Table of SynGAP1 Isoform α2 (UniProt Q96PV0-1) Missense Variants.
| c.dna | Variant | SGM Consensus | Domain | ClinVar | gnomAD | ESM1b | AlphaMissense | REVEL | FoldX | Rosetta | Foldetta | PremPS | PROVEAN | PolyPhen-2 HumDiv | PolyPhen-2 HumVar | FATHMM | SIFT | PAM | Physical | SASA | Normalized B-factor backbone | Normalized B-factor sidechain | SynGAP Structural Annotation | DOI | |||||||||||||||||||||||||||||||||
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| Clinical Status | Review | Subm. | ID | Allele count | Allele freq. | LLR score | Prediction | Pathogenicity | Class | Optimized | Score | Prediction | Average ΔΔG | Prediction | StdDev | ΔΔG | Prediction | ΔΔG | Prediction | ΔΔG | Prediction | Score | Prediction | pph2_prob | Prediction | pph2_prob | Prediction | Nervous System Score | Prediction | Prediction | Status | Conservation | Sequences | PAM250 | PAM120 | Hydropathy Δ | MW Δ | Average | Δ | Δ | StdDev | Δ | StdDev | Secondary | Tertiary bonds | Inside out | GAP-Ras interface | At membrane | No effect | MD Alert | Verdict | Description | |||||
| c.1678G>A | V560M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 V560M missense variant is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6-33440730-G-A). Functional prediction tools that agree on a benign effect include FoldX, Foldetta, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Uncertain predictions come from Rosetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of high‑confidence tools predict a benign impact, with only one consensus pathogenic prediction. Therefore, the variant is most likely benign based on current computational evidence, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 2 | 6-33440730-G-A | 15 | 9.50e-6 | -9.598 | Likely Pathogenic | 0.517 | Ambiguous | Likely Benign | 0.520 | Likely Pathogenic | -0.33 | Likely Benign | 0.1 | 0.88 | Ambiguous | 0.28 | Likely Benign | 0.72 | Ambiguous | -2.42 | Neutral | 0.999 | Probably Damaging | 0.863 | Possibly Damaging | -1.25 | Pathogenic | 0.14 | Tolerated | 3.37 | 35 | 2 | 1 | -2.3 | 32.06 | 234.9 | -52.6 | 0.0 | 0.0 | -0.1 | 0.1 | X | Potentially Benign | Val560 is located on the surface at the end of an α-helix (res. Ala533-Val560). The iso-propyl group of Val560 favorably packs against Asp508 of the opposing α-helix (res. Gln503-Glu519). However, in the variant simulations, the bulkier thioether side chain of Met560 does not form equally favorable inter-helix interactions. Regardless, no negative structural effects are observed during the simulations. | |||||||||
| c.1136C>G | S379W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438041‑C‑G). Prediction tools that indicate a benign effect include premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus as benign. Because the majority of conventional tools favor pathogenicity while the high‑accuracy subset is split, the overall evidence leans toward a pathogenic effect. This conclusion does not contradict the ClinVar uncertain status, which remains unresolved. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Uncertain | 1 | 6-33438041-C-G | -8.898 | Likely Pathogenic | 0.388 | Ambiguous | Likely Benign | 0.520 | Likely Pathogenic | 4.32 | Destabilizing | 3.4 | 3.56 | Destabilizing | 3.94 | Destabilizing | 0.16 | Likely Benign | -1.02 | Neutral | 0.998 | Probably Damaging | 0.844 | Possibly Damaging | 3.82 | Benign | 0.01 | Affected | 4.32 | 11 | -2 | -3 | -0.1 | 99.14 | 271.3 | -75.7 | 1.4 | 1.0 | 0.6 | 0.5 | Uncertain | Ser379 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like tryptophan are rarely tolerated. Although no major negative structural effects are observed in the variant simulations, Trp379 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effect on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn | ||||||||||||
| c.1205T>G | L402R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L402R is listed in ClinVar as Pathogenic (ClinVar ID 559657.0) and is not reported in gnomAD. Prediction tools that agree on 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. High‑accuracy methods give the following results: 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. Based on the overwhelming agreement among pathogenic predictions and the concordance with ClinVar, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Likely Pathogenic | 1 | -13.800 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.522 | Likely Pathogenic | 4.10 | Destabilizing | 0.2 | 3.82 | Destabilizing | 3.96 | Destabilizing | 2.24 | Destabilizing | -4.69 | Deleterious | 0.967 | Probably Damaging | 0.459 | Possibly Damaging | 3.69 | Benign | 0.00 | Affected | 3.38 | 28 | -3 | -2 | -8.3 | 43.03 | 259.5 | -55.4 | 0.0 | 0.0 | 1.4 | 0.0 | X | X | X | Potentially Pathogenic | The iso-butyl side chain of Leu402, located in an anti-parallel β sheet strand (res. Ala399-Ile411), packs with residues inside the hydrophobic core of the C2 domain (e.g., Ile268, Ala404, Leu266, Val400). In the variant simulations, the positively charged guanidinium group of the Arg402 side chain is not suitable for the hydrophobic niche. Consequently, the side chain moves outward from the hydrophobic C2 domain core and stacks with the phenol ring of Tyr363 or forms H-bonds with the carboxamide group of the Gln361 side chain in the β sheet strand (res. Thr359-Tyr364). This movement induces extensive negative effects on the C2 domain structure. | |||||||||
| c.1997A>G | E666G 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant E666G is listed in ClinVar as Benign (ClinVar ID 1115026.0) and is present in gnomAD (ID 6‑33441256‑A‑G). Functional prediction tools that agree on pathogenicity include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. Only FATHMM predicts a benign effect. Predictions marked Uncertain (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as Uncertain. Overall, the majority of evidence points to a pathogenic impact, which contradicts the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Benign | 1 | 6-33441256-A-G | 10 | 6.20e-6 | -12.261 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 0.522 | Likely Pathogenic | 1.57 | Ambiguous | 0.1 | 1.46 | Ambiguous | 1.52 | Ambiguous | 0.93 | Ambiguous | -6.25 | Deleterious | 1.000 | Probably Damaging | 0.970 | Probably Damaging | 3.37 | Benign | 0.02 | Affected | 3.38 | 28 | 0 | -2 | 3.1 | -72.06 | 173.9 | 98.5 | 0.0 | 0.0 | -0.7 | 0.0 | X | Potentially Pathogenic | In the WT simulations, the carboxylate group of Glu666, located on the α-helix (res. Ser641-Glu666), is involved in a highly coordinated hydrogen-bonding network between residues from two α-helices (res. Ser641-Glu666 and res. Arg563-Glu578) and from the α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), such as Lys566, Thr672, and Asn669. In the variant simulations, the carbonyl group of Gly666 occasionally forms hydrogen bonds with Lys566 and Asn669. However, Gly666 lacks a side chain and thus cannot maintain as well-coordinated a hydrogen-bond network as Glu666 in the WT, which may affect the tertiary structure assembly. | ||||||||
| c.1405G>A | A469T 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant A469T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and the Foldetta stability assessment (combining FoldX‑MD and Rosetta). The high‑accuracy subset shows AlphaMissense‑Optimized as benign, whereas SGM Consensus and Foldetta both predict pathogenic. Overall, the majority of evidence supports a pathogenic effect, and this conclusion does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -9.540 | Likely Pathogenic | 0.723 | Likely Pathogenic | Likely Benign | 0.527 | Likely Pathogenic | 2.26 | Destabilizing | 0.1 | 1.90 | Ambiguous | 2.08 | Destabilizing | 0.34 | Likely Benign | -1.46 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | -1.21 | Pathogenic | 0.42 | Tolerated | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||
| c.3794G>C | R1265T 2D  AIThe SynGAP1 missense variant R1265T is reported in ClinVar as Pathogenic (ClinVar ID 522047.0) and is not found in gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool in the dataset predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Pathogenic verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions supports a pathogenic classification, which is consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | Likely Pathogenic | 1 | -10.129 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.529 | Likely Pathogenic | -4.97 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | 3.77 | 5 | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||
| c.3788T>C | I1263T 2D  AIThe SynGAP1 missense variant I1263T is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33446780‑T‑C). Functional prediction tools largely agree on a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report pathogenicity, while only ESM1b predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic classification. 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 pathogenic effect, which aligns with the ClinVar designation of uncertainty but does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | Uncertain | 1 | 6-33446780-T-C | 2 | 1.24e-6 | -6.564 | Likely Benign | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.529 | Likely Pathogenic | -4.15 | Deleterious | 0.946 | Possibly Damaging | 0.673 | Possibly Damaging | 1.81 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0 | -1 | -5.2 | -12.05 | ||||||||||||||||||||||||||
| c.917T>A | V306D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V306D is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All available in‑silico predictors that were evaluated return a pathogenic or likely‑pathogenic assessment: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a benign effect. High‑accuracy methods 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 outputs, is pathogenic. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, 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 Pathogenic | C2 | Uncertain | 1 | -18.289 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.530 | Likely Pathogenic | 4.40 | Destabilizing | 0.3 | 4.29 | Destabilizing | 4.35 | Destabilizing | 2.44 | Destabilizing | -5.44 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.74 | Pathogenic | 0.00 | Affected | 3.38 | 19 | -2 | -3 | -7.7 | 15.96 | 212.3 | -18.3 | -0.2 | 0.4 | 0.0 | 0.2 | X | X | X | Potentially Pathogenic | The isopropyl group of Val396, located at the beginning of an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Leu274, Trp308, Ala271) in the WT simulations. However, in the variant simulations, the negatively charged carboxylate group of the Asp306 side chain is not suitable for this hydrophobic niche. Consequently, the side chain moves out to interact with Ser300 in the β strand (res. Met289-Arg299) and the guanidinium group of Arg299 in the β hairpin loop.In the third simulation, the residue swap disrupts the C2 domain secondary structure and tertiary assembly to a large degree when the amino group of the Lys297 side chain rotates to form a salt bridge with Asp306. This drastic effect could potentially reflect the challenge presented by the residue swap during the C2 domain folding. Because the residue swap affects the C2 domain structure, the SynGAP-membrane association could also be impacted. However, this is beyond the scope of the solvent-only simulations to unravel. | |||||||||
| c.667A>T | T223S 2D  3DClick to see structure in 3D Viewer AISynGAP1 T223S is listed in ClinVar as a variant of uncertain significance and is present in the gnomAD database (ID 6‑33435518‑A‑T). Functional prediction tools that reach consensus classify the variant as benign: FoldX, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict pathogenicity include REVEL, PROVEAN, and SIFT. Predictions that are inconclusive or uncertain are Rosetta, premPS, AlphaMissense‑Default, and ESM1b. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, Foldetta is benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 1‑to‑1 split between benign and pathogenic calls. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | Conflicting | 2 | 6-33435518-A-T | 3 | 1.86e-6 | -7.714 | In-Between | 0.410 | Ambiguous | Likely Benign | 0.535 | Likely Pathogenic | 0.26 | Likely Benign | 0.1 | 0.50 | Ambiguous | 0.38 | Likely Benign | 0.62 | Ambiguous | -2.86 | Deleterious | 0.421 | Benign | 0.058 | Benign | 5.80 | Benign | 0.02 | Affected | 3.41 | 13 | 1 | 1 | -0.1 | -14.03 | 200.7 | 17.3 | -0.2 | 0.2 | 0.0 | 0.0 | X | Uncertain | The introduced residue Ser223 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Its hydroxyl group forms hydrogen bonds with nearby residues Thr228 and Lys207 in the variant simulations, similar to the hydroxyl group of Thr223 in the WT simulations. These hydrogen-bonding interactions at the β sheet surface contribute to the stability of the secondary structure element and may prevent it from unfolding. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||
| c.1802C>T | A601V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A601V is listed in ClinVar (ID 968190.0) with an uncertain clinical significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from Rosetta and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. Four tools (FoldX, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the ClinVar designation of uncertain significance rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -10.447 | Likely Pathogenic | 0.853 | Likely Pathogenic | Ambiguous | 0.535 | Likely Pathogenic | 1.64 | Ambiguous | 0.1 | 0.35 | Likely Benign | 1.00 | Ambiguous | 0.81 | Ambiguous | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 2.74 | Benign | 0.03 | Affected | 3.37 | 35 | 0 | 0 | 2.4 | 28.05 | 228.5 | -45.5 | 0.0 | 0.0 | 0.4 | 0.5 | X | Potentially Benign | The methyl side chain of Ala601, located on an α helix (res. Glu582-Met603), packs hydrophobically against other hydrophobic residues in the inter-helix space (e.g., Phe597, Leu598, Leu506, Phe608).In the variant simulations, Val601, which has similar size and physicochemical properties to alanine, resides in the inter-helix hydrophobic space in a similar manner to Ala601 in the WT, causing no apparent negative effect on the protein structure. However, the effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||
| c.3614T>C | L1205P 2D  AIThe SynGAP1 missense variant L1205P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All available in silico predictors classify the change as pathogenic: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly indicates that the variant is pathogenic, which contradicts the current ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | Uncertain | 1 | -16.878 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.536 | Likely Pathogenic | -5.91 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.45 | Pathogenic | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||
| c.1631G>A | R544Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R544Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33438874‑G‑A). Prediction tools that classify the change as benign include FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Foldetta and Rosetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, which is not contradictory to the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | 6-33438874-G-A | 1 | 6.20e-7 | -10.281 | Likely Pathogenic | 0.596 | Likely Pathogenic | Likely Benign | 0.542 | Likely Pathogenic | 0.19 | Likely Benign | 0.2 | 0.87 | Ambiguous | 0.53 | Ambiguous | 1.40 | Destabilizing | -2.41 | Neutral | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.40 | Pathogenic | 0.09 | Tolerated | 3.37 | 35 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||
| 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 | Likely Benign | 1 | 6-33441250-T-C | 1 | 6.20e-7 | -16.498 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.543 | Likely Pathogenic | 3.75 | Destabilizing | 0.2 | 3.63 | Destabilizing | 3.69 | Destabilizing | 2.77 | Destabilizing | -5.99 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.85 | Benign | 0.00 | Affected | 3.38 | 28 | -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.1651C>A | L551M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L551M is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438894‑C‑A). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, PROVEAN, SIFT, and AlphaMissense‑Optimized, while those that predict pathogenicity are REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Two tools report an uncertain outcome: premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of predictions lean toward a benign effect, and this does not contradict the ClinVar “Uncertain” classification. Thus, the variant is most likely benign based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 1 | 6-33438894-C-A | 7 | 4.34e-6 | -9.937 | Likely Pathogenic | 0.480 | Ambiguous | Likely Benign | 0.544 | Likely Pathogenic | -0.07 | Likely Benign | 0.1 | 0.13 | Likely Benign | 0.03 | Likely Benign | 0.71 | Ambiguous | -0.56 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.48 | Pathogenic | 0.06 | Tolerated | 3.37 | 35 | 4 | 2 | -1.9 | 18.03 | 246.5 | -18.6 | 0.0 | 0.0 | 0.3 | 0.0 | X | Potentially Benign | L551 is located on an α-helix (res. Ala533-Val560). The iso-butyl side chain of Leu551 hydrophobically packs with nearby hydrophobic residues such as Cys547, Phe652, Leu633, and Ile630 in the inter-helix space. In the variant simulations, the thioether side chain of Met551 can maintain similar hydrophobic interactions as Leu551 in the WT, thus causing no negative effect on the protein structure during the simulations. | |||||||||
| c.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 | Likely Pathogenic | 1 | -13.231 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.544 | Likely Pathogenic | 5.34 | Destabilizing | 0.1 | 5.73 | Destabilizing | 5.54 | Destabilizing | 2.14 | Destabilizing | -7.43 | Deleterious | 0.998 | Probably Damaging | 0.938 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 3.37 | 29 | -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.3529G>A | E1177K 2D  AISynGAP1 missense variant E1177K is listed in ClinVar with an Uncertain significance status and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments give AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta stability analysis is unavailable. Overall, the balance of evidence leans toward a benign effect, which does not contradict the ClinVar designation of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | Uncertain | 1 | -3.413 | Likely Benign | 0.944 | Likely Pathogenic | Ambiguous | 0.560 | Likely Pathogenic | -1.75 | Neutral | 0.905 | Possibly Damaging | 0.637 | Possibly Damaging | 5.44 | Benign | 0.11 | Tolerated | 4.32 | 2 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1126G>T | G376C 2D  AISynGAP1 missense variant G376C is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from Rosetta, premPS, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls come from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Two tools report uncertainty: Foldetta and ESM1b. 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, also yields a benign verdict; Foldetta remains uncertain. Overall, the majority of conventional predictors lean toward pathogenicity, whereas the most accurate methods favor a benign effect. Thus, the variant is most likely pathogenic based on the prevailing 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. | C2 | Uncertain | 1 | -7.686 | In-Between | 0.125 | Likely Benign | Likely Benign | 0.560 | Likely Pathogenic | 2.56 | Destabilizing | 0.5 | 0.22 | Likely Benign | 1.39 | Ambiguous | 0.16 | Likely Benign | -1.15 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.32 | Pathogenic | 0.01 | Affected | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||
| c.1485A>C | E495D 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant E495D is listed in ClinVar with an uncertain significance (ClinVar ID 2000233.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions from SIFT and ESM1b, and pathogenic predictions from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN classifies the variant as likely pathogenic. AlphaMissense‑Optimized also predicts pathogenicity, whereas Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of deleterious impact. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Conflicting | 2 | -3.574 | Likely Benign | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.566 | Likely Pathogenic | 1.39 | Ambiguous | 0.1 | 1.03 | Ambiguous | 1.21 | Ambiguous | 0.98 | Ambiguous | -2.52 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | -1.41 | Pathogenic | 0.17 | Tolerated | 3.37 | 35 | 3 | 2 | 0.0 | -14.03 | 220.6 | 38.8 | 0.0 | 0.0 | 0.1 | 0.1 | X | X | Uncertain | Glu495 is located in the α-helix (res. Leu489-Glu519), and its carboxylate group forms salt bridges with the neighboring Lys492 and with Arg596 on an opposing α-helix (res. Glu582-Met603) in the WT simulations. In the variant simulations, the acidic carboxylate side chain of Asp495 can also form salt bridges with both Lys492 and Arg596. However, the shorter side chain of aspartate tends to favor forming a salt bridge with the nearby Arg499 on the same α-helix instead. Asp495 might not maintain the salt bridge with Arg596 on the opposing α-helix as efficiently as Glu495 in the WT, potentially weakening the tertiary structure. Regardless, the potential negative effect is likely to be minor, with no deleterious effects observed on the protein structure during the simulations. However, due to its location at the GAP-Ras interface, the effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||
| c.1402A>G | M468V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from PROVEAN, SIFT, and AlphaMissense‑Optimized, while pathogenic predictions are made by REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools, premPS and AlphaMissense‑Default, return uncertain results. High‑accuracy assessments further clarify the variant’s impact: AlphaMissense‑Optimized predicts a benign effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also classifies the variant as pathogenic. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Uncertain | 1 | -9.461 | Likely Pathogenic | 0.361 | Ambiguous | Likely Benign | 0.570 | Likely Pathogenic | 2.69 | Destabilizing | 0.1 | 2.20 | Destabilizing | 2.45 | Destabilizing | 0.89 | Ambiguous | -1.66 | Neutral | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.21 | Pathogenic | 0.08 | Tolerated | 3.37 | 31 | 1 | 2 | 2.3 | -32.06 | |||||||||||||||||||||
| c.1214G>C | R405P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R405P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict it to be pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores it as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates it is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies it as pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Uncertain | 1 | -14.206 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.572 | Likely Pathogenic | 3.11 | Destabilizing | 0.3 | 5.19 | Destabilizing | 4.15 | Destabilizing | 1.26 | Destabilizing | -6.32 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.62 | Benign | 0.01 | Affected | 3.38 | 28 | -2 | 0 | 2.9 | -59.07 | ||||||||||||||||||||
| c.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 | Uncertain | 1 | -14.889 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.572 | Likely Pathogenic | 2.11 | Destabilizing | 0.1 | 0.69 | Ambiguous | 1.40 | Ambiguous | 1.66 | Destabilizing | -5.63 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.15 | Benign | 0.00 | Affected | 3.37 | 29 | -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.667A>G | T223A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T223A is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33435518‑A‑G). Functional prediction tools that agree on a benign effect include FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL and PROVEAN. Predictions that are inconclusive are Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also resolves to benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | Uncertain | 1 | 6-33435518-A-G | 3 | 1.86e-6 | -7.076 | In-Between | 0.316 | Likely Benign | Likely Benign | 0.574 | Likely Pathogenic | 0.30 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.54 | Ambiguous | 0.74 | Ambiguous | -3.36 | Deleterious | 0.231 | Benign | 0.058 | Benign | 5.74 | Benign | 0.09 | Tolerated | 3.41 | 13 | 1 | 0 | 2.5 | -30.03 | 186.4 | 44.0 | 0.0 | 0.0 | 0.0 | 0.0 | X | X | Uncertain | The introduced residue Ala223 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the hydroxyl group of the Thr223 side chain in the WT protein, the methyl side chain of Ala223 cannot form hydrogen bonds with nearby residues Thr228 and Lys207. Without these hydrogen-bonding interactions at the β sheet surface, the secondary structure element becomes unstable and partially unfolds in the variant simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||
