0.250 | -3.480 | Likely Benign | 0.930 | Likely Pathogenic | Ambiguous | 0.101 | Likely Benign | -0.87 | Neutral | 0.643 | Possibly Damaging | 0.364 | Benign | 3.28 | Benign | 0.00 | Affected | 0.4715 | 0.3091 | 3 | 2 | 0.6 | -28.01 | |||||||||||||||||||||||||||||||||||||||
| c.3163G>T | G1055W 2D  AIThe SynGAP1 missense variant G1055W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is 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 | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -11.436 | Likely Pathogenic | 0.317 | Likely Benign | Likely Benign | 0.367 | Likely Benign | -0.77 | Neutral | 0.997 | Probably Damaging | 0.946 | Probably Damaging | 3.28 | Benign | 0.01 | Affected | 0.0899 | 0.4246 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3164G>T | G1055V 2D AIThe SynGAP1 missense variant G1055V is not reported 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while ESM1b remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments 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. 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 | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -7.434 | In-Between | 0.114 | Likely Benign | Likely Benign | 0.399 | Likely Benign | 0.26 | Neutral | 0.818 | Possibly Damaging | 0.222 | Benign | 3.28 | Benign | 0.17 | Tolerated | 0.1399 | 0.3694 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.1232T>A | I411N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I411N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.339366 | Uncertain | 0.927 | 0.198 | 0.000 | -14.426 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 3.00 | Destabilizing | 0.1 | 3.71 | Destabilizing | 3.36 | Destabilizing | 2.16 | Destabilizing | 0.556 | Likely Pathogenic | -6.42 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.29 | Benign | 0.00 | Affected | 0.0738 | 0.0700 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| 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 | 0.90 | Ambiguous | 0.1 | -0.02 | Likely Benign | 0.44 | Likely Benign | 0.24 | Likely Benign | 0.489 | Likely Benign | -6.38 | Deleterious | 0.998 | Probably Damaging | 0.983 | Probably Damaging | 3.29 | Benign | 0.00 | Affected | 0.0609 | 0.5457 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1276A>C | N426H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N426H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Predictions that are uncertain or inconclusive are FoldX and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign; and Foldetta also predicts a benign outcome. No prediction tool is missing or inconclusive in this set. 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. | GAP | 0.042364 | Structured | 0.394941 | Uncertain | 0.959 | 0.287 | 0.000 | -7.004 | In-Between | 0.248 | Likely Benign | Likely Benign | 0.64 | Ambiguous | 0.0 | -0.14 | Likely Benign | 0.25 | Likely Benign | 0.24 | Likely Benign | 0.237 | Likely Benign | -3.57 | Deleterious | 0.998 | Probably Damaging | 0.985 | Probably Damaging | 3.29 | Benign | 0.14 | Tolerated | 0.1267 | 0.3124 | 2 | 1 | 0.3 | 23.04 | ||||||||||||||||||||||||||||||
| c.1354G>T | V452F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V452F variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect are Rosetta and FATHMM, whereas the remaining tools (REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Based on the preponderance of evidence, the variant is most likely pathogenic, a conclusion that contradicts its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | Uncertain | 1 | -14.769 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 9.21 | Destabilizing | 0.1 | 0.37 | Likely Benign | 4.79 | Destabilizing | 0.61 | Ambiguous | 0.511 | Likely Pathogenic | -4.94 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.29 | Benign | 0.00 | Affected | 3.37 | 34 | 0.0564 | 0.3451 | -1 | -1 | -1.4 | 48.04 | 249.4 | -35.7 | 0.0 | 0.0 | 0.4 | 0.1 | X | Potentially Pathogenic | The iso-propyl side chain of Val452, located in the middle of an α helix (res. Val441-Ser457), packs against hydrophobic residues in the inter-helix space at the intersection of three α helices (e.g., Leu500, His453, Leu465). In the variant simulations, the larger side chain of Phe452 cannot pack against the opposing α helix (res. Leu489-Glu519) as efficiently as valine. Due to space restrictions, the phenol ring adjusts to make room by rotating slightly sideways in the inter-helix space. Besides this small and local shift, no large-scale effects on the protein structure are seen based on the simulations. However, the size difference between the swapped residues could affect the protein folding process. | ||||||||||||||||
| c.1363C>G | L455V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from REVEL and FATHMM, whereas the remaining 11 tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict pathogenicity. High‑accuracy assessments reinforce this trend: 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, also predicts pathogenicity. Taken together, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -12.773 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 2.89 | Destabilizing | 0.1 | 2.38 | Destabilizing | 2.64 | Destabilizing | 1.41 | Destabilizing | 0.276 | Likely Benign | -2.83 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 3.29 | Benign | 0.02 | Affected | 0.1149 | 0.3056 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1379A>T | K460M 2D 3DClick to see structure in 3D Viewer AISynGAP1 K460M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic calls arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: FoldX and AlphaMissense‑Optimized. When high‑accuracy methods are considered separately, AlphaMissense‑Optimized remains inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts 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 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 | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -10.351 | Likely Pathogenic | 0.943 | Likely Pathogenic | Ambiguous | 0.61 | Ambiguous | 0.0 | 0.18 | Likely Benign | 0.40 | Likely Benign | 0.20 | Likely Benign | 0.252 | Likely Benign | -4.