| c.1169G>A | G390E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G390E is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, FoldX, Rosetta, Foldetta, SIFT, FATHMM, and AlphaMissense‑Default. A high‑accuracy assessment shows AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions support a pathogenic effect, and this aligns with the ClinVar designation of uncertain significance rather than contradicting it. 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. | C2 | Uncertain | 1 | -7.913 | In-Between | 0.646 | Likely Pathogenic | Likely Benign | 0.575 | Likely Pathogenic | 2.61 | Destabilizing | 0.9 | 4.28 | Destabilizing | 3.45 | Destabilizing | 0.47 | Likely Benign | -0.87 | Neutral | 0.276 | Benign | 0.045 | Benign | 1.32 | Pathogenic | 0.05 | Affected | 4.32 | 8 | 0 | -2 | -3.1 | 72.06 | 241.5 | -108.4 | 0.6 | 0.5 | -0.1 | 0.1 | Uncertain | Gly390 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. This loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play significant roles in protein functions that require flexibility, and so they are rich in glycine residues, prolines, and to a lesser extent, small hydrophilic residues to ensure maximum flexibility. Thus, the variant’s Glu390 may not be as well tolerated in the Ω loop. Additionally, the carboxylate group of Glu390 occasionally forms H-bonds with other loop residues in the variant simulations. The interaction between the acidic carboxylate side chain and the acidic membrane lipids may further influence the SynGAP-membrane complex. However, since the effects on the Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||||||
| c.937G>A | E313K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313K is listed in ClinVar as Benign (ClinVar ID 3695040.0) and is not reported in gnomAD. Prediction tools that report a benign effect are absent; all available predictors that provide a definitive call classify the variant as pathogenic. These include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus indicates Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) is Uncertain. Based on the overwhelming pathogenic predictions, 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 | C2 | Likely Benign | 1 | -12.902 | Likely Pathogenic | 0.959 | Likely Pathogenic | Likely Pathogenic | 0.575 | Likely Pathogenic | 0.64 | Ambiguous | 0.6 | 1.40 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | -3.31 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 1.90 | Pathogenic | 0.02 | Affected | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||
| c.877C>T | R293C 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R293C is listed in ClinVar with an uncertain significance (ClinVar ID 2500611.0) and is present in gnomAD (6‑33437782‑C‑T). Prediction tools that classify the variant as benign include premPS, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Consequently, the overwhelming majority of computational evidence indicates a pathogenic impact for R293C. This prediction aligns with the ClinVar designation of uncertain significance, not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Uncertain | 1 | 6-33437782-C-T | 3 | 1.86e-6 | -12.844 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.579 | Likely Pathogenic | 1.38 | Ambiguous | 0.1 | 0.62 | Ambiguous | 1.00 | Ambiguous | 0.02 | Likely Benign | -7.35 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.46 | Pathogenic | 0.00 | Affected | 3.38 | 23 | -4 | -3 | 7.0 | -53.05 | 226.0 | 96.5 | 0.0 | 0.0 | 0.1 | 0.1 | X | X | X | Potentially Pathogenic | The guanidinium group of the Arg293 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), packs against the phenol ring of the Tyr281 side chain or forms a salt bridge with the carboxylate group of Glu283 on the outer side of the C2 domain. The positively charged guanidinium side chain of arginine is on the outside surface of the hydrophobic C2 domain, resulting in a twist in the β strand. Although this twist is maintained in the variant simulations, replacing the positively charged residue with a more hydrophobic one, such as cysteine, could remove the twist during protein folding.Because Arg293 is positioned at the C2 and PH domain interface, the residue swap could significantly impact the tertiary structure assembly. Notably, Arg293 is located at the SynGAP-Ras interface, and its role in complex formation cannot be fully understood through solvent-only simulations. | ||||||
| c.1726T>C | C576R 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant C576R is listed in ClinVar with an uncertain significance (ClinVar ID 2780076.0) 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, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores it pathogenic, the SGM‑Consensus (derived from the majority of high‑confidence predictors) is pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Taken together, the overwhelming majority of computational evidence indicates that C576R is likely pathogenic, a conclusion that is consistent with, but not in conflict with, the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Conflicting | 2 | -14.886 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.579 | Likely Pathogenic | 7.20 | Destabilizing | 1.0 | 4.09 | Destabilizing | 5.65 | Destabilizing | 1.64 | Destabilizing | -10.88 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.38 | Benign | 0.00 | Affected | 3.37 | 35 | -3 | -4 | -7.0 | 53.05 | ||||||||||||||||||||
| c.1606T>G | L536V 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant L536V is listed in ClinVar (ID 1690714.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic verdict. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. No evidence from FoldX or Rosetta alone is available. Overall, the majority of evidence points toward a pathogenic effect, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -9.014 | Likely Pathogenic | 0.269 | Likely Benign | Likely Benign | 0.586 | Likely Pathogenic | 1.25 | Ambiguous | 0.3 | 1.22 | Ambiguous | 1.24 | Ambiguous | 1.20 | Destabilizing | -2.81 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | -1.34 | Pathogenic | 0.09 | Tolerated | 3.37 | 34 | 2 | 1 | 0.4 | -14.03 | 204.7 | 26.4 | 0.2 | 0.0 | -0.2 | 0.2 | X | Potentially Benign | Leu536 is located on an α-helix (res. Ala533-Val560) at the membrane interface. The iso-butyl group of Leu536 interacts with nearby hydrophobic residues in the preceding loop (e.g., Val526, Pro528, Cys531). In the variant simulations, the iso-propyl side chain of Val536 forms similar hydrophobic interactions as Leu536 in the WT, causing no negative structural effects. | |||||||||||
| c.1673A>G | H558R 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant H558R is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from AlphaMissense‑Optimized, Rosetta, SIFT, and polyPhen‑2 HumVar, while pathogenic predictions arise from REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and FATHMM. Four tools give inconclusive results: AlphaMissense‑Default, SGM‑Consensus, FoldX, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign effect, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the majority of evidence points toward a pathogenic impact, which does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -14.445 | Likely Pathogenic | 0.554 | Ambiguous | Likely Benign | 0.587 | Likely Pathogenic | -1.14 | Ambiguous | 0.1 | -0.23 | Likely Benign | -0.69 | Ambiguous | 1.03 | Destabilizing | -4.94 | Deleterious | 0.677 | Possibly Damaging | 0.239 | Benign | -1.24 | Pathogenic | 0.14 | Tolerated | 3.37 | 35 | 0 | 2 | -1.3 | 19.05 | ||||||||||||||||||||
| c.1802C>A | A601E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A601E is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Conflicting | 2 | -16.752 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.588 | Likely Pathogenic | 6.68 | Destabilizing | 0.8 | 5.76 | Destabilizing | 6.22 | Destabilizing | 1.24 | Destabilizing | -4.98 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.54 | Benign | 0.00 | Affected | 3.37 | 35 | 0 | -1 | -5.3 | 58.04 | 240.0 | -82.3 | 0.0 | 0.0 | 0.7 | 0.1 | X | X | X | Potentially Pathogenic | The methyl side chain of Ala601, located on an α helix (res. Glu582-Met603), packs hydrophobically against other hydrophobic residues in the inter-helix space (e.g., Phe597, Leu598, Leu506, Phe608).In the variant simulations, the carboxylate group of Glu601 faces the inter-helix space and is forced to shift slightly away from the hydrophobic niche. Additionally, in two of the simulations, Glu601 forms a salt bridge with Arg499, causing the otherwise stable salt bridge between Arg499 and Glu496 at the outer surface of an α helix (res. Leu489-Glu519) to break due to the residue swap.These effects suggest that the protein folding process could be seriously affected. Moreover, due to its location at the GAP-Ras interface, it could also impact the complex formation with the GTPase. | |||||||||
| c.859G>C | D287H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D287H missense variant is listed in ClinVar as Pathogenic (ClinVar ID 1700054.0) and is not reported in gnomAD. Functional prediction tools that assess the variant’s effect on protein function largely agree on a deleterious outcome. Benign predictions come from FoldX, Rosetta, and Foldetta, whereas pathogenic predictions are reported by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS remains uncertain. High‑accuracy assessments further support a pathogenic classification: 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, predicts benign. Overall, the majority of evidence points to a pathogenic effect, consistent with the ClinVar designation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Likely Pathogenic | 1 | -14.518 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.589 | Likely Pathogenic | 0.48 | Likely Benign | 0.3 | 0.32 | Likely Benign | 0.40 | Likely Benign | 0.63 | Ambiguous | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.51 | Pathogenic | 0.00 | Affected | 3.38 | 23 | 1 | -1 | 0.3 | 22.05 | 235.6 | 3.8 | 0.1 | 1.2 | 0.1 | 0.1 | X | X | Potentially Pathogenic | The carboxylate group of Asp287, located at the beginning of a β hairpin loop connecting two anti-parallel β sheet strands (res. Arg279-Leu286, res. Met289-Pro298), maintains a salt bridge with the guanidinium group of Arg324 in the β sheet during the WT simulations. In the variant simulations, the imidazole ring of the His287 side chain is unable to form a salt bridge with Arg324 or establish any other stable compensatory interactions, which could weaken the beta sandwich assembly of the C2 domain. This destabilization of the C2 domain could adversely affect the stability of the SynGAP-membrane association. | ||||||||||
| c.1635G>A | M545I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M545I is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions arise from FoldX, Rosetta, and SIFT, whereas pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default; premPS remains inconclusive. High‑accuracy methods provide mixed evidence: AlphaMissense‑Optimized indicates pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also suggests likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the preponderance of conventional tools and the SGM Consensus lean toward pathogenicity, whereas the Foldetta result is an outlier. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict its ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -8.348 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.592 | Likely Pathogenic | 0.47 | Likely Benign | 0.1 | 0.14 | Likely Benign | 0.31 | Likely Benign | 0.63 | Ambiguous | -3.61 | Deleterious | 0.935 | Possibly Damaging | 0.941 | Probably Damaging | -1.27 | Pathogenic | 0.28 | Tolerated | 3.37 | 35 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||
| c.1390T>G | F464V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 F464V variant is listed in ClinVar with an “Uncertain” status (ClinVar ID 1716596.0) and is not reported in gnomAD. Prediction tools that agree on 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 (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective predictions, the variant is most likely pathogenic, 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 | Uncertain | 1 | -12.254 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.592 | Likely Pathogenic | 3.61 | Destabilizing | 0.1 | 2.89 | Destabilizing | 3.25 | Destabilizing | 1.40 | Destabilizing | -6.96 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 3.36 | Benign | 0.04 | Affected | 3.37 | 34 | -1 | -1 | 1.4 | -48.04 | 210.1 | 40.5 | -0.1 | 0.0 | -0.9 | 0.3 | X | Potentially Pathogenic | The phenyl ring of Phe464, located in the middle of an α helix (res. Ala461–Phe476), packs against hydrophobic residues (e.g., Met468, Leu451, Leu455, and Tyr428) in the inter-helix space formed with two other α helices (res. Asn440-Lys460 and res. Pro413-Glu436). The iso-propyl side chain of Val464 is similarly hydrophobic but considerably smaller than the original phenyl ring of Phe464. To compensate for the size difference, neighboring residues need to fill in the gap in the variant simulations.The phenolic side chain of Tyr428, located at the middle bend of an α helix (res. Glu436-Pro413), assumes a new position in the inter-helix space or rotates inward next to the third α helix (res. Asn440-Lys460) when the stable H-bond between Tyr428 and Asp467 seen in the WT simulations breaks. The residue swap also leads to the loss of the methionine-aromatic interaction between the Met468 and Phe464 side chains, which could weaken the integrity of the parent α helix (res. Ala461-Phe476). Although the simulations likely underestimate the full adverse effect of the introduced mutation during folding, the two opposing α helices (res. Ala461–Phe476 and res. Glu436-Pro413) move substantially closer to each other in the variant simulations. | |||||||||||
| c.1621G>C | A541P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A541P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenicity. No predictions are inconclusive or missing. Overall, the collective evidence points to a pathogenic effect for A541P, which is in contrast to the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -14.733 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.594 | Likely Pathogenic | 2.47 | Destabilizing | 0.3 | 7.26 | Destabilizing | 4.87 | Destabilizing | 0.86 | Ambiguous | -3.16 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.34 | Pathogenic | 0.07 | Tolerated | 3.37 | 35 | 1 | -1 | -3.4 | 26.04 | 170.4 | -11.2 | 0.1 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | Ala541 is located on the outer surface of an α-helix (res. Ala533-Val560). The methyl group of Ala541 is on the surface and does not form any interactions. Proline lacks a free backbone amide group, and thus, Pro541 is unable to form a hydrogen bond with the carbonyl group of Ala537 in the variant simulations. Consequently, Pro541 disrupts the continuity of the secondary structure element, causing the α-helix to bend slightly in the variant simulations. | |||||||||||
| c.1172G>T | G391V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G391V is listed in ClinVar as Benign (ClinVar ID 1014488.0) and is present in gnomAD (variant ID 6‑33438077‑G‑T). Prediction tools that classify the variant as benign include premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. Tools that predict pathogenicity are REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. With two high‑accuracy tools supporting benign and one supporting pathogenic, the overall prediction leans toward a benign effect. This conclusion aligns with the ClinVar benign classification, so there is no contradiction with the existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | Likely Benign | 1 | 6-33438077-G-T | 3 | 1.86e-6 | -6.642 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 0.595 | Likely Pathogenic | 4.23 | Destabilizing | 1.3 | 4.81 | Destabilizing | 4.52 | Destabilizing | -0.11 | Likely Benign | -0.98 | Neutral | 0.994 | Probably Damaging | 0.887 | Possibly Damaging | 1.32 | Pathogenic | 0.10 | Tolerated | 3.69 | 8 | -1 | -3 | 4.6 | 42.08 | 228.6 | -69.0 | 0.0 | 0.8 | -0.5 | 0.3 | Uncertain | Gly387 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. This loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play significant roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are visualized in the variant’s simulations, Val391 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. Since the effects on the Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||
| c.3632T>A | M1211K 2D  AIThe SynGAP1 missense variant M1211K is listed in ClinVar (ID 834052.0) as benign and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FATHMM and AlphaMissense‑Optimized, while the remaining seven tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—classify the change as pathogenic. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts a benign effect, whereas the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta data are unavailable. Overall, the preponderance of evidence from standard predictors and the SGM Consensus supports a pathogenic interpretation, which contradicts the benign classification reported in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | Likely Benign | 1 | -9.013 | Likely Pathogenic | 0.662 | Likely Pathogenic | Likely Benign | 0.595 | Likely Pathogenic | -2.95 | Deleterious | 0.987 | Probably Damaging | 0.979 | Probably Damaging | 5.59 | Benign | 0.01 | Affected | 3.77 | 5 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| 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 | Pathogenic | 1 | -13.873 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.596 | Likely Pathogenic | 3.24 | Destabilizing | 0.1 | 3.27 | Destabilizing | 3.26 | Destabilizing | 2.76 | Destabilizing | -5.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.06 | Benign | 0.00 | Affected | 3.42 | 17 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||
| c.1453C>T | R485C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R485C (gnomAD ID 6‑33438485‑C‑T) is listed in ClinVar with an uncertain significance. Functional prediction tools largely disagree: benign calls come from Rosetta and premPS, whereas pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus is labeled likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. With the majority of evidence pointing to pathogenicity and no contradictory data from ClinVar, the variant is most likely pathogenic, although ClinVar has not yet reached a definitive classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 2 | 6-33438485-C-T | 9 | 5.58e-6 | -14.294 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.597 | Likely Pathogenic | 1.00 | Ambiguous | 0.1 | 0.26 | Likely Benign | 0.63 | Ambiguous | 0.44 | Likely Benign | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.90 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -4 | -3 | 7.0 | -53.05 | 225.5 | 99.6 | -0.1 | 0.0 | -0.3 | 0.2 | X | Uncertain | The guanidinium group of Arg485 is located in a short helical structure (res. Glu480-Leu482) within an α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. The side chain of Arg485 acts as the “arginine finger” of SynGAP, playing a crucial role in Ras-GTPase activation. Consequently, the residue swap inhibits the conversion of GTP to GDP at the enzyme’s active site. Although no negative effects on the protein structure are observed during the simulations, no definite conclusions can be drawn due to the critical role of Arg485 in GTPase activation. | ||||||||
| c.1193C>T | P398L 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant P398L (ClinVar ID 2415189.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33438098‑C‑T). Functional prediction tools that agree on a benign effect include Foldetta, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, and SIFT. Predictions that are uncertain or inconclusive are FoldX, Rosetta, premPS, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Based on the available predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Uncertain | 1 | 6-33438098-C-T | 8 | 4.96e-6 | -7.518 | In-Between | 0.547 | Ambiguous | Likely Benign | 0.599 | Likely Pathogenic | 1.48 | Ambiguous | 0.2 | -0.54 | Ambiguous | 0.47 | Likely Benign | 0.62 | Ambiguous | -7.10 | Deleterious | 0.961 | Probably Damaging | 0.256 | Benign | 5.72 | Benign | 0.01 | Affected | 3.40 | 16 | -3 | -3 | 5.4 | 16.04 | 245.8 | -68.6 | -0.1 | 0.0 | -0.3 | 0.2 | X | Potentially Pathogenic | Pro398 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. Although the residue swap does not influence the nearby secondary structure elements, proline is often found at the ends of β sheets due to its disfavored status during folding.Additionally, the Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone. Ω loops are known to play significant roles in protein functions that require flexibility, and thus hydrophobic residues like leucine are rarely tolerated. Although no negative structural effects are visualized in the variant’s simulations, Leu398 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. Since the effects on the Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||
| c.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 | Uncertain | 1 | -13.383 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.601 | Likely Pathogenic | 2.35 | Destabilizing | 0.3 | 3.74 | Destabilizing | 3.05 | Destabilizing | 0.93 | Ambiguous | -3.98 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 2.89 | Benign | 0.00 | Affected | 3.37 | 35 | 0 | 1 | -1.7 | 34.02 | ||||||||||||||||||||
| c.1855A>T | T619S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T619S is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated algorithms—SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized reports a benign outcome, whereas the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, yields an uncertain result. Overall, the majority of evidence points to a pathogenic effect for T619S, and this conclusion does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -8.608 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.602 | Likely Pathogenic | 1.09 | Ambiguous | 0.2 | 1.35 | Ambiguous | 1.22 | Ambiguous | 0.85 | Ambiguous | -3.42 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.30 | Pathogenic | 0.05 | Affected | 3.37 | 35 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||
| c.1760G>C | R587T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R587T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include SIFT and AlphaMissense‑Optimized, whereas a majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic outcome. Uncertain predictions from FoldX, Rosetta, Foldetta, and premPS are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for R587T, which does not contradict the ClinVar “Uncertain” classification but suggests that the variant is more likely pathogenic rather than benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -9.697 | Likely Pathogenic | 0.784 | Likely Pathogenic | Likely Benign | 0.603 | Likely Pathogenic | 1.14 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.94 | Ambiguous | 0.98 | Ambiguous | -4.71 | Deleterious | 0.998 | Probably Damaging | 0.847 | Possibly Damaging | -1.19 | Pathogenic | 0.08 | Tolerated | 3.37 | 35 | -1 | -1 | 3.8 | -55.08 | 227.2 | 87.4 | 0.0 | 0.0 | 0.5 | 0.1 | X | Potentially Pathogenic | The guanidinium group of Arg587, located on an α helix (res. Glu582-Met603), is constantly rotating and breaking/forming multiple hydrogen bonds and/or salt bridges at the surface intersection of α helices in the WT simulations. The positively charged Arg587 side chain can form a salt bridge with either the carboxylate group of Asp583 or Asp586 in the same helix, or with Glu480 on the opposing short helical loop structure (res. Glu480-Leu482).Importantly, the Arg587 side chain also hydrogen bonds with the backbone carbonyl groups of Ala634 and Asn635, as well as the carboxamide group of Asn635 at the end of another α helix (res. Asp616-Phe636). However, in the variant simulations, the neutral hydroxyl group of the Thr587 side chain is unable to form these salt bridges. Due to its smaller size, it also does not form the hydrogen bonds that the Arg587 side chain could. Instead, the hydroxyl group of Thr587 hydrogen bonds with the backbone carbonyl group of Asp583, which could weaken the integrity of the α helix, although this is not observed in the simulations.Overall, the residue swap could weaken the tertiary structure assembly and negatively affect the overall protein folding process. | |||||||||||
| c.1453C>A | R485S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R485S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FoldX, which scores the variant as benign. In contrast, the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that return uncertain results are Rosetta, Foldetta, and premPS. 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 R485S, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -15.603 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.609 | Likely Pathogenic | 0.40 | Likely Benign | 0.1 | 1.07 | Ambiguous | 0.74 | Ambiguous | 0.82 | Ambiguous | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||
| c.2050G>C | D684H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684H 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; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, 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 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. No predictions are inconclusive or missing. Based on the overwhelming majority of pathogenic predictions, the variant is most likely pathogenic, 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 | Uncertain | 1 | -14.194 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.613 | Likely Pathogenic | 3.36 | Destabilizing | 1.0 | 2.95 | Destabilizing | 3.16 | Destabilizing | 0.55 | Ambiguous | -6.98 | Deleterious | 1.000 | Probably Damaging | 0.972 | Probably Damaging | 3.36 | Benign | 0.00 | Affected | 3.42 | 17 | -1 | 1 | 0.3 | 22.05 | ||||||||||||||||||||
| c.1454G>A | R485H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 R485H missense variant is listed in ClinVar as Benign (ClinVar ID 3707943.0) and is present in the gnomAD database (gnomAD ID 6‑33438486‑G‑A). Functional prediction tools that agree on a benign effect are Rosetta and Foldetta, while the majority of tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the preponderance of evidence points to a pathogenic effect, which contradicts the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Benign | 1 | 6-33438486-G-A | 13 | 8.05e-6 | -13.628 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.618 | Likely Pathogenic | 0.77 | Ambiguous | 0.1 | 0.12 | Likely Benign | 0.45 | Likely Benign | 1.13 | Destabilizing | -4.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.93 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0 | 2 | 1.3 | -19.05 | |||||||||||||||||
| c.1142G>T | G381V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G381V is listed in ClinVar with an uncertain significance (ClinVar ID 1940172.0) and is present in the gnomAD database (6‑33438047‑G‑T). Functional prediction tools that report a benign effect include premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, FoldX, Rosetta, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a majority‑benign vote and is reported as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions lean toward 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 | C2 | Uncertain | 1 | 6-33438047-G-T | 2 | 1.25e-6 | -5.967 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 0.618 | Likely Pathogenic | 7.16 | Destabilizing | 1.0 | 4.10 | Destabilizing | 5.63 | Destabilizing | -0.32 | Likely Benign | -0.95 | Neutral | 0.386 | Benign | 0.157 | Benign | 1.32 | Pathogenic | 0.10 | Tolerated | 4.32 | 9 | -1 | -3 | 4.6 | 42.08 | 214.6 | -68.8 | 0.3 | 0.7 | -0.5 | 0.3 | Uncertain | Gly381 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are observed in the variant simulations, Val381 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effects on Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | |||||||||
| 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 | Likely Benign | 1 | 6-33440914-G-A | 19 | 1.18e-5 | -14.682 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 0.621 | Likely Pathogenic | 0.81 | Ambiguous | 0.1 | 1.13 | Ambiguous | 0.97 | Ambiguous | 1.35 | Destabilizing | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.82 | Benign | 0.01 | Affected | 3.37 | 35 | 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.953C>T | P318L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P318L is listed in ClinVar with an uncertain significance (ClinVar ID 956570.0) and is present in gnomAD (6‑33437858‑C‑T). Functional prediction tools that agree on a benign effect are Rosetta and premPS. The remaining tools—REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized reports pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Taken together, the preponderance of evidence points to a pathogenic effect for P318L, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Uncertain | 3 | 6-33437858-C-T | 3 | 1.86e-6 | -10.090 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.624 | Likely Pathogenic | 1.33 | Ambiguous | 0.1 | 0.26 | Likely Benign | 0.80 | Ambiguous | 0.43 | Likely Benign | -8.96 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.82 | Pathogenic | 0.03 | Affected | 3.38 | 23 | -3 | -3 | 5.4 | 16.04 | 228.6 | -68.9 | -0.7 | 0.7 | -0.4 | 0.1 | X | Potentially Benign | The cyclic five-membered pyrrolidine ring of Pro318, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Asp330-Ala322, res. Thr305-Asn315), packs against the hydrophobic side chain of Ile205 at the end of the anti-parallel β sheet in the PH domain. In the variant simulations, the iso-butyl side chain of Leu318 is unable to do the same, potentially weakening the PH and C2 domain association. Importantly, the residue swap could also affect loop formation during folding, as proline can make tighter turns than leucine. Because the residue swap could affect the C2 domain stability, it could also negatively impact the SynGAP-membrane association. | ||||||||
| c.1424G>A | R475Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R475Q is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6-33438456‑G‑A). Prediction tools that indicate a benign effect include AlphaMissense‑Optimized, Foldetta, and Rosetta. Those that predict a pathogenic effect comprise SGM Consensus, SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Default; FoldX and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points toward 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 | Uncertain | 2 | 6-33438456-G-A | 5 | 3.10e-6 | -12.087 | Likely Pathogenic | 0.721 | Likely Pathogenic | Likely Benign | 0.632 | Likely Pathogenic | 0.71 | Ambiguous | 0.1 | 0.12 | Likely Benign | 0.42 | Likely Benign | 0.82 | Ambiguous | -3.65 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 3.39 | 28 | 1 | 1 | 1.0 | -28.06 | 253.6 | 52.7 | 0.0 | 0.0 | -0.8 | 0.0 | X | X | X | Potentially Pathogenic | In the WT simulations, the guanidinium group of Arg475, located near the end of an α-helix (res. Ala461-Phe476), stacks with the phenyl ring of Phe476 and forms a salt bridge with Glu472. Additionally, Arg475 occasionally forms another salt bridge with the carboxylate group of Glu486 on the α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. Therefore, Arg475 potentially plays a key role in positioning the loop by interacting with Glu486, which is necessary for the positioning of the “arginine finger” (Arg485) and, ultimately, for RasGTPase activation. In the variant simulations, Asn475 forms a hydrogen bond with Arg479 on the proceeding α-α loop. The absence of Phe476/Arg475 stacking and the Arg475-Glu472 salt bridge weakens the integrity of the terminal end of the α-helix during the variant simulations. Lastly, the potential effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||
| c.1786C>T | R596C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R596C is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33440838‑C‑T). Prediction tools that indicate a benign effect include only premPS. All other evaluated algorithms—REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—classify the variant as pathogenic or likely pathogenic, while Rosetta remains inconclusive. High‑accuracy assessments 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, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. **Thus, the variant is most likely pathogenic based on the collective 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 | Conflicting | 2 | 6-33440838-C-T | 6 | 3.72e-6 | -10.805 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.633 | Likely Pathogenic | 2.94 | Destabilizing | 0.0 | 1.49 | Ambiguous | 2.22 | Destabilizing | -0.03 | Likely Benign | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.41 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -4 | -3 | 7.0 | -53.05 | 230.7 | 97.9 | -0.1 | 0.0 | -0.3 | 0.4 | X | X | Potentially Pathogenic | The guanidinium group of Arg596, located in an α helix (res. Glu582-Met603), forms a salt bridge with the carboxylate group of Glu495 from another α helix (res. Leu489-Glu519). In the WT simulations, the side chain of Arg596 hydrogen bonds with the backbone carbonyl groups of Asn487, Glu486, Arg485, and Phe484. Additionally, Arg596 can hydrogen bond with the carboxamide group of the Asn487 side chain on an opposing loop that links two α helices (res. Ala461-Arg475, res. Leu489-Glu519).In the variant simulations, the thiol group of the Cys596 side chain is unable to form salt bridges or any of the hydrogen bonds that the Arg596 side chain can. Thus, the residue swap could affect the tertiary structure assembly more profoundly than observed in the simulations. Notably, Arg596 plays a key role in positioning the aforementioned loop, which is crucial for the placement of the “arginine finger” or the Arg485 side chain during RasGTPase activation. | |||||||
| c.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 | Uncertain | 1 | 6-33440863-C-T | 6 | 3.72e-6 | -14.683 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.639 | Likely Pathogenic | -0.94 | Ambiguous | 0.1 | -1.24 | Ambiguous | -1.09 | Ambiguous | -0.31 | Likely Benign | -5.97 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 3.37 | 35 | -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.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 | Uncertain | 1 | -10.420 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.640 | Likely Pathogenic | 2.94 | Destabilizing | 0.1 | 2.70 | Destabilizing | 2.82 | Destabilizing | 2.23 | Destabilizing | -4.18 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.04 | Benign | 0.00 | Affected | 0 | -1 | -5.2 | -12.05 | ||||||||||||||||||||||
| 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 | Likely Pathogenic | 1 | -15.047 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.643 | Likely Pathogenic | 16.72 | Destabilizing | 5.0 | 11.07 | Destabilizing | 13.90 | Destabilizing | 0.00 | Likely Benign | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.18 | Benign | 0.00 | Affected | 3.38 | 28 | -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.1738G>A | G580S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G580S is listed in ClinVar with an “Uncertain” status (ClinVar ID 1487029.0) and is present in the gnomAD database (gnomAD ID 6‑33440790‑G‑A). Among the available in‑silico predictors, the majority (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) indicate a pathogenic effect, whereas only SIFT predicts a benign outcome. Predictions that are inconclusive or uncertain include Rosetta, Foldetta, premPS, AlphaMissense‑Optimized, and the SGM‑Consensus (which is derived from the pathogenic majority of the four contributing tools). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain (combining a pathogenic FoldX result with an uncertain Rosetta result). Overall, the preponderance of evidence points to a pathogenic effect, which is in contrast to the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | 6-33440790-G-A | 1 | 6.20e-7 | -10.788 | Likely Pathogenic | 0.861 | Likely Pathogenic | Ambiguous | 0.644 | Likely Pathogenic | 2.84 | Destabilizing | 0.2 | 0.59 | Ambiguous | 1.72 | Ambiguous | 0.87 | Ambiguous | -5.73 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.23 | Pathogenic | 0.07 | Tolerated | 3.37 | 34 | 1 | 0 | -0.4 | 30.03 | 233.9 | -49.3 | 0.8 | 0.0 | 0.6 | 0.1 | X | Potentially Benign | Gly580 is located on the outer surface in a short α-α loop turn connecting two α-helices (res. Arg563-Glu578, res. Glu582-Phe608) in the WT simulations. In the variant simulations, the side chain of Ser580 faces outward, and its hydroxyl group does not make any new or additional interactions compared to Gly580 in the WT simulations that could affect the protein structure. | ||||||||
| c.1513T>C | Y505H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505H is listed in ClinVar as Pathogenic (ClinVar ID 3064218.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic effect. High‑accuracy consensus methods reinforce this view: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is also Pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among predictive tools, the variant is most likely pathogenic, consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -11.383 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.646 | Likely Pathogenic | 2.91 | Destabilizing | 0.1 | 2.88 | Destabilizing | 2.90 | Destabilizing | 1.60 | Destabilizing | -4.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.64 | Benign | 0.00 | Affected | 3.37 | 35 | 2 | 0 | -1.9 | -26.03 | ||||||||||||||||||||
| c.1702G>T | V568L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V568L is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Among the available in‑silico predictors, eight tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic effect, whereas three tools (FoldX, Foldetta, and polyPhen‑2 HumVar) predict a benign outcome; the remaining three (Rosetta, premPS, AlphaMissense‑Optimized) are inconclusive. 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 preponderance 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 | Uncertain | 1 | -9.503 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | 0.651 | Likely Pathogenic | -0.30 | Likely Benign | 0.3 | 0.57 | Ambiguous | 0.14 | Likely Benign | 0.56 | Ambiguous | -2.69 | Deleterious | 0.511 | Possibly Damaging | 0.147 | Benign | -1.23 | Pathogenic | 0.04 | Affected | 3.37 | 35 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||
| c.1349C>A | A450E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A450E is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include SIFT and FATHMM, whereas the majority of tools predict it to be pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No predictions are inconclusive. Overall, the evidence strongly favors a pathogenic impact for A450E, which does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -16.578 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.653 | Likely Pathogenic | 3.86 | Destabilizing | 0.2 | 5.23 | Destabilizing | 4.55 | Destabilizing | 1.59 | Destabilizing | -4.67 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.38 | Benign | 0.07 | Tolerated | 3.37 | 32 | 0 | -1 | -5.3 | 58.04 | 240.1 | -82.6 | 0.0 | 0.0 | 0.7 | 0.0 | X | X | Potentially Pathogenic | The methyl group of Ala450, located in an α helix (res. Asn440-Thr458), packs against hydrophobic residues in the inter-helix space (e.g., Leu692). In the variant simulations, the carboxylate group of the Glu450 side chain rotates outward, away from the hydrophobic niche, where it does not form any lasting salt bridges or H-bonds. Although the residue swap does not negatively affect the protein structure based on the simulations, it is possible that the introduction of the negatively charged residue adversely affects the folding process or tertiary assembly. | ||||||||||
| c.980T>C | L327P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L327P (ClinVar ID 660421.0) is reported as Pathogenic and is not present in gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a Likely Pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports pathogenic. Consequently, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Pathogenic | 3 | -16.602 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.658 | Likely Pathogenic | 5.38 | Destabilizing | 0.1 | 4.00 | Destabilizing | 4.69 | Destabilizing | 2.62 | Destabilizing | -5.97 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.52 | Pathogenic | 0.01 | Affected | 3.38 | 23 | -3 | -3 | -5.4 | -16.04 | 221.7 | 69.4 | 0.1 | 0.0 | 0.6 | 0.1 | X | Potentially Pathogenic | The backbone amide group of Leu327, located in the middle of an anti-parallel β sheet strand (res. Ala322-Asp330), forms a hydrogen bond with the carbonyl group of Gly344 on a neighboring β strand (res. Lys336-Pro349) in the WT simulations. In contrast, in the variant simulations, the introduction of Pro327 destabilizes the hydrogen bonding between the two anti-parallel β strands because proline lacks the backbone amide group altogether. Additionally, in the WT simulations, the iso-butyl side chain of Leu327 packs against multiple hydrophobic residues (e.g., Leu274, V400, Val343), whereas the less bulky cyclic five-membered pyrrolidine ring of Pro327 cannot fill the same space as effectively. Thus, although no large-scale unfolding is observed during the variant simulations, the residue swap is likely to cause severe problems for the correct C2 domain folding, which could also affect the SynGAP-membrane association. | 10.1016/j.ajhg.2020.11.011 | ||||||||||
| 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 | Likely Pathogenic | 1 | -14.222 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.659 | Likely Pathogenic | 6.78 | Destabilizing | 0.3 | 11.59 | Destabilizing | 9.19 | Destabilizing | 2.29 | Destabilizing | -6.39 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.91 | Benign | 0.05 | Affected | 3.37 | 29 | -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.859G>T | D287Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D287Y missense variant is reported in ClinVar as Pathogenic (ClinVar ID 2263930.0) and is not found in gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Rosetta, Foldetta, and premPS, whereas pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. High‑accuracy assessments give a pathogenic verdict from AlphaMissense‑Optimized, a Likely Pathogenic consensus from SGM, and a benign outcome from Foldetta. Overall, the majority of evidence points to a deleterious effect. Therefore, the variant is most likely pathogenic, in agreement with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Likely Pathogenic | 1 | -12.877 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.663 | Likely Pathogenic | 0.21 | Likely Benign | 0.2 | 0.48 | Likely Benign | 0.35 | Likely Benign | 0.27 | Likely Benign | -8.27 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.51 | Pathogenic | 0.00 | Affected | 3.38 | 23 | -4 | -3 | 2.2 | 48.09 | 257.8 | -44.4 | -0.6 | 1.6 | 0.2 | 0.3 | X | X | Potentially Pathogenic | The carboxylate group of Asp287, located at the beginning of a β hairpin loop linking two anti-parallel β sheet strands (res. Arg279-Leu286, res. Met289-Pro298), maintains a salt bridge with the guanidinium group of Arg324 in the β sheet during the WT simulations. In the variant simulations, the phenol group of the Tyr287 side chain is unable to form a salt bridge with the guanidinium group of Arg324, which could weaken the tertiary structure assembly of the C2 domain. However, the phenol group of Tyr287 frequently stacks with the Arg324 guanidinium side chain, which could help maintain the tertiary structure, especially compared to the D287H variant. The destabilization of the C2 domain could adversely affect the stability of the SynGAP-membrane association. | ||||||||||
| c.930G>C | E310D 2D 3DClick to see structure in 3D Viewer AISynGAP1 E310D is reported in ClinVar (ID 975473.0) as Pathogenic and is not found in gnomAD. Prediction tools that assess the variant’s effect all converge on a deleterious outcome: REVEL, FoldX (uncertain), Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, leaving no tool in the benign category. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also reports Pathogenic. The single uncertain result from FoldX is treated as unavailable. Overall, the variant is most likely pathogenic, and this assessment is consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Likely Pathogenic | 1 | -11.218 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.666 | Likely Pathogenic | 1.87 | Ambiguous | 0.5 | 2.39 | Destabilizing | 2.13 | Destabilizing | 1.04 | Destabilizing | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.19 | Pathogenic | 0.02 | Affected | 3.38 | 19 | 3 | 2 | 0.0 | -14.03 | 232.6 | 27.2 | 0.1 | 0.0 | 0.1 | 0.1 | X | Potentially Benign | The carboxylate group of Glu310, located in an anti-parallel β sheet strand (res. Thr305-Asn315), is ideally positioned to interact with the hydroxyl and backbone amide groups of Thr295 on a twisted anti-parallel β strand. Because the carboxylate group can also interact with the GAP domain residues (e.g., Gln612, Tyr614), Glu310 potentially plays a key role in maintaining the tertiary assembly between the C2 and GAP domains. In the variant simulations, the carboxylate group of Asp310 can form the same interactions as glutamate; however, due to its one hydrocarbon shorter length, the connections are less stable or less optimal. | |||||||||||
| c.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 | Uncertain | 1 | -16.447 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.668 | Likely Pathogenic | 9.19 | Destabilizing | 0.1 | 13.20 | Destabilizing | 11.20 | Destabilizing | 1.69 | Destabilizing | -6.98 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.06 | Benign | 0.00 | Affected | 3.42 | 17 | -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.1835A>C | Q612P 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q612P is listed in ClinVar (ID 3660462.0) with an uncertain significance annotation and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, PolyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, PROVEAN, and the SGM Consensus score (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The high‑accuracy AlphaMissense‑Optimized predicts benign, whereas the SGM Consensus predicts likely pathogenic; Foldetta, a folding‑stability method combining FoldX‑MD and Rosetta outputs, returns an uncertain result and is therefore not factored into the consensus. Overall, the majority of evidence supports a pathogenic effect, which contrasts with the ClinVar uncertain classification. Thus, based on current predictions, the variant is most likely pathogenic, contradicting the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -9.684 | Likely Pathogenic | 0.673 | Likely Pathogenic | Likely Benign | 0.671 | Likely Pathogenic | -0.19 | Likely Benign | 0.3 | 3.06 | Destabilizing | 1.44 | Ambiguous | 0.56 | Ambiguous | -5.84 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.31 | Pathogenic | 0.19 | Tolerated | 0 | -1 | 1.9 | -31.01 | ||||||||||||||||||||||
| c.1736G>A | R579Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R579Q is listed in ClinVar with an uncertain significance (ClinVar ID 3964539.0) and is present in gnomAD (variant ID 6‑33440788‑G‑A). Prediction tools that classify the variant as benign include SIFT and AlphaMissense‑Optimized, whereas the majority of other in‑silico predictors (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict it to be pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized reports a benign effect, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an inconclusive result. FoldX and Rosetta individually report uncertain effects. Overall, the preponderance of evidence from both general and high‑accuracy tools indicates that R579Q is most likely pathogenic, which is consistent with its ClinVar status of uncertain significance rather than a benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | 6-33440788-G-A | 18 | 1.12e-5 | -9.193 | Likely Pathogenic | 0.690 | Likely Pathogenic | Likely Benign | 0.673 | Likely Pathogenic | 0.65 | Ambiguous | 0.1 | 0.70 | Ambiguous | 0.68 | Ambiguous | 1.13 | Destabilizing | -3.31 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.34 | Pathogenic | 0.06 | Tolerated | 3.37 | 34 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||