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.29 | Benign | 0.02 | Affected | 0.1148 | 0.4522 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.1380G>C | K460N 2D AIThe SynGAP1 missense variant K460N 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, Rosetta, SIFT, and FATHMM, whereas those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic signal: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic; and the protein‑folding stability method Foldetta, which integrates FoldX‑MD and Rosetta outputs, indicates a benign effect. Overall, the balance of evidence—six pathogenic versus five benign predictions, a pathogenic SGM Consensus, and a pathogenic AlphaMissense‑Optimized—suggests that K460N is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant is not currently catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -11.988 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.25 | Likely Benign | 0.5 | 0.45 | Likely Benign | 0.35 | Likely Benign | 0.89 | Ambiguous | 0.202 | Likely Benign | -4.13 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.29 | Benign | 0.06 | Tolerated | 0.3669 | 0.1599 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1380G>T | K460N 2D AIThe SynGAP1 K460N missense variant is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus methods further support a pathogenic interpretation: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic; whereas Foldetta, which integrates FoldX‑MD and Rosetta outputs, indicates a benign effect. Overall, the majority of evidence—including the high‑accuracy tools—points to a pathogenic impact for K460N. 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 | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -11.988 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.25 | Likely Benign | 0.5 | 0.45 | Likely Benign | 0.35 | Likely Benign | 0.89 | Ambiguous | 0.202 | Likely Benign | -4.13 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.29 | Benign | 0.06 | Tolerated | 0.3669 | 0.1599 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.2011G>T | D671Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D671Y missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split consensus: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized and the SGM‑Consensus both indicate pathogenicity, while Foldetta predicts a benign effect on protein stability. Because the majority of standard predictors lean toward pathogenicity and the two high‑confidence tools also favor a deleterious outcome, the variant is most likely pathogenic. This assessment does not contradict ClinVar, 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 | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -13.107 | Likely Pathogenic | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.31 | Likely Benign | 0.1 | 0.05 | Likely Benign | 0.18 | Likely Benign | 0.11 | Likely Benign | 0.385 | Likely Benign | -6.05 | Deleterious | 1.000 | Probably Damaging | 0.961 | Probably Damaging | 3.29 | Benign | 0.00 | Affected | 0.0564 | 0.6376 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.2048T>C | I683T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683T has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include SIFT, FATHMM, and AlphaMissense‑Optimized, whereas a majority of tools predict pathogenicity: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support this pattern: AlphaMissense‑Optimized classifies the variant as benign, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates it is likely pathogenic; the Foldetta stability analysis is inconclusive and therefore unavailable. Taken together, the preponderance of evidence points to a pathogenic effect for I683T. This conclusion does not contradict 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 | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -9.891 | Likely Pathogenic | 0.775 | Likely Pathogenic | Likely Benign | 1.67 | Ambiguous | 0.1 | 1.35 | Ambiguous | 1.51 | Ambiguous | 1.25 | Destabilizing | 0.548 | Likely Pathogenic | -4.77 | Deleterious | 0.999 | Probably Damaging | 0.981 | Probably Damaging | 3.29 | Benign | 0.08 | Tolerated | 0.1090 | 0.0880 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.2048T>G | I683S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. No prediction or folding stability result is missing or inconclusive; all available evidence points to a deleterious effect. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -11.443 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 2.53 | Destabilizing | 0.2 | 1.94 | Ambiguous | 2.24 | Destabilizing | 1.35 | Destabilizing | 0.552 | Likely Pathogenic | -5.88 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 3.29 | Benign | 0.05 | Affected | 0.1936 | 0.1320 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.2053T>A | L685M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain predictions come from premPS, Foldetta, Rosetta, and AlphaMissense‑Optimized. High‑accuracy methods give inconclusive results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑to‑2 tie and therefore uncertain; Foldetta also reports an uncertain stability change. Consequently, the overall computational evidence is mixed, with a slight tilt toward pathogenicity. Thus, the variant is most likely pathogenic based on predictions, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -10.790 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | 0.35 | Likely Benign | 0.1 | 1.01 | Ambiguous | 0.68 | Ambiguous | 0.83 | Ambiguous | 0.281 | Likely Benign | -2.00 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.29 | Benign | 0.01 | Affected | 0.0814 | 0.2758 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.2098C>A | L700M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L700M is not 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only Rosetta predicts a pathogenic outcome, while Foldetta’s stability assessment is uncertain. The high‑accuracy consensus (SGM Consensus) is derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, all of which are benign, yielding a “Likely Benign” classification. AlphaMissense‑Optimized also predicts benign, whereas Foldetta remains inconclusive. Overall, the preponderance of evidence indicates that 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 | GAP | 0.113710 | Structured | 0.416255 | Uncertain | 0.927 | 0.331 | 0.000 | -4.617 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.11 | Likely Benign | 0.0 | 2.79 | Destabilizing | 1.45 | Ambiguous | 0.35 | Likely Benign | 0.039 | Likely Benign | -0.32 | Neutral | 0.211 | Benign | 0.081 | Benign | 3.29 | Benign | 0.08 | Tolerated | 0.0733 | 0.2397 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
Found 8751 rows. Show 800 rows per page. Page 6/11 « Previous | Next »