| 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 | Likely Pathogenic | 1 | -16.926 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.678 | Likely Pathogenic | 6.66 | Destabilizing | 0.2 | 10.84 | Destabilizing | 8.75 | Destabilizing | 2.13 | Destabilizing | -6.58 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.00 | Benign | 0.00 | Affected | 3.46 | 13 | -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.1408A>C | M470L 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant M470L is listed in ClinVar as benign (ClinVar ID 536996.0) and is present in gnomAD (variant ID 6‑33438440‑A‑C). Functional prediction tools cluster into two groups: benign predictions come from SIFT and AlphaMissense‑Optimized, while pathogenic predictions are made by REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No definitive folding‑stability change is reported by FoldX or Rosetta individually. Overall, the majority of predictive algorithms favor a pathogenic effect, directly contradicting the benign classification in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Benign | 1 | 6-33438440-A-C | 1 | 6.20e-7 | -8.993 | Likely Pathogenic | 0.406 | Ambiguous | Likely Benign | 0.678 | Likely Pathogenic | 0.73 | Ambiguous | 0.1 | 0.84 | Ambiguous | 0.79 | Ambiguous | 1.04 | Destabilizing | -2.72 | Deleterious | 0.484 | Possibly Damaging | 0.654 | Possibly Damaging | -1.22 | Pathogenic | 0.16 | Tolerated | 3.37 | 34 | 4 | 2 | 1.9 | -18.03 | 225.3 | 17.9 | 0.0 | 0.0 | -0.8 | 0.5 | X | Potentially Benign | The thioether group of Met470, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues in the inter-helix space (e.g., Val473, Leu558) formed by two other α helices (res. Ser604–Arg581, res. Pro562–Arg579). In the WT simulations, Met470 also packs against the positively charged guanidinium groups of Arg575, Arg429, and Arg579, which form salt bridges with the negatively charged carboxylate groups of the Asp474 and Asp467 side chains at the protein surface. In the variant simulations, the iso-butyl side chain of Leu470 packs similarly with the hydrophobic residues as methionine, resulting in no negative effects on the protein structure during the simulation. | ||||||||
| c.1741C>T | R581W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R581W is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only Rosetta, whereas the remaining pathogenic‑predicating tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—consistently classify the variant as deleterious. Uncertain or inconclusive results come from FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain”; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Pathogenic”; and Foldetta remains “Uncertain.” Overall, the preponderance of evidence points to a pathogenic impact, which contrasts with the ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 2 | -12.855 | Likely Pathogenic | 0.920 | Likely Pathogenic | Ambiguous | 0.678 | Likely Pathogenic | 1.32 | Ambiguous | 0.1 | -0.32 | Likely Benign | 0.50 | Ambiguous | 0.68 | Ambiguous | -6.79 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.37 | Pathogenic | 0.01 | Affected | 3.37 | 34 | 2 | -3 | 3.6 | 30.03 | 257.8 | 36.0 | 0.1 | 0.1 | 0.1 | 0.3 | X | X | Potentially Pathogenic | Arg581 is located on a short α-α loop between two α helices (res. Arg563-Glu578 and res. Glu582-Ser604). In the WT simulations, the guanidinium group of Arg581 forms salt bridges with the carboxylate groups of Asp583 within the same helix, as well as with Glu478 and/or Glu480 in a slightly α-helical loop (res. Glu478-Thr488) preceding another α helix (res. Ala461-Phe476).In the variant simulations, the neutral indole ring of the Trp581 side chain cannot form any of these salt bridges. Instead, it packs hydrophobically against Met477 and Ile587 without forming any direct hydrogen bonds. The tendency of the loop (res. Asp477-Thr488) to acquire an α-helical structure seems to marginally increase, potentially due to Trp581's inability to coordinate stable hydrogen bonds with the loop residues (e.g., Glu478-Arg581 salt bridge). Additionally, the residue swap could weaken the tertiary structure assembly and negatively affect the overall protein folding process. | ||||||||||
| c.791T>A | L264Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264Q is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign outcome. High‑accuracy methods 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. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Uncertain | 1 | -15.729 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.678 | Likely Pathogenic | 3.43 | Destabilizing | 0.1 | 2.41 | Destabilizing | 2.92 | Destabilizing | 2.48 | Destabilizing | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.49 | Pathogenic | 0.00 | Affected | 3.38 | 18 | -2 | -2 | -7.3 | 14.97 | 254.7 | -7.6 | 0.0 | 0.0 | 0.0 | 0.3 | X | X | X | Potentially Pathogenic | The iso-butyl branched hydrocarbon side chain of Leu264, located at the end of an anti-parallel β sheet strand (res. Arg259-Arg272), packs against multiple hydrophobic residues such as Leu266, Phe314, Leu317, and Leu323 in the WT simulations. In the variant simulations, the hydrophilic carboxamide group of the Gln264 side chain is not suitable for the hydrophobic niche, causing the hydrophobic residues to make room for the swapped residue. Additionally, the carboxamide group of Gln264 forms hydrogen bonds with the backbone amide groups of Arg405 and Lys256 in the β sheet and the carbonyl group of Val350 in an α helical section of a nearby loop (res. Pro359-Phe358). The residue swap disrupts the packing of the C2 domain, which could adversely affect the C2 domain structure during folding. This disruption could potentially weaken the stability of the SynGAP-membrane association. | |||||||||
| c.775C>T | R259W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R259W is listed in ClinVar with an uncertain significance (ClinVar ID 2014570.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining evaluated algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic impact. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. 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 stability calculations, remains inconclusive. Overall, the preponderance of evidence indicates that R259W is most likely pathogenic, a conclusion that does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Uncertain | 1 | -12.186 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.691 | Likely Pathogenic | 1.95 | Ambiguous | 0.8 | 0.51 | Ambiguous | 1.23 | Ambiguous | 0.51 | Ambiguous | -7.35 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | 3.39 | 15 | 2 | -3 | 3.6 | 30.03 | 254.0 | 40.0 | 0.2 | 0.2 | 0.2 | 0.4 | X | X | X | Potentially Pathogenic | The guanidinium group of Arg259, located at the beginning of an anti-parallel β sheet strand (res. Arg259-Arg272), forms salt bridges with the carboxylate groups of Asp684 at the end of an α helix (res. Ile683-Gln702, GAP domain) and Asp261 on the same β strand. The Arg259 side chain also frequently forms hydrogen bonds with the backbone carbonyl groups of Ser257, Asn256, and Asp255. In the variant simulations, the indole ring of the Trp259 side chain cannot form salt bridges or maintain hydrogen bonding with the carboxylate group of Asp684 or other nearby residues. Notably, the amino group of the Lys254 side chain maintains a salt bridge with Asp684 and Glu244 throughout the variant simulations, while it forms a cation-π bond with the indole ring of Trp259 in the variant. This salt bridge is not maintained in the WT simulations. Additionally, the partially or loosely α helical conformation of a lysine-containing loop (res. Lys251-Ser257), which extends to a nearby α helix (res. Met414-Asn426), could be stabilized due to the residue swap. Moreover, the bulky size of the Trp259 side chain requires nearby residues to adjust their positioning to accommodate the introduced residue, weakening the tertiary structure assembly between the C2, PH, and GAP domains. The residue swap potentially causes more severe effects during protein folding or for the SynGAP-membrane interaction than the solvent-only simulations imply. | |||||||||
| c.968T>G | L323R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L323R is listed in ClinVar (ID 978601.0) as Pathogenic and is not reported in gnomAD. All available in‑silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Consequently, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Likely Pathogenic | 1 | -14.568 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.692 | Likely Pathogenic | 3.75 | Destabilizing | 0.4 | 4.47 | Destabilizing | 4.11 | Destabilizing | 2.15 | Destabilizing | -4.70 | Deleterious | 0.999 | Probably Damaging | 0.969 | Probably Damaging | 0.59 | Pathogenic | 0.01 | Affected | 3.39 | 22 | -3 | -2 | -8.3 | 43.03 | 261.8 | -61.6 | -0.4 | 0.2 | 0.8 | 0.2 | X | X | X | Potentially Pathogenic | The iso-butyl side chain of Leu323, located at the beginning of an anti-parallel β sheet strand (res. Ala322-Asp330), packs against multiple hydrophobic leucine residues (e.g., Leu264, Leu266, Leu284, Leu286). In contrast, in the variant simulations, the positively charged guanidinium group of the Arg323 side chain is unsuitable for the hydrophobic niche. Consequently, the side chain either rotates away from the center of the C2 domain or, if it remains within the C2 domain core, it reorients nearby residues to form hydrogen bonds. Regardless, the residue swap extensively disrupts the C2 domain structure. | |||||||||
| c.1898T>C | L633P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L633P (ClinVar ID 858973.0) is listed as Pathogenic and is not reported 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 scores it as Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta, which integrates 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 | Pathogenic/Likely path. | 2 | -15.669 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.693 | Likely Pathogenic | 6.60 | Destabilizing | 0.2 | 10.15 | Destabilizing | 8.38 | Destabilizing | 2.42 | Destabilizing | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.70 | Benign | 0.00 | Affected | 3.37 | 34 | -3 | -3 | -5.4 | -16.04 | 193.2 | 65.1 | 0.0 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | The iso-butyl side chain of Leu633, located in the middle of an α helix (res. Glu617-Asn635), packs hydrophobically with nearby residues (e.g., Leu653, Val629, Leu551) in the WT simulations.In the variant simulations, the pyrrolidine side chain of Pro633 is not as optimal for hydrophobic packing as Leu633 in the WT. Additionally, proline lacks a free backbone amide group, so Pro633 cannot form a hydrogen bond with the backbone carbonyl group of Val629, which disrupts the continuity of the secondary structure element. | |||||||||||
| c.742C>T | R248W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R248W is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from Rosetta, Foldetta, and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results from FoldX and premPS are treated as unavailable. 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 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 | PH | Uncertain | 1 | -11.647 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.699 | Likely Pathogenic | 1.17 | Ambiguous | 0.3 | -0.20 | Likely Benign | 0.49 | Likely Benign | 0.89 | Ambiguous | -6.98 | Deleterious | 1.000 | Probably Damaging | 0.948 | Probably Damaging | 5.62 | Benign | 0.00 | Affected | 3.41 | 14 | 2 | -3 | 3.6 | 30.03 | 266.4 | 42.3 | 0.0 | 0.0 | 0.3 | 0.1 | X | Potentially Pathogenic | The guanidinium group of Arg248, located on an α helix (res. Ala236-Val250), forms two very stable salt bridges with Asp255 (from a short α helical section, res. Lys254-Asn256) and Glu244 (from a nearby loop) in the WT simulations. In the variant simulations, the indole group of Trp248 cannot form any salt bridges, which could negatively affect the tertiary structure assembly of the PH domain. Instead, in the variant simulations, the indole ring of Trp248 stacks against Pro252, which makes a turn after the α helix. | |||||||||||
| c.718G>A | D240N 2D  AIThe SynGAP1 missense variant D240N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Benign predictions are provided by FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. High‑accuracy methods give a split: AlphaMissense‑Optimized predicts benign, SGM‑Consensus predicts pathogenic, and Foldetta predicts benign. Overall, the majority of tools favor a benign effect, and this consensus does not contradict the ClinVar uncertain status. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | Uncertain | 1 | -12.942 | Likely Pathogenic | 0.755 | Likely Pathogenic | Likely Benign | 0.701 | Likely Pathogenic | 0.22 | Likely Benign | 0.9 | 0.47 | Likely Benign | 0.35 | Likely Benign | 0.37 | Likely Benign | -4.37 | Deleterious | 0.993 | Probably Damaging | 0.984 | Probably Damaging | 5.88 | Benign | 0.01 | Affected | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||
| c.1084T>C | W362R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W362R (ClinVar ID 41461.0) is listed as Pathogenic and is not reported in gnomAD. All available in silico predictors classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments concur: 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. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Pathogenic | 2 | -14.004 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.706 | Likely Pathogenic | 2.64 | Destabilizing | 0.3 | 3.90 | Destabilizing | 3.27 | Destabilizing | 1.10 | Destabilizing | -12.87 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.28 | Pathogenic | 0.00 | Affected | 3.39 | 24 | 2 | -3 | -3.6 | -30.03 | 287.5 | -34.1 | -0.2 | 0.1 | -0.6 | 0.2 | X | X | X | Potentially Pathogenic | The indole ring of Trp362, located on the surface of an anti-parallel β sheet (res. Thr359-Pro364) in the C2 domain, stacks with nearby residues (e.g., Arg401, Arg272). In the variant simulations, the guanidinium group of the introduced residue Arg362 forms a salt bridge with the carboxylate group of Glu273 and, like Trp362, stacks with other arginine residues (e.g., Arg401, Arg272). This residue is at both the C2-membrane interface and the C2-RasGTPase interface, so the residue swap could potentially affect both interactions. However, these phenomena cannot be addressed using solvent-only simulations. Notably, Arg272, which stacks with both the non-mutated Trp362 and the mutated Arg362, forms a salt bridge directly with Asp105 of Ras in the WT simulations. Therefore, the residue swap could affect the C2 domain stability, the SynGAP-membrane association, and the SynGAP-Ras association. | 10.1016/j.ajhg.2020.11.011 | ||||||||
| c.812C>A | A271D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271D is listed in ClinVar as Pathogenic (ClinVar ID 2019732.0) and is not reported in gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Based on the unanimous computational evidence, 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 | C2 | Pathogenic | 1 | -18.590 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.706 | Likely Pathogenic | 4.71 | Destabilizing | 0.4 | 2.67 | Destabilizing | 3.69 | Destabilizing | 1.59 | Destabilizing | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.62 | Pathogenic | 0.00 | Affected | 3.38 | 19 | 0 | -2 | -5.3 | 44.01 | 226.2 | -63.4 | 0.0 | 0.0 | 0.9 | 0.1 | X | X | X | X | Potentially Pathogenic | The methyl group of Ala271, located near the end of an anti-parallel β sheet strand (res. Arg259-Arg272), packs against multiple hydrophobic residues such as Val400, Val306, and Leu274 in the WT simulations. In the variant simulations, the carboxylate group of Asp271 is not suitable for the hydrophobic niche, causing the hydrophobic residues to make room for the swapped residue. Additionally, the carboxylate group of the Asp271 side chain forms hydrogen bonds with the backbone amide groups of Arg272 and Ala399 in the β sheet, or even forms a salt bridge with the amino group of the Lys394 side chain. This directly affects the integrity of the anti-parallel β sheet at the end. In short, the residue swap disrupts the C2 domain packing during folding, which could weaken the stability of the SynGAP-membrane association. | ||||||||
| c.1724G>A | R575H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R575H (ClinVar ID 1029088.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33440776‑G‑A). Prediction tools that indicate a benign effect include Rosetta, Foldetta, PROVEAN, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, Foldetta as Benign, and the SGM Consensus as Pathogenic. Overall, the majority of evidence points to a pathogenic impact, which contrasts with the ClinVar designation of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | Conflicting | 4 | 6-33440776-G-A | 204 | 1.27e-4 | -11.142 | Likely Pathogenic | 0.496 | Ambiguous | Likely Benign | 0.707 | Likely Pathogenic | 0.81 | Ambiguous | 0.2 | -0.22 | Likely Benign | 0.30 | Likely Benign | 1.31 | Destabilizing | -2.34 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.33 | Pathogenic | 0.05 | Affected | 3.37 | 35 | 2 | 0 | 1.3 | -19.05 | 244.7 | 80.6 | 0.0 | 0.0 | 0.3 | 0.0 | X | Potentially Pathogenic | The guanidinium group of Arg575, located in an α-helix (res. Arg563-Glu578), forms salt bridges with the carboxylate groups of Asp463 and Asp467, and it also hydrogen bonds with the hydroxyl group of Ser466 on an opposing α-helix (res. Ala461-Phe476) in the WT simulations. In the variant simulations, the imidazole ring of His575 (in its neutral epsilon protonated form) cannot form the same salt bridges as the guanidinium group of the non-mutated Arg575. Instead, His575 only forms weak hydrogen bonds with the hydroxyl groups of Ser466 and Ser571. Overall, the residue swap has the potential to substantially affect the tertiary structure assembly during the protein folding process. | |||||||||
| c.767A>G | N256S 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256S is listed in ClinVar as Pathogenic (ClinVar ID 2584352.0) and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic calls come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy subset gives 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 Benign. Overall, the majority of predictions support a pathogenic effect, aligning with the ClinVar classification. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Likely Pathogenic | 1 | -10.640 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.707 | Likely Pathogenic | 0.31 | Likely Benign | 0.2 | 0.36 | Likely Benign | 0.34 | Likely Benign | 0.48 | Likely Benign | -4.33 | Deleterious | 0.997 | Probably Damaging | 0.970 | Probably Damaging | 5.87 | Benign | 0.02 | Affected | 3.39 | 15 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||
| c.1723C>T | R575C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R575C is listed in ClinVar with an “Uncertain” status (ClinVar ID 537013.0) and is present in gnomAD (ID 6‑33440775‑C‑T). Prediction tools that indicate a benign effect include only AlphaMissense‑Optimized. All other evaluated algorithms predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of predictions support a pathogenic effect. Thus, the variant is most likely pathogenic, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Conflicting | 3 | 6-33440775-C-T | 23 | 1.43e-5 | -11.179 | Likely Pathogenic | 0.630 | Likely Pathogenic | Likely Benign | 0.715 | Likely Pathogenic | 1.39 | Ambiguous | 0.2 | 0.50 | Ambiguous | 0.95 | Ambiguous | 0.73 | Ambiguous | -5.43 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.30 | Pathogenic | 0.02 | Affected | 3.37 | 35 | -4 | -3 | 7.0 | -53.05 | 227.7 | 99.2 | 0.0 | 0.0 | 0.0 | 0.1 | X | Potentially Pathogenic | The guanidinium group of Arg575, located in an α-helix (res. Arg563-Glu578), forms salt bridges with the carboxylate groups of Asp463 and Asp467, and it also hydrogen bonds with the hydroxyl group of Ser466 on an opposing α-helix (res. Ala461-Phe476) in the WT simulations. In the variant simulations, the thiol group of the Cys575 side chain, which is neither positively charged nor particularly hydrophilic, packs against the hydrophobic Met470 on an opposing α-helix (res. Ala461-Arg475). Additionally, although the thiol group is not an effective hydrogen bonder, the Cys575 side chain rotates to hydrogen bond with the backbone carbonyl group of Ser571 in the same α-helix, which could theoretically lower the helix integrity. Overall, the residue swap has the potential to substantially affect the tertiary structure assembly during the protein folding process. | ||||||||
| c.1819C>G | L607V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L607V is listed in ClinVar with an uncertain significance (ClinVar ID 1450275.0) and is present in gnomAD (ID 6‑33440871‑C‑G). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized reports benign, whereas the SGM‑Consensus, derived from the majority of pathogenic predictions, indicates pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive and therefore not considered evidence. Overall, the preponderance of computational evidence points to a pathogenic effect for L607V, a conclusion that contrasts with the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 2 | 6-33440871-C-G | 2 | 1.24e-6 | -11.190 | Likely Pathogenic | 0.637 | Likely Pathogenic | Likely Benign | 0.715 | Likely Pathogenic | 1.04 | Ambiguous | 0.2 | 1.36 | Ambiguous | 1.20 | Ambiguous | 0.90 | Ambiguous | -2.99 | Deleterious | 0.985 | Probably Damaging | 0.992 | Probably Damaging | -1.50 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 2 | 1 | 0.4 | -14.03 | 216.3 | 28.1 | 0.1 | 0.0 | 0.9 | 0.2 | X | Potentially Benign | Leu607 is located in a short helical region (res. Ser606-Phe608) within an α-α loop connecting two α helices (res. Glu582-Met603 and res. Glu617-Asn635). In the WT simulations, the iso-butyl side chain of Leu607 does not interact with any other residues, but it could potentially interact directly with Ras due to its location at the GAP domain.In the variant simulations, Val607, which has similar size and physicochemical properties to leucine, does not cause any negative effects on the protein structure. However, due to its location at the GAP-Ras interface, the residue swap could affect the complex formation with the GTPase, but this cannot be investigated using solvent-only simulations. | ||||||||
| c.1787G>A | R596H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R596H is listed in ClinVar as benign (ClinVar ID 1989474.0) and is present in gnomAD (ID 6‑33440839‑G‑A). Functional prediction tools largely agree on a deleterious effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus all report pathogenicity, while only Rosetta predicts a benign outcome. Two tools are inconclusive: AlphaMissense‑Optimized and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from the four pathogenic votes) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact, directly contradicting the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Benign | 1 | 6-33440839-G-A | 15 | 9.29e-6 | -11.128 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.717 | Likely Pathogenic | 3.00 | Destabilizing | 0.9 | 0.43 | Likely Benign | 1.72 | Ambiguous | 1.35 | Destabilizing | -4.97 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 2 | 0 | 1.3 | -19.05 | 223.5 | 80.5 | -0.1 | 0.0 | -0.1 | 0.3 | X | X | Potentially Pathogenic | The guanidinium group of Arg596, located in an α helix (res. Glu582-Met603), forms a salt bridge with the carboxylate group of Glu495 from another α helix (res. Leu489-Glu519). In the WT simulations, the side chain of Arg596 hydrogen bonds with the backbone carbonyl groups of Asn487, Glu486, Arg485, and Phe484. Additionally, Arg596 can hydrogen bond with the carboxamide group of the Asn487 side chain on an opposing loop that links two α helices (res. Ala461-Arg475, res. Leu489-Glu519).In the variant simulations, the imidazole ring of His596 can form hydrogen bonds with the same residues as arginine; however, these interactions are not as coordinated or strong in comparison. Thus, the residue swap could affect the tertiary structure assembly more profoundly than observed in the simulations. Notably, Arg596 plays a key role in positioning the aforementioned loop, which is crucial for the placement of the “arginine finger” or the Arg485 side chain during RasGTPase activation. | |||||||
| c.1813C>T | P605S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All evaluated in‑silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce 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. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, which contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -10.830 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.718 | Likely Pathogenic | 3.40 | Destabilizing | 0.1 | 3.34 | Destabilizing | 3.37 | Destabilizing | 1.00 | Destabilizing | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.70 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 1 | -1 | 0.8 | -10.04 | 213.8 | -15.4 | -0.3 | 0.2 | 0.2 | 0.1 | X | X | Potentially Pathogenic | Pro605 is located in a short turn between an α helix (res. Glu582-Met603) and a short α helical section (res. Ser606-Phe608). The pyrrolidine side chain of Pro605 packs hydrophobically with nearby hydrophobic residues (e.g., Ile514, Leu623, Leu610) in the inter-helix space. Additionally, proline lacks a free backbone amide group, which breaks the α helix and facilitates the turn in the WT structure.In the variant simulations, the hydroxyl side chain of Ser605 forms hydrogen bonds with the backbone carbonyl groups of Ala601 and Ile602. Importantly, the helix end is more stable than with Pro605 in the WT. Indeed, proline is a more effective secondary structure breaker compared to serine.Thus, 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, due to its location at the GAP-Ras interface, the residue swap could affect the GAP-Ras association. | ||||||||||
| c.1513T>G | Y505D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505D is listed in ClinVar as Pathogenic (ClinVar ID 3172759.0) and is not reported in gnomAD. Prediction tools that indicate a benign effect are limited to FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized scores the variant as Pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as Pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -14.078 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.718 | Likely Pathogenic | 4.98 | Destabilizing | 0.1 | 4.72 | Destabilizing | 4.85 | Destabilizing | 2.49 | Destabilizing | -9.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.60 | Benign | 0.00 | Affected | 3.37 | 35 | -3 | -4 | -2.2 | -48.09 | ||||||||||||||||||||
| c.1465C>T | L489F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489F is listed in ClinVar with an uncertain significance (ClinVar ID 522018.0) and is present in the gnomAD database (gnomAD ID 6‑33438497‑C‑T). In silico prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic outcome, while no tool predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No prediction or folding‑stability result is missing or ambiguous. **Thus, the variant is most likely pathogenic based on the collective predictions, and this does not contradict the ClinVar uncertain status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 2 | 6-33438497-C-T | 1 | 6.20e-7 | -12.066 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.724 | Likely Pathogenic | 1.72 | Ambiguous | 0.5 | 1.14 | Ambiguous | 1.43 | Ambiguous | 0.56 | Ambiguous | -3.76 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.51 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 2 | 0 | -1.0 | 34.02 | 246.4 | -17.8 | 0.0 | 0.0 | 0.6 | 0.1 | X | Potentially Benign | The iso-butyl side chain of Leu489, located in the α-helix (res. Leu489-Glu519) within an inter-helix space of four helices (res. Ala461-Phe476, res. Val441-Ser457, and res. Met414-Glu436), packs with hydrophobic residues (e.g., Cys432, Ala448, Lys444, Ala493, Val447, Met468) in the inter-helix space. In the variant simulations, the phenyl ring of the Phe489 side chain can also pack favorably in the hydrophobic region. However, due to the size difference, the aromatic side chain of Phe489 tends to reposition to escape the tight region to accommodate the larger side chain, stacking with Lys444. 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.1423C>T | R475W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R475W is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33438455‑C‑T). Prediction tools that agree on a benign effect include only Foldetta, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) uniformly predict a pathogenic impact; FoldX, Rosetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar “Uncertain” classification but suggests that the variant is more likely pathogenic rather than benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | 6-33438455-C-T | 1 | 6.20e-7 | -13.235 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.725 | Likely Pathogenic | 1.44 | Ambiguous | 0.4 | -0.92 | Ambiguous | 0.26 | Likely Benign | 0.56 | Ambiguous | -7.56 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.45 | Pathogenic | 0.00 | Affected | 3.39 | 28 | 2 | -3 | 3.6 | 30.03 | 266.9 | 39.6 | 0.0 | 0.0 | 0.0 | 0.1 | X | X | X | Potentially Pathogenic | In the WT simulations, the guanidinium group of Arg475, located near the end of an α-helix (res. Ala461-Phe476), stacks with the phenyl ring of Phe476 and forms a salt bridge with Glu472. Additionally, Arg475 occasionally forms another salt bridge with the carboxylate group of Glu486 on the α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. Therefore, Arg475 potentially plays a key role in positioning the loop by interacting with Glu486, which is necessary for the positioning of the “arginine finger” (Arg485) and, ultimately, for RasGTPase activation.In the variant simulations, Trp475 moves and stacks with Arg479 on the proceeding α-α loop, disrupting the terminal end of the α-helix. Lastly, the potential effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||
| c.1544G>A | R515H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R515H is listed in ClinVar with an uncertain significance (ClinVar ID 638438.0) and is present in gnomAD (variant ID 6‑33438787‑G‑A). Prediction tools that agree on a benign effect include AlphaMissense‑Default and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus remains pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Overall, the balance of evidence favors a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | 6-33438787-G-A | 3 | 1.86e-6 | -10.774 | Likely Pathogenic | 0.337 | Likely Benign | Likely Benign | 0.730 | Likely Pathogenic | 1.07 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.91 | Ambiguous | 1.09 | Destabilizing | -3.44 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 2 | 0 | 1.3 | -19.05 | 239.2 | 77.8 | 0.0 | 0.0 | 0.4 | 0.2 | X | Potentially Benign | The guanidinium group of Arg515, located in the middle of an α-helix at the GAP domain (res. Gly502-Tyr518), forms salt bridges with the carboxylate groups of Glu512 on the same helix and Glu217 on a loop in the PH domain. Additionally, the positively charged Arg515 side chain forms hydrogen bonds with Leu610 and Gln612 in an opposing loop (res. Gly609-Asp616). In contrast, in the variant simulations, the imidazole ring of His515 cannot form salt bridges with either of the acidic residues, and its side chain is too short to form hydrogen bonds with the loop residues. Accordingly, the residue swap could weaken the tertiary structure assembly of the protein. Due to the missing N-terminal part of the SynGAP model, the effect could be largely underestimated or missing. Notably, the doubly protonated and positively charged form of histidine was not simulated here. | ||||||||
| c.1718G>A | R573Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R573Q is reported in ClinVar as Pathogenic (ClinVar ID 1176819.0) and is not present in gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default, while only SIFT predicts a benign outcome. Two tools give inconclusive results: Rosetta (Uncertain) and AlphaMissense‑Optimized (Uncertain). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized remains uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -9.900 | Likely Pathogenic | 0.923 | Likely Pathogenic | Ambiguous | 0.733 | Likely Pathogenic | 2.28 | Destabilizing | 0.8 | 1.94 | Ambiguous | 2.11 | Destabilizing | 1.08 | Destabilizing | -3.16 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.31 | Pathogenic | 0.12 | Tolerated | 3.37 | 35 | 1 | 1 | 1.0 | -28.06 | 230.1 | 49.9 | 0.0 | 0.0 | -0.6 | 0.0 | X | X | Potentially Pathogenic | The guanidinium group of Arg573, located in an α-helix (res. Arg563-Glu578), forms a salt bridge with the carboxylate groups of Glu582 and/or Asp586 from a nearby α-helix (res. Glu582-Met603) in the WT simulations. Additionally, the Arg573 side chain stacks planarly with the aromatic phenol ring of Tyr665 and hydrogen bonds with the hydroxyl group of Ser668 from another α-helix (res. Ser641-Ser668). In the variant simulations, although the carboxamide group of the Gln573 side chain can hydrogen bond with the carboxylate group of Glu582 or the hydroxyl group of Ser668, these interactions are not as coordinated, stable, or strong as those of the positively charged Arg573. Consequently, the integrity of the opposing α-helix end (res. Glu582-Met603) is weakened. Overall, the residue swap has the potential to substantially affect the tertiary structure assembly during the protein folding process. | ||||||||||
| c.1784T>A | L595Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L595Q 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, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized—predict a pathogenic effect, and the SGM‑Consensus score indicates a likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized returns a pathogenic prediction, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a likely pathogenic result, while Foldetta’s stability analysis is inconclusive. Overall, the majority of computational evidence points to a pathogenic effect, which does not contradict the ClinVar designation of uncertain significance but suggests a higher likelihood of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -15.101 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.733 | Likely Pathogenic | 0.79 | Ambiguous | 0.1 | 1.40 | Ambiguous | 1.10 | Ambiguous | 1.99 | Destabilizing | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.75 | Benign | 0.00 | Affected | 3.37 | 35 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||
| c.1517T>C | L506P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L506P is listed in ClinVar (ID 975474.0) as Pathogenic and is not reported in gnomAD. All available in‑silico predictors classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, which aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -12.088 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.737 | Likely Pathogenic | 5.48 | Destabilizing | 0.7 | 10.19 | Destabilizing | 7.84 | Destabilizing | 2.50 | Destabilizing | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.55 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -3 | -3 | -5.4 | -16.04 | 182.6 | 64.9 | 0.1 | 0.0 | 0.2 | 0.1 | X | Potentially Pathogenic | Leu506 is located in the middle of an α-helix (res. Gly502-Tyr518) within the inter-helix space of two helices (res. Gly502-Tyr518 and res. Glu582-Met603). In the WT simulations, the iso-butyl side chain of Leu506 hydrophobically packs with residues in the inter-helix space (e.g., Ile510, Phe597, Leu598, Ala601). In the variant simulations, the cyclic five-membered pyrrolidine ring of Pro506 is not as optimal as Leu506 for hydrophobic packing with nearby residues. Additionally, Pro506 cannot maintain the hydrogen bond with the backbone oxygen of Gly502 as Leu506 does in the WT, which disrupts the secondary structure element. | |||||||||||
| c.924G>C | W308C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308C is listed in ClinVar as Pathogenic (ClinVar ID 981381.0) and is not reported in gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Pathogenic”; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Pathogenic/Likely path. | 2 | -12.791 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.738 | Likely Pathogenic | 5.56 | Destabilizing | 0.3 | 4.38 | Destabilizing | 4.97 | Destabilizing | 1.26 | Destabilizing | -11.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.48 | Pathogenic | 0.00 | Affected | 3.38 | 19 | -8 | -2 | 3.4 | -83.07 | 230.8 | 60.5 | -0.3 | 0.1 | -0.4 | 0.4 | X | Potentially Pathogenic | The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The introduced Cys308 is smaller than the tryptophan it replaced. The thiol group of the Cys308 side chain is well-suited for the inner hydrophobic part of the C2 domain. Although the negative effects are essentially missing from the simulations, the side chain size difference between the residues is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association. | |||||||||||
| c.1406C>A | A469D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A469D is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that assess the variant’s effect fall into two groups: the single benign prediction from SIFT, and a consensus of pathogenic predictions from the remaining 15 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus). High‑accuracy methods further support a deleterious impact: 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) also indicates pathogenic. Taken together, the overwhelming majority of evidence points to a pathogenic 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 Pathogenic | GAP | Uncertain | 1 | -14.643 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.738 | Likely Pathogenic | 5.09 | Destabilizing | 0.2 | 4.16 | Destabilizing | 4.63 | Destabilizing | 1.68 | Destabilizing | -3.48 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.34 | Pathogenic | 0.21 | Tolerated | 3.37 | 34 | 0 | -2 | -5.3 | 44.01 | 237.0 | -58.2 | -0.2 | 0.1 | 0.8 | 0.1 | X | X | Potentially Pathogenic | The methyl group of Ala469, located in an α helix (res. Ala461–Phe476), interacts with hydrophobic residues (e.g., Trp572, Leu588, Met470) in an inter-helix space formed by two other α helices (res. Glu582–Ser604, res. Arg563–Gly580). In the variant simulations, Asp469 introduces a negatively charged and bulky side chain into the hydrophobic niche. Consequently, the side chain of Asp469 rotates outward, allowing the carboxylate group to form a salt bridge with the guanidinium group of Arg575 on the protein surface. This interaction affects the continuity of the parent α helix (Ala461–Phe476). Due to the importance of hydrophobic packing, the structural effects could be more pronounced during actual protein folding. | ||||||||||
| 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 | Uncertain | 1 | 6-33438495-C-T | 2 | 1.24e-6 | -12.459 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.746 | Likely Pathogenic | 0.66 | Ambiguous | 0.3 | 1.62 | Ambiguous | 1.14 | Ambiguous | 0.46 | Likely Benign | -5.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.21 | Benign | 0.00 | Affected | 3.37 | 35 | -1 | -1 | 2.6 | 30.09 | |||||||||||||||||
| c.1784T>C | L595P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L595P is listed in ClinVar with an “Uncertain” status (ClinVar ID 3172762.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic outcome. 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 (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, 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 | Uncertain | 1 | -11.856 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.747 | Likely Pathogenic | 2.09 | Destabilizing | 0.8 | 5.88 | Destabilizing | 3.99 | Destabilizing | 1.78 | Destabilizing | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.72 | Benign | 0.00 | Affected | 3.37 | 35 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||
| c.1352T>C | L451P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L451P is reported in ClinVar as Pathogenic (ClinVar ID 3064222.0) and is not found in gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on these predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -14.549 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.750 | Likely Pathogenic | 6.92 | Destabilizing | 0.2 | 8.57 | Destabilizing | 7.75 | Destabilizing | 2.58 | Destabilizing | -6.81 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 3.37 | 34 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||
| c.1625A>G | N542S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N542S is listed in ClinVar as benign (ClinVar ID 833567.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include SIFT and AlphaMissense‑Optimized, whereas the majority of tools predict pathogenicity: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, SGM‑Consensus predicting likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect, which is in conflict with the ClinVar benign designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Benign | 1 | -9.675 | Likely Pathogenic | 0.767 | Likely Pathogenic | Likely Benign | 0.752 | Likely Pathogenic | 0.98 | Ambiguous | 0.1 | 0.99 | Ambiguous | 0.99 | Ambiguous | 0.91 | Ambiguous | -4.40 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | -1.36 | Pathogenic | 0.13 | Tolerated | 3.37 | 35 | 1 | 1 | 2.7 | -27.03 | 212.5 | 32.1 | 0.0 | 0.0 | -0.6 | 0.3 | X | Potentially Pathogenic | Asn542 is located in an α-helix (res. Ala533-Val560) next to an α-α loop between two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the carboxamide group of the Asn542 side chain forms a hydrogen bond with the backbone carbonyl group of Asn523 and packs favourably against Glu522 from the loop. In contrast, in the variant simulations, the hydroxyl group of the Ser542 side chain is unable to maintain either the hydrogen bond with Asn523 or the packing against the Glu522 side chain. Instead, the hydroxyl group of Ser542 occasionally forms a hydrogen bond with the backbone carbonyl group of Glu538.Altogether, the residue swap results in a looser helix-loop association, which is especially evident in the third replica simulation, where Asn523 moves away from its initial placement next to the α-helix. In short, based on the simulations, the residue swap weakens the GAP domain tertiary structure assembly, which in turn could negatively affect protein folding. | |||||||||||
| c.1787G>T | R596L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 R596L missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect are Foldetta and premPS, whereas the remaining pathogenic‑predicting tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all indicate a deleterious impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (derived from the same four high‑confidence predictors) also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the preponderance of evidence points to a pathogenic effect for R596L, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -13.197 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.756 | Likely Pathogenic | 1.51 | Ambiguous | 0.3 | -0.58 | Ambiguous | 0.47 | Likely Benign | -0.02 | Likely Benign | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.45 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -3 | -2 | 8.3 | -43.03 | 234.2 | 63.4 | -0.1 | 0.0 | -0.5 | 0.6 | X | X | Potentially Pathogenic | The guanidinium group of Arg596, located in an α helix (res. Glu582-Met603), forms a salt bridge with the carboxylate group of Glu495 from another α helix (res. Leu489-Glu519). In the WT simulations, the side chain of Arg596 hydrogen bonds with the backbone carbonyl groups of Asn487, Glu486, Arg485, and Phe484. Additionally, Arg596 can hydrogen bond with the carboxamide group of the Asn487 side chain on an opposing loop that links two α helices (res. Ala461-Arg475, res. Leu489-Glu519).However, in the variant simulations, the branched hydrocarbon side chain of Leu596 cannot form any of the hydrogen bonds or salt bridges maintained by the considerably bulkier and positively charged Arg596 side chain. Instead, Leu596 packs hydrophobically with the phenyl ring of Phe484 in the linker loop or residues from the opposing helix (e.g., Ile494, Thr491).Thus, the residue swap could affect the tertiary structure assembly more profoundly than observed in the simulations. Notably, Arg596 plays a key role in positioning the aforementioned loop, which is crucial for the placement of the “arginine finger” or the Arg485 side chain during RasGTPase activation. | 10.1016/j.ajhg.2020.11.011 | |||||||||
| c.762G>C | K254N 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant K254N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The majority of other in silico predictors—REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—indicate a pathogenic effect. Stability‑based methods FoldX, Rosetta, and Foldetta returned uncertain results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as unavailable. Overall, the preponderance of evidence supports a pathogenic classification, which contradicts the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | Uncertain | 1 | -13.306 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.757 | Likely Pathogenic | 0.73 | Ambiguous | 0.2 | 1.87 | Ambiguous | 1.30 | Ambiguous | 1.19 | Destabilizing | -4.23 | Deleterious | 0.384 | Benign | 0.070 | Benign | 5.93 | Benign | 0.01 | Affected | 3.39 | 15 | 1 | 0 | 0.4 | -14.07 | 215.3 | -21.0 | -1.0 | 1.7 | 0.2 | 0.3 | X | Potentially Pathogenic | The amino group of Lys254, located in an α-β loop connecting the PH and C2 domains (res. Lys251-Arg258), forms salt bridges with the carboxylate groups of Glu244 and Asp684. Since the neutral carboxamide group of the Asn254 side chain cannot form salt bridges with acidic residues, the residue swap potentially weakens the tertiary structure assembly and/or influences the loop positioning. Regardless, in both the variant and WT simulations, all hydrogen bonds formed by the residue’s side chain were broken, and the residue rotated outwards. The partially α helical conformation of the loop, which extends to a nearby α helix (res. Met414-Asn426), is dynamic, making it unclear if the mutation affects it. | |||||||||||
| c.1717C>T | R573W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R573W is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a pathogenic effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta yields an uncertain stability change. Overall, the majority of evidence points to 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 | Conflicting | 8 | -14.078 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.758 | Likely Pathogenic | 2.37 | Destabilizing | 0.7 | 0.57 | Ambiguous | 1.47 | Ambiguous | 0.88 | Ambiguous | -6.94 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.48 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 2 | -3 | 3.6 | 30.03 | 257.6 | 39.0 | 0.1 | 0.0 | 0.2 | 0.0 | X | X | Potentially Pathogenic | The guanidinium group of Arg573, located in an α-helix (res. Arg563-Glu578), forms a salt bridge with the carboxylate groups of Glu582 and/or Asp586 from a nearby α-helix (res. Glu582-Met603) in the WT simulations. Additionally, the Arg573 side chain stacks planarly with the aromatic phenol ring of Tyr665 and hydrogen bonds with the hydroxyl group of Ser668 from another α-helix (res. Ser641-Ser668). In the variant simulations, the indole ring of the Trp573 side chain is unable to maintain the same level of coordination as the positively charged Arg573 side chain. Indeed, Trp573 is seen hydrogen bonding only briefly with the carboxylate group of Glu582. Consequently, the integrity of the opposing α-helix end (res. Glu582-Met603) is weakened. Overall, the residue swap has the potential to substantially affect the tertiary structure assembly during the protein folding process. | ||||||||||
| c.1667A>T | N556I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N556I is catalogued in ClinVar as benign (ClinVar ID 2692844.0) and is observed in gnomAD (ID 6‑33438910‑A‑T). Functional prediction tools cluster into two groups: benign predictions come from Rosetta, Foldetta, and premPS, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. Two tools report uncertainty: FoldX and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta outputs) as benign. Taken together, the majority of predictions favor a pathogenic effect, whereas the ClinVar annotation indicates benign. Thus, the computational evidence contradicts the ClinVar status, suggesting the variant is more likely pathogenic rather than benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Benign | 1 | 6-33438910-A-T | -13.391 | Likely Pathogenic | 0.929 | Likely Pathogenic | Ambiguous | 0.761 | Likely Pathogenic | 0.64 | Ambiguous | 0.0 | 0.17 | Likely Benign | 0.41 | Likely Benign | 0.26 | Likely Benign | -7.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.35 | Pathogenic | 0.02 | Affected | 3.37 | 35 | -3 | -2 | 8.0 | -0.94 | |||||||||||||||||||
| c.1658A>C | K553T 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant K553T is listed in ClinVar with an uncertain significance (ClinVar ID 2007142.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include Rosetta and SIFT, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, both polyPhen‑2 HumDiv and HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Uncertain results are reported by FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the consensus of the available predictions indicates that K553T is most likely pathogenic, which does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -15.328 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.761 | Likely Pathogenic | 1.06 | Ambiguous | 0.2 | 0.48 | Likely Benign | 0.77 | Ambiguous | 0.79 | Ambiguous | -5.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.34 | Pathogenic | 0.14 | Tolerated | 3.37 | 35 | 0 | -1 | 3.2 | -27.07 | 218.2 | -10.7 | 0.0 | 0.0 | -0.2 | 0.5 | X | Potentially Pathogenic | Lys533 is located on an α-helix (res. Ala533-Val560). In the WT simulations, Lys533 packs against Phe513, and its amino side chain occasionally forms an ionic interaction with the carboxylate group of Glu512 from an opposing α-helix (res. Gln503-Tyr518). In the variant simulations, Thr533 is unable to reproduce these interactions, potentially weakening the integrity of the tertiary structure. Additionally, Thr533 forms a hydrogen bond with the backbone carbonyl group of Leu549 in the same helix, which could potentially weaken the secondary structure. Regardless, the residue swap does not cause significant structural effects based on the simulations. | |||||||||||
| c.1631G>C | R544P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R544P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Across the available in‑silico predictors, none indicate a benign effect; all 13 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic outcome. High‑accuracy methods reinforce this view: 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. Consequently, the variant is most likely pathogenic based on current predictions, which contradicts the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 2 | -16.905 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.762 | Likely Pathogenic | 4.70 | Destabilizing | 0.1 | 4.19 | Destabilizing | 4.45 | Destabilizing | 1.14 | Destabilizing | -4.88 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.48 | Pathogenic | 0.05 | Affected | 3.37 | 35 | 0 | -2 | 2.9 | -59.07 | 192.0 | 123.8 | 0.1 | 0.0 | -0.3 | 0.0 | X | X | Potentially Pathogenic | Arg544 is located in the middle of an α-helix (res. Ala533-Val560). In the WT simulations, the guanidinium side chain of Arg544 forms a salt bridge with the carboxylate groups of Glu548 on the same α-helix, and with Glu651 and Glu656 on an opposing α-helix (res. Glu666-Asp644). In the variant simulations, the pyrrolidine side chain of Pro544 cannot form any of the salt bridges that Arg544 does in the WT, potentially weakening the tertiary structure assembly. Additionally, Pro544 lacks the amide group, and thus, unlike Arg544 in the WT, is unable to form a hydrogen bond with the carbonyl of Gln540. This disruption breaks the continuity of the secondary structure element, causing the α-helix to bend slightly in the variant simulations. These negative structural effects could be more pronounced during protein folding and are likely to be undermined in the MD simulations. | ||||||||||
| c.968T>C | L323P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L323P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a benign effect. High‑accuracy assessments corroborate 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 unanimous computational evidence, 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 | C2 | Uncertain | 1 | -12.507 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.762 | Likely Pathogenic | 3.39 | Destabilizing | 0.6 | 8.46 | Destabilizing | 5.93 | Destabilizing | 2.20 | Destabilizing | -4.80 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 0.59 | Pathogenic | 0.01 | Affected | 4.29 | 398 | -3 | -3 | -5.4 | -16.04 | 201.9 | 68.2 | 0.0 | 0.1 | 0.6 | 0.3 | X | Potentially Pathogenic | The iso-butyl side chain of Leu323, located at the beginning of an anti-parallel β sheet strand (res. Ala322-Asp330), packs against multiple hydrophobic leucine residues (e.g., Leu264, Leu266, Leu284, Leu286). In contrast, in the variant simulations, the less bulky cyclic five-membered pyrrolidine ring of Pro323 cannot fill the hydrophobic space as effectively as the branched hydrocarbon side chain of leucine. Notably, the backbone amide group of Leu323 forms a hydrogen bond with the backbone carbonyl group of Cys285. Pro323 cannot form this bond due to the absence of the backbone amide group, resulting in partial unfolding of the anti-parallel β sheet end in the variant simulations. | |||||||||||
| c.1409T>C | M470T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M470T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic impact. High‑accuracy methods further support this: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus 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 consensus of pathogenic predictions, the variant is most likely pathogenic, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -8.104 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.763 | Likely Pathogenic | 3.19 | Destabilizing | 0.1 | 2.68 | Destabilizing | 2.94 | Destabilizing | 1.49 | Destabilizing | -5.30 | Deleterious | 0.996 | Probably Damaging | 0.985 | Probably Damaging | -1.08 | Pathogenic | 0.24 | Tolerated | 3.37 | 34 | -1 | -1 | -2.6 | -30.09 | 213.8 | 46.5 | 0.0 | 0.0 | -0.2 | 0.2 | X | X | Potentially Pathogenic | The thioether group of Met470, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues in the inter-helix space (e.g., Val473, Leu558, Cys576, Trp572) formed by two other α helices (res. Ser604–Arg581, res. Pro562–Arg579). In the WT simulations, the Met470 side chain also packs against the positively charged guanidinium groups of Arg575, Arg429, and Arg579, which form salt bridges with the negatively charged carboxylate groups of the Asp474 and Asp467 side chains at the protein surface. In the variant simulations, the hydroxyl group of the Thr470 side chain forms an H-bond with the backbone carbonyl group of Ser466 in the α helix, potentially lowering its structural integrity. Importantly, the hydroxyl group of Thr470 also forms an H-bond with the guanidinium group of Arg575, which helps it form a more permanent salt bridge with Asp467. | ||||||||||
| c.928G>A | E310K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310K is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all return a deleterious signal: REVEL, FoldX (uncertain), Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenic or likely pathogenic. No tool in the dataset predicts a benign effect. 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 outputs, is pathogenic. Consequently, the variant is most likely pathogenic based on the available predictions, 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 Pathogenic | C2 | Conflicting | 4 | -14.601 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.764 | Likely Pathogenic | 1.97 | Ambiguous | 1.2 | 3.66 | Destabilizing | 2.82 | Destabilizing | 1.02 | Destabilizing | -3.68 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 1.19 | Pathogenic | 0.01 | Affected | 3.38 | 19 | 0 | 1 | -0.4 | -0.94 | 213.4 | 58.0 | 0.1 | 0.0 | 0.2 | 0.1 | X | Potentially Pathogenic | The carboxylate group of Glu310, located in an anti-parallel β sheet strand (res. Thr305-Asn315), is ideally positioned to interact with the side chain hydroxyl and backbone amide groups of Thr295 on a twisted anti-parallel β strand (res. Met289-Arg299). Because the carboxylate group can also interact with the GAP domain residues (e.g., Gln612, Tyr614), Glu310 plays a key role in maintaining the tertiary assembly between the C2 and GAP domains. In the variant simulations, the amino group of the Lys310 side chain hydrogen bonds with the GAP domain residues and forms a salt bridge with Glu613. Although no apparent negative effects are seen due to the residue swap, it is possible that the loss of hydrogen bonding with the hydroxyl group of the Thr295 side chain causes problems during folding, potentially compromising the twisting of the β sheet. | |||||||||||
| c.791T>C | L264P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset reports a benign outcome. High‑accuracy methods 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. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Uncertain | 1 | -12.285 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.767 | Likely Pathogenic | 5.73 | Destabilizing | 0.3 | 6.57 | Destabilizing | 6.15 | Destabilizing | 2.65 | Destabilizing | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.49 | Pathogenic | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||
| c.1408A>G | M470V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M470V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Consensus from most in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM all score it as deleterious. Only two tools—SIFT and AlphaMissense‑Optimized—classify it as benign, while Rosetta and AlphaMissense‑Default remain inconclusive. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized reports a benign outcome, but the SGM‑Consensus (derived from a majority of pathogenic calls among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining pathogenic FoldX with uncertain Rosetta) both predict pathogenicity. Overall, the preponderance of evidence supports a likely pathogenic classification, which does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -8.856 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 0.770 | Likely Pathogenic | 2.73 | Destabilizing | 0.1 | 1.88 | Ambiguous | 2.31 | Destabilizing | 1.31 | Destabilizing | -3.58 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.20 | Pathogenic | 0.15 | Tolerated | 3.37 | 34 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||
| c.772C>T | R258C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R258C missense variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33437677‑C‑T). Prediction tools that agree on a benign effect include only FATHMM. All other evaluated predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—indicate a pathogenic or likely pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Based on the preponderance 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 | C2 | Uncertain | 1 | 6-33437677-C-T | 1 | 6.20e-7 | -10.285 | Likely Pathogenic | 0.790 | Likely Pathogenic | Ambiguous | 0.771 | Likely Pathogenic | 1.17 | Ambiguous | 0.4 | 1.76 | Ambiguous | 1.47 | Ambiguous | 0.87 | Ambiguous | -6.79 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 5.77 | Benign | 0.00 | Affected | 3.39 | 15 | -3 | -4 | 7.0 | -53.05 | |||||||||||||||||
| c.821T>A | L274Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L274Q is reported in ClinVar with an uncertain significance (ClinVar ID 1810279.0) and is not found in gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while Rosetta remains inconclusive. No tool predicts a benign outcome. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Uncertain | 1 | -15.518 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.774 | Likely Pathogenic | 2.54 | Destabilizing | 0.3 | 1.74 | Ambiguous | 2.14 | Destabilizing | 1.97 | Destabilizing | -5.42 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.00 | Pathogenic | 0.00 | Affected | 3.38 | 19 | -2 | -2 | -7.3 | 14.97 | 245.9 | 1.8 | 0.0 | 0.0 | 0.1 | 0.2 | X | X | X | Potentially Pathogenic | The aliphatic side chain of Leu274, located in a β hairpin loop (res. Glu273-Lys278) connecting two anti-parallel β sheet strands, packs against multiple hydrophobic residues facing the β sheet (e.g., Ala271, Leu327, Tyr280, Val306). The hydrophilic carboxamide group of the Gln274 side chain is not suitable for this hydrophobic niche, causing nearby residues to adjust to make room for the hydrophilic glutamine. Additionally, a new hydrogen bond forms with the backbone carboxyl group of Arg272 in another β strand (res. Glu273-Arg259).As a result, the backbone amide group of Ala399 and the carbonyl group of Arg272, which connect two β strands at the β sheet end, form fewer hydrogen bonds in the variant than in the WT simulations. Although no major secondary structure disruption is observed in the variant simulations, the residue swap could profoundly affect the C2 domain folding, as the hydrophobic packing of Leu274 is crucial for maintaining the loop's contact with the rest of the C2 domain. Lastly, because the Leu274-containing loop faces the membrane surface, the residue swap could also negatively impact the SynGAP-membrane association. | |||||||||
| c.3119G>T | G1040V 2D AIThe SynGAP1 missense variant G1040V is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443671‑G‑T). Prediction tools that agree on a benign effect are ESM1b and AlphaMissense‑Optimized; those that predict a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta results are unavailable. Overall, the majority of predictions indicate a pathogenic impact, and this is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Uncertain | 1 | 6-33443671-G-T | 4 | 2.48e-6 | -3.453 | Likely Benign | 0.645 | Likely Pathogenic | Likely Benign | 0.774 | Likely Pathogenic | -2.89 | Deleterious | 0.827 | Possibly Damaging | 0.456 | Possibly Damaging | -0.74 | Pathogenic | 0.01 | Affected | 3.77 | 5 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||
| c.1715G>C | W572S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W572S is listed in ClinVar as Pathogenic (ClinVar ID 1069317.0) and is not reported in gnomAD. All available in silico predictors classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments confirm 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) predicts pathogenic. Therefore, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Pathogenic | 1 | -17.461 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.775 | Likely Pathogenic | 5.78 | Destabilizing | 0.2 | 3.37 | Destabilizing | 4.58 | Destabilizing | 1.79 | Destabilizing | -12.74 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.24 | Pathogenic | 0.01 | Affected | 3.37 | 35 | -2 | -3 | 0.1 | -99.14 | 235.1 | 76.6 | 0.0 | 0.0 | -0.4 | 0.1 | X | Potentially Pathogenic | The introduced residue Ser572, located in an α-helix (res. Arg563-Glu578), is considerably smaller than the tryptophan it replaced. The indole ring of the Trp572 side chain lies in a hydrophobic inter-helix space, where it makes extensive hydrophobic interactions with nearby residues such as Met470, Phe569, Leu588, and Ile589. In the variant simulations, all these favorable packing interactions are completely removed, as the introduced residue Ser572 is too hydrophilic or small to fill the hydrophobic niche occupied by the indole ring. Moreover, the hydroxyl group of Ser572 forms hydrogen bonds with the carbonyl groups of Glu567 and Val568 within the same α-helix, potentially lowering its integrity. Overall, the residue swap is highly likely to cause critical protein folding problems that are underestimated based on the effects seen in the variant simulations. | |||||||||||
| c.707C>T | A236V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A236V is listed in ClinVar as Benign (ID 469162.0) and is present in gnomAD (6‑33435558‑C‑T). Prediction tools that report benign include polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, and ESM1b. Four tools give uncertain or inconclusive results: FoldX, Rosetta, Foldetta, and premPS. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because the votes are evenly split. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as uncertain, and the SGM Consensus as unavailable. Consequently, the overall prediction profile is mixed, but the most reliable high‑accuracy evidence points toward a benign effect. Therefore, the variant is most likely benign, which aligns with its ClinVar classification and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | Benign/Likely benign | 2 | 6-33435558-C-T | 6 | 3.72e-6 | -8.752 | Likely Pathogenic | 0.267 | Likely Benign | Likely Benign | 0.777 | Likely Pathogenic | 0.61 | Ambiguous | 0.2 | 1.08 | Ambiguous | 0.85 | Ambiguous | 0.64 | Ambiguous | -3.55 | Deleterious | 0.981 | Probably Damaging | 0.446 | Benign | 5.79 | Benign | 0.03 | Affected | 3.40 | 14 | 0 | 0 | 2.4 | 28.05 | 213.8 | -44.7 | 0.0 | 0.0 | -0.2 | 0.2 | X | Potentially Benign | The methyl side chain of Ala236, located on an α helix (residues Ala236-Val250) facing an anti-parallel β sheet strand (residues Ile205-Val209), interacts hydrophobically with nearby residues such as Arg239 and Phe218. In the variant simulations, the isopropyl branched hydrocarbon side chain of Val236 maintains similar hydrophobic interactions as alanine in the WT, with an overall arrangement remarkably similar to Ala236. The residue swap does not affect the protein structure based on the simulations. | |||||||||
| c.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 | Uncertain | 1 | -13.961 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.777 | Likely Pathogenic | 5.75 | Destabilizing | 0.9 | 10.77 | Destabilizing | 8.26 | Destabilizing | 2.43 | Destabilizing | -6.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.77 | Benign | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||
| c.1394T>C | L465P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L465P is listed in ClinVar as Pathogenic (ClinVar ID 1067821.0) and is not reported in gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments 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 unanimous computational evidence, 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 | Likely Pathogenic | 1 | -14.824 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.778 | Likely Pathogenic | 7.18 | Destabilizing | 0.3 | 10.85 | Destabilizing | 9.02 | Destabilizing | 2.73 | Destabilizing | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | 3.37 | 34 | -3 | -3 | -5.4 | -16.04 | 211.1 | 65.9 | 0.1 | 0.0 | -0.2 | 0.0 | X | Potentially Pathogenic | The iso-butyl side chain of Leu465, located in the middle of an α helix (res. Ala461–Phe476), packs with hydrophobic residues (e.g., Phe464, Met468, Tyr497, Ile494) in an inter-helix space formed with two other α helices (res. Ala461–Phe476 and res. Thr488-Gly502). In the variant simulations, the cyclic five-membered pyrrolidine ring of Pro465 is not as optimal as the side chain of Leu465 for filling the three α helix hydrophobic niche. Although the residue swap does not cause a large-scale conformational shift during the simulations, the H-bond between the backbone amide group of Leu465 and the backbone carbonyl group of Ala461 is lost. This, in turn, breaks the continuity of the α helix secondary structure element. | |||||||||||
| c.1202G>A | R401Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R401Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438107‑G‑A). Prediction tools that agree on a benign effect are limited to FATHMM, whereas the majority of algorithms (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy methods reinforce the pathogenic prediction: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic,” and Foldetta’s stability assessment is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect, 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 | C2 | Uncertain | 1 | 6-33438107-G-A | -11.213 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.780 | Likely Pathogenic | 0.96 | Ambiguous | 0.1 | 1.50 | Ambiguous | 1.23 | Ambiguous | 1.20 | Destabilizing | -3.69 | Deleterious | 0.999 | Probably Damaging | 0.978 | Probably Damaging | 5.47 | Benign | 0.04 | Affected | 3.38 | 27 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||
| c.1030G>A | G344S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G344S is listed in ClinVar (ID 981240.0) as Pathogenic and is not reported in gnomAD. Prediction tools that assess pathogenicity all agree: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic; the only inconclusive result is premPS, which is marked Uncertain. No tool predicts a benign effect. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Pathogenic | 5 | -11.254 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.790 | Likely Pathogenic | 9.02 | Destabilizing | 0.7 | 6.08 | Destabilizing | 7.55 | Destabilizing | 0.98 | Ambiguous | -5.28 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -0.45 | Pathogenic | 0.04 | Affected | 3.37 | 25 | 1 | 0 | -0.4 | 30.03 | 217.3 | -51.7 | 0.0 | 0.1 | 0.2 | 0.1 | X | X | Potentially Pathogenic | Because Gly344 lacks a proper side chain, it allows the anti-parallel β sheet strand (res. Gly341-Pro349) to have a slight twist. Within a β strand, side chains normally alternate between outward and inward positions, but glycine is an exception as it allows the alternating pattern to skip a residue. Introducing serine or any other residue with a side chain at position 344 prevents this unique skip in the alternating pattern, causing structural strain or likely preventing correct folding altogether. Additionally, Tyr342 shields Gly344 from the solvent, contributing to twist formation in the β sheet and stabilizing the β-strand.In the variant simulations, the side chain of Ser344 assumes the inward position. However, the hydrophobic niche formed by multiple C2 domain residues (e.g., Val365, Val343, Leu327) is not accommodating for its hydroxyl group. The outward position, not seen in the simulations, would be equally disadvantageous due to the presence of hydrophobic residues on that side as well (e.g., Leu345, Tyr342). Serine is also not well-suited for twist formation, as it tends to suppress twisting and bending in β sheets. At this position, the hydroxyl group of Ser344 could also form hydrogen bonds with the backbone atoms of the Gly-rich Ω loop in the C2 domain (e.g., Thr366, Leu367, Gly378; res. Pro364-Pro398), potentially adversely affecting membrane-loop dynamics and ultimately compromising the stability of the SynGAP-membrane association. | ||||||||||
| c.680G>A | G227E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227E is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33435531-G-A). Functional prediction tools largely agree on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all report pathogenicity, while only polyPhen‑2 (HumVar) and FATHMM predict a benign outcome; premPS remains inconclusive. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Taken together, the overwhelming majority of evidence points to a pathogenic effect. This conclusion is consistent with the ClinVar “Uncertain” classification, which does not contradict the predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | Conflicting | 2 | 6-33435531-G-A | 3 | 1.86e-6 | -9.186 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.792 | Likely Pathogenic | 2.56 | Destabilizing | 0.4 | 5.36 | Destabilizing | 3.96 | Destabilizing | 0.94 | Ambiguous | -6.49 | Deleterious | 0.906 | Possibly Damaging | 0.360 | Benign | 5.72 | Benign | 0.01 | Affected | 3.43 | 12 | 0 | -2 | -3.1 | 72.06 | 237.7 | -112.1 | 0.1 | 0.3 | 0.0 | 0.3 | X | X | Uncertain | The introduced residue Glu227 is located in a β hairpin loop connecting two anti-parallel β sheet strands (res. Cys219-Thr224 and Thr228-Ala232). In the variant simulations, the carboxylate group of Glu227 frequently forms a salt bridge with the amino group of the neighboring residue Lys229. Despite this interaction, the integrity of the secondary structure element is not compromised. However, the β hairpins are potential nucleation sites during the initial stages of protein folding. Additionally, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||
| c.851T>C | L284P 2D AIThe SynGAP1 missense variant L284P is listed in ClinVar as Pathogenic (ClinVar ID 3344808.0) and is not reported in gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Based on the unanimous computational evidence, 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 | C2 | Likely Pathogenic | 1 | -15.588 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.794 | Likely Pathogenic | 5.83 | Destabilizing | 0.2 | 5.81 | Destabilizing | 5.82 | Destabilizing | 1.89 | Destabilizing | -6.17 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.64 | Pathogenic | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||
| c.1403T>C | M468T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468T is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database. Prediction tools that are available all converge on a pathogenic interpretation: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool reports a benign outcome. High‑accuracy assessments are consistent: AlphaMissense‑Optimized is “Uncertain,” SGM Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. **Based on the aggregate predictions, the variant is most likely pathogenic, 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 | Uncertain | 2 | 6-33438435-T-C | 1 | 6.20e-7 | -12.399 | Likely Pathogenic | 0.862 | Likely Pathogenic | Ambiguous | 0.801 | Likely Pathogenic | 3.47 | Destabilizing | 0.1 | 3.10 | Destabilizing | 3.29 | Destabilizing | 1.84 | Destabilizing | -3.85 | Deleterious | 0.994 | Probably Damaging | 0.985 | Probably Damaging | -1.31 | Pathogenic | 0.01 | Affected | 3.37 | 31 | -1 | -1 | -2.6 | -30.09 | 214.6 | 47.1 | 0.0 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | The thioether group of Met468, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues (e.g., Phe464, Leu465, Leu489) in an inter-helix space formed by two other α helices (res. Ala461–Phe476, res. Thr488–Gly502). In the variant simulations, the hydrophilic side chain of Thr468 does not pack favorably in the hydrophobic niche, and the methionine-aromatic stacking is lost. Although the hydroxyl group of Thr468 forms an H-bond with the backbone carbonyl group of Phe464, the integrity of the α helix is not affected in the simulations. No large-scale structural changes are observed during the variant simulations; however, due to the importance of hydrophobic packing, the effects could be more pronounced during protein folding. | ||||||||
| c.700C>T | R234W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R234W missense variant is listed in ClinVar (ID 856396.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33435551‑C‑T). Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of other in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) indicate a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain”; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is “Uncertain.” Overall, the preponderance of evidence points to a pathogenic effect, which is consistent with the ClinVar designation of uncertainty rather than a benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | Uncertain | 1 | 6-33435551-C-T | 3 | 1.86e-6 | -12.625 | Likely Pathogenic | 0.947 | Likely Pathogenic | Ambiguous | 0.805 | Likely Pathogenic | 0.96 | Ambiguous | 0.3 | 0.69 | Ambiguous | 0.83 | Ambiguous | 0.13 | Likely Benign | -5.52 | Deleterious | 0.997 | Probably Damaging | 0.803 | Possibly Damaging | 5.76 | Benign | 0.01 | Affected | 3.40 | 14 | 2 | -3 | 3.6 | 30.03 | 262.8 | 39.6 | -0.1 | 0.0 | -0.2 | 0.2 | X | Potentially Pathogenic | The guanidinium group of Arg234, located in a β-α loop between an anti-parallel β sheet strand (residues Gly227-Phe231) and an α helix (res. Ala236-Val250), forms a salt bridge with the carboxylate group of Glu238 in the α helix. Occasionally, it also bonds with the GAP domain residues Ser678 and Glu680. Thus, the positively charged Arg234 could contribute to the tertiary structure assembly between the PH and GAP domains. In contrast, the indole side chain of Trp234 in the variant is located on the protein surface in the variant simulations and is unable to form any interactions. | ||||||||
| c.1490A>G | Y497C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497C is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all return a deleterious signal: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict pathogenic. No tool reports a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM Consensus as “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) as “Pathogenic.” Overall, the variant is most likely pathogenic based on the consensus of predictive algorithms, which contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -11.872 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.806 | Likely Pathogenic | 3.88 | Destabilizing | 0.1 | 4.76 | Destabilizing | 4.32 | Destabilizing | 1.40 | Destabilizing | -8.82 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.65 | Pathogenic | 0.03 | Affected | 3.37 | 35 | 0 | -2 | 3.8 | -60.04 | 209.9 | 59.1 | -0.1 | 0.0 | -0.3 | 0.1 | X | X | Potentially Pathogenic | Tyr497 is located in the α-helix (res. Leu489-Glu519) within the inter-helix space of four α-helices (res. Leu489-Ile501, res. Val441-Ser457, res. Arg563-Glu578, res. Ala461-Val473). In the WT simulations, the phenol ring of Tyr497 hydrophobically packs with other residues in the inter-helix space (e.g., Leu465, Leu565, Val568). The hydroxyl group of Tyr497 also alternately forms hydrogen bonds with the carboxylate side chain of Gln456 and the backbone carbonyl of Glu564. Thus, Tyr497 plays a role in the folding and maintenance of the tertiary structure assembly between these four helices.In the variant simulations, the comparatively smaller residue, Cys497, cannot maintain any of the interactions seen with Tyr497 in the WT. Although no severe deleterious consequences are observed in the simulations, the structural effects could be more pronounced during actual protein folding. Indeed, the tertiary structure is seen to slightly break apart in the variant simulations. | ||||||||||
| c.1199T>A | V400E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V400E is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect are polyPhen‑2 HumVar and FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Based on the preponderance 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 | C2 | Uncertain | 1 | -13.686 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.810 | Likely Pathogenic | 3.70 | Destabilizing | 0.2 | 2.46 | Destabilizing | 3.08 | Destabilizing | 2.29 | Destabilizing | -4.88 | Deleterious | 0.920 | Possibly Damaging | 0.335 | Benign | 5.31 | Benign | 0.00 | Affected | 3.38 | 27 | -2 | -2 | -7.7 | 29.98 | 249.1 | -38.8 | -0.1 | 0.1 | 1.0 | 0.0 | X | X | X | Potentially Pathogenic | The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). In the variant simulations, the negatively charged carboxylate group of the Glu400 side chain is not suitable for occupying the hydrophobic niche. Consequently, the side chain escapes the center of the C2 domain and interacts with the backbone amide groups of Leu402 in the same β strand and/or Ile269 and Glu270 in a neighboring β strand (res. Arg259-Arg272). This residue swap disrupts the hydrophobic packing and generally has extensive negative effects on the C2 domain structure. At a minimum, the residue swap could affect the C2 domain stability and membrane association. | |||||||||
| 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 | Uncertain | 1 | -16.504 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.812 | Likely Pathogenic | 2.52 | Destabilizing | 0.2 | 2.32 | Destabilizing | 2.42 | Destabilizing | 2.75 | Destabilizing | -6.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.77 | Benign | 0.00 | Affected | 3.37 | 35 | -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.1487A>G | E496G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E496G missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess the variant’s effect fall into two groups: no tool predicts a benign outcome, while eight tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic effect. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus remains likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the preponderance of evidence points to a pathogenic effect, contradicting the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -13.529 | Likely Pathogenic | 0.850 | Likely Pathogenic | Ambiguous | 0.825 | Likely Pathogenic | 1.83 | Ambiguous | 0.1 | 1.76 | Ambiguous | 1.80 | Ambiguous | 0.92 | Ambiguous | -6.16 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.45 | Pathogenic | 0.02 | Affected | 3.37 | 35 | 0 | -2 | 3.1 | -72.06 | 173.9 | 103.1 | 0.0 | 0.0 | -0.7 | 0.0 | X | X | Potentially Pathogenic | Glu496 is located in the α-helix (res. Leu489-Glu519), and its carboxylate group forms salt bridges with the neighbouring residues Lys492 and Arg499 in the WT simulations. Glu496 also forms a hydrogen bond with Ser449 on an opposing helix (res. Val441-Ser457). In the variant simulations, Gly496 cannot form these salt bridges, which could weaken the secondary structure. Additionally, the loss of the hydrogen bond with Ser449 on the opposite helix can weaken the tertiary structure assembly. Moreover, glycine is an α-helix breaker, and it is seen to weaken the integrity of the helix as the hydrogen bonding between the backbone atoms of Gly496 and Ala493 breaks down. Also, due to its location at the GAP-Ras interface, the interaction of Glu496 with Arg499 and Lys492 might play a role in complex association and stability, which cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||
| c.1403T>A | M468K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468K is listed in ClinVar (ID 642691.0) as Pathogenic and is not reported in gnomAD. All available in silico predictors classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -16.982 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.828 | Likely Pathogenic | 3.21 | Destabilizing | 0.1 | 3.30 | Destabilizing | 3.26 | Destabilizing | 2.57 | Destabilizing | -4.61 | Deleterious | 0.878 | Possibly Damaging | 0.922 | Probably Damaging | -1.34 | Pathogenic | 0.04 | Affected | 3.37 | 31 | 0 | -1 | -5.8 | -3.02 | 188.7 | 69.3 | 0.0 | 0.0 | -0.1 | 0.2 | X | X | Potentially Pathogenic | The thioether group of Met468, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues (e.g., Phe464, Leu465, Leu489) in an inter-helix space formed by two other α helices (res. Ala461–Phe476, res. Thr488–Gly502). In the variant simulations, the positively charged side chain of Lys468 rotates outward to escape the hydrophobic niche, forming an H-bond with the hydroxyl group of the Ser471 side chain and a salt bridge with the carboxylate group of the Glu472 side chain. This residue swap also disrupts the methionine-aromatic stacking with the phenyl ring of the Phe464 side chain. Although no large-scale structural changes are observed during the variant simulations, the importance of hydrophobic packing suggests that the effects could be more pronounced during protein folding. | ||||||||||
| c.1306G>A | E436K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E436K 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, whereas the remaining evaluated algorithms (REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) uniformly predict a pathogenic impact; FoldX, Foldetta, and premPS are inconclusive. 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 preponderance of evidence points to a pathogenic effect for E436K, which does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -13.869 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.829 | Likely Pathogenic | 0.56 | Ambiguous | 0.1 | 2.86 | Destabilizing | 1.71 | Ambiguous | 0.82 | Ambiguous | -3.77 | Deleterious | 0.994 | Probably Damaging | 0.951 | Probably Damaging | 4.71 | Benign | 0.02 | Affected | 3.37 | 29 | 0 | 1 | -0.4 | -0.94 | 186.8 | 39.8 | 0.0 | 0.0 | -0.2 | 0.0 | X | X | X | Potentially Pathogenic | The carboxylate group of Glu436, located on the α helix (res. Met414-Glu436), forms a salt bridge with the amino group of the Lys444 side chain on an opposing α helix (res. Val441-Ser457). The backbone carbonyl of Glu436 also H-bonds with the Lys444 side chain, which helps keep the ends of the two α helices tightly connected. In contrast, in the variant simulations, the salt bridge formation with Lys444 is not possible. Instead, the repelled Lys436 side chain rotates outward, causing a change in the α helix backbone H-bonding: the amide group of Lys444 H-bonds with the carbonyl of Ala433 instead of the carbonyl of Cys432. | |||||||||
| c.1685C>T | P562L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P562L is listed in ClinVar as Pathogenic (ClinVar ID 41462.0) and is present in gnomAD (ID 6‑33440737‑C‑T). Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Benign predictions are reported only by premPS and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. No other high‑confidence stability or pathogenicity scores are available. Overall, the majority of evidence supports a pathogenic classification, which is consistent with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Pathogenic/Likely path. | 10 | 6-33440737-C-T | -13.438 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.829 | Likely Pathogenic | 3.54 | Destabilizing | 0.8 | 0.17 | Likely Benign | 1.86 | Ambiguous | -0.14 | Likely Benign | -9.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.58 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -3 | -3 | 5.4 | 16.04 | 228.8 | -68.5 | -0.1 | 0.0 | 0.1 | 0.2 | X | Potentially Pathogenic | Pro562 is located on an α-α loop between two α-helices (res. Ala533-Val560 and res. Arg563-Glu578). The cyclic pyrrolidine side chain of Pro562 hydrophobically packs with other residues in the inter-helix space, such as Leu565, Ile501, and Phe561. In the variant simulations, Leu562 packs more favorably with the nearby hydrophobic residues, and the backbone amide group of Leu562 (absent in proline) does not form any intra-protein hydrogen bonds. However, prolines are well-suited for unstructured regions like loops, and thus, Pro562 in the WT is necessary at the end of the helix to induce a tight turn during folding. Although no negative structural effects are observed during the simulations, the residue swap could potentially cause extensive damage to the protein structure during folding. | 10.1016/j.ajhg.2020.11.011 | |||||||||
| c.1767C>G | I589M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I589M is listed in ClinVar with an uncertain significance (ClinVar ID 964298.0) and is not reported in gnomAD. Functional prediction tools that provide a definitive call overwhelmingly predict a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all indicate pathogenicity, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely pathogenic outcome. Tools that are inconclusive—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—are listed as uncertain and do not influence the overall assessment. High‑accuracy methods specifically show AlphaMissense‑Optimized as uncertain, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the majority of available predictions support a pathogenic effect, which is consistent with the ClinVar uncertain designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -12.225 | Likely Pathogenic | 0.926 | Likely Pathogenic | Ambiguous | 0.830 | Likely Pathogenic | 0.74 | Ambiguous | 0.2 | 1.54 | Ambiguous | 1.14 | Ambiguous | 1.33 | Destabilizing | -2.99 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.94 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 2 | 1 | -2.6 | 18.03 | 267.6 | -24.5 | 0.0 | 0.0 | -0.1 | 0.1 | X | Potentially Benign | A hydrophobic residue, Ile589, located in an α helix (res. Glu582-Met603), is swapped for another hydrophobic residue, methionine. The sec-butyl hydrocarbon side chain of Ile589 packs favourably with multiple residues in the inter-helix hydrophobic space (e.g., Phe569, Ile667, and Leu664).Although the S-methyl thioether group of the Met589 side chain in the variant is longer than the branched side chain of isoleucine, it stacks favourably with the aromatic phenol ring. Additionally, the polar sulphur atom forms a weak hydrogen bond with the guanidinium group of Arg573, which in turn forms a salt bridge with the carboxylate group of Asp586.Overall, the hydrophobic packing in the inter-helix space does not appear to be disrupted in the variant simulations. | |||||||||||
| c.773G>A | R258H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R258H is listed as Benign in ClinVar (ID 949697.0) and is present in gnomAD (6‑33437678‑G‑A). Prediction tools that agree on a benign effect include FATHMM and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Uncertain calls come from FoldX, Rosetta, Foldetta, and AlphaMissense‑Default. The high‑accuracy consensus (SGM) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic verdict. AlphaMissense‑Optimized remains benign, while Foldetta is inconclusive. Overall, the majority of evidence points to a pathogenic impact, which contradicts the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | Benign/Likely benign | 3 | 6-33437678-G-A | 10 | 6.20e-6 | -10.533 | Likely Pathogenic | 0.525 | Ambiguous | Likely Benign | 0.830 | Likely Pathogenic | 1.60 | Ambiguous | 0.6 | 1.00 | Ambiguous | 1.30 | Ambiguous | 1.47 | Destabilizing | -4.06 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 5.77 | Benign | 0.01 | Affected | 3.39 | 15 | 2 | 0 | 1.3 | -19.05 | 212.5 | 81.8 | 0.1 | 0.0 | -0.5 | 0.2 | X | Potentially Pathogenic | The guanidinium group of Arg258, located at the end of an α-β loop connecting the PH domain to the C2 domain (res. Lys251-Arg258), forms hydrogen bonds with the carboxamide groups of Asn727 and Asn729 side chains, as well as with the backbone carbonyl groups of Ala724, Leu725, and Asn727 in the WT simulations. Although the imidazole group of His258 can act as a hydrogen bond donor/acceptor, the swapped residue is unable to maintain an equally well-coordinated hydrogen bond network for linking the C2 and GAP domains in the variant simulations. | |||||||||
| c.1559C>T | S520F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include Rosetta, Foldetta, and premPS. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX gives an uncertain result. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, whereas Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign impact. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -12.541 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.833 | Likely Pathogenic | -1.20 | Ambiguous | 0.4 | 0.39 | Likely Benign | -0.41 | Likely Benign | 0.25 | Likely Benign | -5.57 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.36 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -2 | -3 | 3.6 | 60.10 | ||||||||||||||||||||
| c.1718G>T | R573L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R573L is listed in ClinVar as Pathogenic (ClinVar ID 521291.0) and is not reported in gnomAD. Functional prediction tools that assess sequence conservation and structural impact uniformly indicate a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic. No tool in the dataset predicts a benign outcome. Predictions that rely on protein‑folding stability (FoldX, Rosetta, Foldetta, premPS) are inconclusive and are therefore treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports pathogenic; Foldetta remains uncertain. Based on the collective evidence, the variant is most likely pathogenic, which is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -13.120 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.833 | Likely Pathogenic | 1.30 | Ambiguous | 0.6 | 1.11 | Ambiguous | 1.21 | Ambiguous | 0.80 | Ambiguous | -5.74 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.41 | Pathogenic | 0.01 | Affected | 3.37 | 35 | -3 | -2 | 8.3 | -43.03 | 237.4 | 60.7 | 0.0 | 0.0 | -0.7 | 0.3 | X | X | Potentially Pathogenic | The guanidinium group of Arg573, located in an α-helix (res. Arg563-Glu578), forms a salt bridge with the carboxylate groups of Glu582 and/or Asp586 from a nearby α-helix (res. Glu582-Met603) in the WT simulations. Additionally, the Arg573 side chain stacks planarly with the aromatic phenol ring of Tyr665 and hydrogen bonds with the hydroxyl group of Ser668 from another α-helix (res. Ser641-Ser668). In the variant simulations, the aliphatic iso-butyl group of the Leu573 side chain fails to establish any of these interactions, which, in turn, lowers the integrity of the opposing α-helix end (res. Glu582-Met603). Overall, the residue swap has the potential to substantially affect the tertiary structure assembly during the protein folding process. | 10.1016/j.ajhg.2020.11.011 | |||||||||
| c.1712C>T | S571L 2D 3DClick to see structure in 3D Viewer AISynGAP1 S571L is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33440764‑C‑T). Prediction tools cluster into two groups: benign predictions come from premPS and AlphaMissense‑Optimized, while the remaining nine tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—indicate pathogenicity. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic (a majority vote of pathogenic predictions from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain due to conflicting FoldX‑MD and Rosetta outputs. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | 6-33440764-C-T | 1 | 6.23e-7 | -11.651 | Likely Pathogenic | 0.660 | Likely Pathogenic | Likely Benign | 0.841 | Likely Pathogenic | -1.53 | Ambiguous | 0.1 | -1.05 | Ambiguous | -1.29 | Ambiguous | 0.27 | Likely Benign | -5.61 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | -1.25 | Pathogenic | 0.04 | Affected | 3.37 | 35 | -2 | -3 | 4.6 | 26.08 | |||||||||||||||||
| c.1814C>G | P605R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605R is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains inconclusive. Grouping by consensus, the benign category is empty and the pathogenic category contains all available predictions. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields pathogenic; and Foldetta, integrating FoldX‑MD and Rosetta outputs, reports a destabilizing, pathogenic effect. Consequently, the variant is most likely pathogenic, which does not contradict its current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -13.745 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.845 | Likely Pathogenic | 8.71 | Destabilizing | 2.5 | 6.46 | Destabilizing | 7.59 | Destabilizing | 0.92 | Ambiguous | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.69 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0 | -2 | -2.9 | 59.07 | 281.7 | -118.1 | -0.2 | 0.0 | 0.5 | 0.1 | X | X | X | X | Potentially Pathogenic | Pro605 is located in a short turn between an α helix (res. Glu582-Met603) and a short α helical section (res. Ser606-Phe608). The pyrrolidine side chain of Pro605 packs hydrophobically with nearby hydrophobic residues (e.g., Ile514, Leu623, Leu610) in the inter-helix space. Additionally, proline lacks a free backbone amide group, which breaks the α helix and facilitates the turn in the WT structure.In the variant simulations, the guanidinium side chain of Arg605 is bulkier than proline, and its positively charged guanidinium group faces mostly hydrophobic residues (e.g., Ile514, Leu623, Leu610). As a result, it needs to rotate away from the hydrophobic niche. 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.Moreover, due to its location at the GAP-Ras interface, the residue swap could affect the GAP-Ras association. | ||||||||
| c.743G>C | R248P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R248P is listed in ClinVar as Pathogenic (ClinVar ID 1065478.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized returns a pathogenic score, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Based on the overwhelming consensus of pathogenic predictions and the high‑accuracy tool results, the variant is most likely pathogenic, which aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | Likely Pathogenic | 1 | -10.751 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.848 | Likely Pathogenic | 3.09 | Destabilizing | 0.6 | 8.87 | Destabilizing | 5.98 | Destabilizing | 1.21 | Destabilizing | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.878 | Possibly Damaging | 5.64 | Benign | 0.00 | Affected | 3.41 | 14 | 0 | -2 | 2.9 | -59.07 | 223.8 | 126.6 | 0.0 | 0.0 | -0.2 | 0.1 | X | X | Potentially Pathogenic | The guanidinium group of Arg248, located on an α helix (residues Ala236-Val250), forms two very stable salt bridges with Asp255 (from a short α helical section, res. Lys254-Asn256) and Glu244 (from a nearby loop) in the WT simulations. In the variant simulations, the pyrrolidine side chain of Pro248 cannot form any salt bridges, which could negatively affect the tertiary structure assembly of the PH domain. Additionally, Pro248 lacks a free amide group needed for hydrogen bonding with the backbone carbonyl group of Asn245, disrupting the continuity of the α helix. | ||||||||||
| c.929A>G | E310G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310G is listed in ClinVar as Pathogenic (ClinVar ID 2732842.0) and is not reported in gnomAD. Prediction tools that assess the variant’s effect largely agree on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while only premPS predicts a benign effect. 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 stability outputs, also predicts pathogenicity. Consequently, the variant is most likely pathogenic, and this prediction is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Pathogenic | 1 | -14.132 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.848 | Likely Pathogenic | 2.38 | Destabilizing | 0.7 | 3.56 | Destabilizing | 2.97 | Destabilizing | 0.36 | Likely Benign | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.12 | Pathogenic | 0.00 | Affected | 3.38 | 19 | -2 | 0 | 3.1 | -72.06 | ||||||||||||||||||||
| c.1558T>C | S520P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic outcome, while premPS remains inconclusive. No tool predicts a benign effect. 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. Overall, the evidence strongly supports a pathogenic impact for S520P, 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 Pathogenic | GAP | Uncertain | 1 | -12.707 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.855 | Likely Pathogenic | 3.72 | Destabilizing | 0.8 | 8.86 | Destabilizing | 6.29 | Destabilizing | 0.83 | Ambiguous | -4.57 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||
| c.662A>G | E221G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221G 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 polyPhen‑2 HumVar and FATHMM, while the majority of other in silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) indicate a pathogenic impact; FoldX, Rosetta, Foldetta, and premPS are inconclusive. 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. Based on the collective evidence, the variant is most likely pathogenic, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | Uncertain | 1 | -12.221 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.863 | Likely Pathogenic | 1.40 | Ambiguous | 0.1 | 1.74 | Ambiguous | 1.57 | Ambiguous | 0.71 | Ambiguous | -5.56 | Deleterious | 0.596 | Possibly Damaging | 0.201 | Benign | 5.79 | Benign | 0.00 | Affected | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||
| c.1484A>G | E495G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E495G missense variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438516‑A‑G). Among the available in‑silico predictors, the following tools uniformly indicate a pathogenic effect: REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which itself is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). No tool in the dataset predicts a benign outcome; predictions that are uncertain (FoldX, Foldetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Pathogenic,” and Foldetta as “Uncertain.” Overall, the preponderance of pathogenic predictions strongly suggests that the variant is most likely pathogenic, 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 | Uncertain | 1 | 6-33438516-A-G | 1 | 6.20e-7 | -9.400 | Likely Pathogenic | 0.923 | Likely Pathogenic | Ambiguous | 0.867 | Likely Pathogenic | 1.21 | Ambiguous | 0.0 | 2.06 | Destabilizing | 1.64 | Ambiguous | 0.78 | Ambiguous | -6.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.46 | Pathogenic | 0.02 | Affected | 3.37 | 35 | -2 | 0 | 3.1 | -72.06 | |||||||||||||||||
| c.922T>C | W308R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308R is listed in ClinVar (ID 391294.0) as Pathogenic and is not reported in gnomAD. All available in‑silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | Pathogenic | 1 | -12.264 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.868 | Likely Pathogenic | 5.40 | Destabilizing | 0.5 | 4.27 | Destabilizing | 4.84 | Destabilizing | 1.88 | Destabilizing | -12.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.48 | Pathogenic | 0.00 | Affected | 3.38 | 19 | 2 | -3 | -3.6 | -30.03 | 290.4 | -26.7 | -0.1 | 0.1 | 0.0 | 0.2 | X | X | X | Potentially Pathogenic | The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The guanidinium group of Arg308 is comparably sized to the tryptophan it replaced; however, it is also positively charged.In the variant simulations, the charged side chain remains buried deep in the hydrophobic part of the C2 domain, where it forms new hydrogen bonds with the backbone carbonyl atoms of surrounding residues (e.g., Val306, Ile268). However, the residue swap is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association. | |||||||||
| c.1493T>G | M498R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498R is listed in ClinVar as Pathogenic (ClinVar ID 3907767.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only polyPhen‑2 HumVar; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) 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 predictions or stability results are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -8.812 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.869 | Likely Pathogenic | 3.85 | Destabilizing | 0.2 | 2.35 | Destabilizing | 3.10 | Destabilizing | 1.76 | Destabilizing | -4.53 | Deleterious | 0.464 | Possibly Damaging | 0.120 | Benign | -1.36 | Pathogenic | 0.00 | Affected | 0 | -1 | -6.4 | 24.99 | ||||||||||||||||||||||
| c.1483G>A | E495K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E495K is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include FoldX and Foldetta, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools with inconclusive results (Rosetta and premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus also as pathogenic, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) indicates a benign effect. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic effect for E495K, which is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -11.478 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.869 | Likely Pathogenic | 0.15 | Likely Benign | 0.2 | 0.66 | Ambiguous | 0.41 | Likely Benign | 0.70 | Ambiguous | -3.91 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.29 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||
| c.703T>C | S235P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235P is listed in ClinVar as Pathogenic (ClinVar ID 1067856.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM; all other evaluated algorithms—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports pathogenic. No predictions or stability results are missing or inconclusive. **Based on the collective predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | Likely Pathogenic | 1 | -14.857 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.870 | Likely Pathogenic | 4.02 | Destabilizing | 0.1 | 6.91 | Destabilizing | 5.47 | Destabilizing | 1.23 | Destabilizing | -4.24 | Deleterious | 0.917 | Possibly Damaging | 0.446 | Benign | 5.47 | Benign | 0.01 | Affected | 3.40 | 14 | 1 | -1 | -0.8 | 10.04 | 201.5 | 17.0 | 0.1 | 0.0 | -0.6 | 0.0 | X | Potentially Pathogenic | In the WT, the hydroxyl group of Ser235, located in a β-α loop between an anti-parallel β sheet strand (res. Gly227-Phe231) and an α helix (residues Ala236-Val250), forms hydrogen bonds with the GAP domain loop residue Glu680 and with the backbone amide groups of Ala237 and Glu238 from the α helix. In the variant simulations, the pyrrolidine ring of Pro235 cannot stabilize the α helix end or maintain tertiary bonding interactions between the PH and GAP domains via hydrogen bonding as effectively as serine. | |||||||||||
| c.1640G>A | C547Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C547Y (ClinVar ID 1404191.0) is listed as Pathogenic in ClinVar and is not reported in gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, 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 from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Taken together, the overwhelming majority of computational evidence indicates a pathogenic effect, which is in agreement with the ClinVar classification. Thus, the variant is most likely pathogenic and does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Pathogenic | 1 | -15.871 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.874 | Likely Pathogenic | 8.53 | Destabilizing | 1.8 | 6.20 | Destabilizing | 7.37 | Destabilizing | 0.62 | Ambiguous | -10.57 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.33 | Pathogenic | 0.06 | Tolerated | 3.37 | 35 | 0 | -2 | -3.8 | 60.04 | 280.1 | -54.8 | 0.0 | 0.0 | 0.0 | 0.0 | X | X | X | Potentially Pathogenic | Cys547 is located in an α-helix (res. Ala533-Val560). The thiol side chain of Cys547 is situated in a hydrophobic inter-helix space, where it packs hydrophobically with other residues such as Ile626, Leu551, and Phe652. Additionally, the thiol side chain of Cys weakly hydrogen bonds with the carbonyl group of Leu543 in the same α-helix. In the variant simulations, the bulkier phenol ring of Tyr547, with its polar hydroxyl group, is less suited for the hydrophobic space. Consequently, it moves outside and forms a hydrogen bond with the carbonyl group of Phe652 in the neighboring α-helix (res. Glu666-Asp644). This causes the two helices to slightly separate, negatively affecting the secondary structure integrity of the latter helix. These negative structural effects could be more pronounced during protein folding and are likely to be undermined in the MD simulations. | |||||||||
| c.662A>T | E221V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E221V missense variant is reported in ClinVar as Pathogenic (ClinVar ID 2413181.0) and is not found in gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Benign predictions are limited to premPS, polyPhen‑2 HumVar, and FATHMM. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments reinforce the pathogenic interpretation: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus also indicates Likely Pathogenic, while Foldetta remains Uncertain. Taken together, the preponderance of evidence supports a pathogenic effect for E221V, and this conclusion aligns with the ClinVar classification, showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | Likely Pathogenic | 1 | -14.954 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.875 | Likely Pathogenic | -0.66 | Ambiguous | 0.2 | -0.89 | Ambiguous | -0.78 | Ambiguous | 0.49 | Likely Benign | -5.54 | Deleterious | 0.596 | Possibly Damaging | 0.203 | Benign | 5.86 | Benign | 0.00 | Affected | 3.41 | 13 | -2 | -2 | 7.7 | -29.98 | 234.5 | 50.6 | 0.0 | 0.0 | -0.4 | 0.2 | X | Uncertain | The introduced residue Val221 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the carboxylate group of Glu221, Val221 cannot form hydrogen bonds with Thr223 or a salt bridge with the amino group of the Lys207 side chain. Despite this, the WT simulations containing Glu221 do not show significant differences compared to the variant simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||
| c.1468G>C | A490P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A490P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Among the available in‑silico predictors, 10 tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) uniformly predict a pathogenic effect, whereas only Foldetta predicts a benign outcome; FoldX, Rosetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) is benign. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, 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 | Uncertain | 1 | -12.905 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.878 | Likely Pathogenic | -1.27 | Ambiguous | 0.1 | 1.31 | Ambiguous | 0.02 | Likely Benign | 1.07 | Destabilizing | -4.81 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.42 | Pathogenic | 0.01 | Affected | 3.37 | 35 | -1 | 1 | -3.4 | 26.04 | ||||||||||||||||||||
| c.1714T>C | W572R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W572R is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic.” No tool in the dataset predicts a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, which is consistent with its ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Not provided | 1 | -17.511 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.894 | Likely Pathogenic | 4.84 | Destabilizing | 0.1 | 6.19 | Destabilizing | 5.52 | Destabilizing | 1.79 | Destabilizing | -12.81 | Deleterious | -1.25 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 2 | -3 | -3.6 | -30.03 | 312.6 | -37.6 | 0.0 | 0.0 | -1.0 | 0.0 | X | X | Potentially Pathogenic | The indole ring of Trp572, located in an α-helix (res. Arg563-Glu578), lies in a hydrophobic inter-helix space, where it makes extensive hydrophobic interactions with nearby residues such as Met470, Phe569, Leu588, and Ile589. The guanidinium group of Arg572 is similarly sized to the tryptophan it replaced; however, it is also positively charged. In the variant simulations, Arg572 forms hydrogen bonds with other residues in the inter-helix space, such as Ser592 and the backbone carbonyl atom of Leu465. Additionally, Arg572 hydrophobically packs its carbon chain with surrounding residues such as Phe569 and Ile589.However, the introduced residue arginine is too hydrophilic and charged for the hydrophobic space, disrupting the hydrophobic packing of the inter-helix space. Indeed, in the second simulation, Arg572 successfully escapes the hydrophobic niche completely, causing the whole protein to partially unfold.Overall, the residue swap is highly likely to cause critical protein folding problems, as evidenced by the effects seen in the variant simulations. | ||||||||||||||
| c.1499T>C | L500P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L500P is listed in ClinVar (ID 2708686.0) as Pathogenic and is not reported in gnomAD. All available in‑silico predictors classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments confirm 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) predicts pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Pathogenic | 1 | -15.898 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.894 | Likely Pathogenic | 5.91 | Destabilizing | 0.3 | 8.90 | Destabilizing | 7.41 | Destabilizing | 1.92 | Destabilizing | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.37 | Pathogenic | 0.01 | Affected | 3.37 | 35 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||
| c.1639T>C | C547R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C547R is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while no tool in the dataset predicts a benign outcome. High‑accuracy methods 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, also predicts pathogenicity. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -16.967 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.900 | Likely Pathogenic | 7.76 | Destabilizing | 0.8 | 5.83 | Destabilizing | 6.80 | Destabilizing | 1.69 | Destabilizing | -11.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.33 | Pathogenic | 0.02 | Affected | 3.37 | 35 | -4 | -3 | -7.0 | 53.05 | 267.4 | -90.3 | 0.0 | 0.0 | -0.1 | 0.1 | X | X | X | X | Potentially Pathogenic | Cys547 is located in an α-helix (res. Ala533-Val560). The thiol side chain of Cys is situated in a hydrophobic inter-helix space, where it packs hydrophobically with other residues such as Ile626, Leu551, and Phe652. Additionally, the thiol side chain of Cys547 weakly hydrogen bonds with the carbonyl group of Leu543 in the same α-helix. In the variant simulations, the bulkier, positively charged guanidinium group of Arg547 must rotate out of the hydrophobic space. Consequently, it forms ionic interactions with the carboxylate groups of Glu548 in the same helix and Glu656 in the neighboring α-helix (res. Glu666-Asp644). This causes the two helices to slightly separate, significantly affecting the secondary structure integrity of the latter helix. These negative structural effects could be more pronounced during protein folding and are likely to be undermined in the MD simulations. | ||||||||
| c.1714T>G | W572G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W572G is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: 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. Based on the uniform pathogenic predictions from both general and high‑accuracy tools, 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 | Uncertain | 1 | -17.692 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.900 | Likely Pathogenic | 6.57 | Destabilizing | 0.2 | 7.57 | Destabilizing | 7.07 | Destabilizing | 1.83 | Destabilizing | -11.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.24 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -7 | -2 | 0.5 | -129.16 | 195.2 | 127.9 | 0.0 | 0.0 | -1.0 | 0.0 | X | Potentially Pathogenic | The introduced residue Gly572, located in an α-helix (res. Arg563-Glu578), is considerably smaller than the tryptophan it replaced. The indole ring of the Trp572 side chain lies in a hydrophobic inter-helix space, where it makes extensive hydrophobic interactions with nearby residues such as Met470, Phe569, Leu588, and Ile589. In the variant simulations, all these favorable packing interactions are completely removed, as the introduced residue Gly572 essentially lacks a side chain altogether. Although not observed in the simulations, the residue swap could also weaken the integrity of the helix (res. Arg563-Glu578), as glycine is known as an “α-helix breaker.” Overall, the residue swap is highly likely to cause critical protein folding problems that are underestimated based on the effects seen in the variant simulations. | |||||||||||
| c.1579G>T | D527Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant D527Y is listed in ClinVar with an uncertain significance (ClinVar ID 1698369.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: the single benign prediction from premPS versus a consensus of pathogenic predictions from the remaining 12 tools (REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Protein‑stability calculations from FoldX and Rosetta are also uncertain. Overall, the preponderance of evidence indicates that D527Y is most likely pathogenic, which does not contradict the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -15.386 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.905 | Likely Pathogenic | -0.77 | Ambiguous | 0.2 | 1.89 | Ambiguous | 0.56 | Ambiguous | -0.14 | Likely Benign | -8.79 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -2.41 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -4 | -3 | 2.2 | 48.09 | 270.9 | -45.7 | 0.1 | 0.1 | -0.1 | 0.0 | X | Potentially Pathogenic | Asp527 is located on an α-α loop between the two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the carboxylate group of the Asp527 side chain forms hydrogen bonds with the backbone atoms of loop residues (e.g., Ile529, Lys530) facing the membrane surface. In the variant simulations, Tyr527 is a bulkier residue that faces away from the loop and stacks with Phe646 in a nearby α-helix (res. Ser614-Ser668). Regardless, no negative structural effects are observed during the variant simulations. However, due to its location near the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||
| c.1481T>G | I494R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I494R is listed in ClinVar as Pathogenic (ClinVar ID 1685460.0) and is not reported in gnomAD. Prediction tools that assess functional impact all converge on a pathogenic outcome: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity. No tool predicts a benign effect. 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 (combining FoldX‑MD and Rosetta outputs) is pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -15.758 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.911 | Likely Pathogenic | 6.71 | Destabilizing | 0.3 | 3.40 | Destabilizing | 5.06 | Destabilizing | 2.19 | Destabilizing | -6.43 | Deleterious | 0.999 | Probably Damaging | 0.957 | Probably Damaging | -1.41 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -2 | -3 | -9.0 | 43.03 | 273.9 | -59.8 | 0.0 | 0.0 | 0.0 | 0.1 | X | X | X | X | Potentially Pathogenic | The sec-butyl side chain of Ile494, located in an α-helix (res. Leu489-Glu519), packs against hydrophobic residues (e.g., Phe484, Leu465, Trp572, Ala493, Met468) in an inter-helix space (res. Leu489-Glu519 and res. Ala461-Phe476). In the variant simulations, the bulkier and positively charged residue, Arg494, weakens the integrity of the opposing helix. Additionally, the bulkier Arg494 stacks with Phe484, causing the α-helices to move farther apart to accommodate it. This mutation could have substantial negative effects due to the fundamental role of hydrophobic packing, which is disrupted by Arg494 during protein folding. | ||||||||
| c.719A>G | D240G 2D  AIThe SynGAP1 missense variant D240G is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Benign predictions are provided by premPS and FATHMM, whereas pathogenic predictions are made by REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. FoldX‑MD is inconclusive, and AlphaMissense‑Optimized is uncertain. High‑accuracy methods show that AlphaMissense‑Optimized is inconclusive, SGM Consensus predicts pathogenic, and Foldetta predicts pathogenic. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the ClinVar uncertain status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | Uncertain | 1 | -12.825 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.912 | Likely Pathogenic | 1.85 | Ambiguous | 0.1 | 2.72 | Destabilizing | 2.29 | Destabilizing | 0.24 | Likely Benign | -6.19 | Deleterious | 0.993 | Probably Damaging | 0.984 | Probably Damaging | 5.79 | Benign | 0.01 | Affected | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||
| c.1505G>A | G502D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502D is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: 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. Based on the uniform predictions, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -14.796 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.915 | Likely Pathogenic | 3.79 | Destabilizing | 0.9 | 5.69 | Destabilizing | 4.74 | Destabilizing | 1.38 | Destabilizing | -6.80 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | -1.66 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 1 | -1 | -3.1 | 58.04 | 224.2 | -80.0 | -0.8 | 0.7 | 0.6 | 0.3 | X | X | X | Potentially Pathogenic | Gly502 is located in a hinge in the middle of an α-helix (res. Leu489-Glu519). In the WT, Gly502 acts as an α-helix breaker due to its lack of a side chain, facilitating a bend in the middle of the α-helix. In the variant simulations, the carboxylate group of Asp502 forms hydrogen bonds with neighboring residues (e.g., Ser677, Lys504), disrupting the hinge. Additionally, Asp502 struggles to fit into the α-helix hinge and cannot generate a similar bend as Gly502, which would drastically affect the secondary structure during folding. Thus, the deleterious effect seen in the simulations is likely an underestimate of the impact of the residue swap on the protein structure during protein folding. | |||||||||
| c.1706T>C | F569S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F569S is listed in ClinVar (ID 1878965.0) as Pathogenic and is not reported in gnomAD. Across the available in‑silico predictors, every tool examined (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classifies the variant as pathogenic; no tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Pathogenic | 2 | -13.384 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.916 | Likely Pathogenic | 5.70 | Destabilizing | 0.1 | 5.38 | Destabilizing | 5.54 | Destabilizing | 2.45 | Destabilizing | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.32 | Pathogenic | 0.00 | Affected | 3.37 | 34 | -3 | -2 | -3.6 | -60.10 | 213.7 | 67.9 | -0.1 | 0.0 | -1.0 | 0.1 | X | Potentially Pathogenic | Phe569 is located on an α-helix (res. Arg563-Glu578). In the WT simulations, the phenyl side chain of Phe569 packs with hydrophobic residues such as Trp572, Leu565, Ile589, Ile667, and Phe561, originating from three different α-helices (res. Ala533-Val560, res. Arg563-Glu578, and res. Ser641-Glu666). In the variant simulations, the acceptor/donor hydroxyl group of Ser569 forms hydrogen bonds with the carbonyl groups of Glu567 and Lys566 on the same α-helix, which could affect the α-helix integrity, although this is not observed in the simulations. While the simulations do not show large-scale effects, the residue swap could have a substantial impact on the protein structure due to the fundamental role of hydrophobic packing during protein folding. | |||||||||||
| c.1529T>G | I510S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I510S is listed in ClinVar as Pathogenic (ClinVar ID 449946.0) and is not reported in gnomAD. Prediction tools that assess the variant’s effect all converge on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate pathogenicity. No tool predicts a benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized is uncertain, SGM‑Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -11.661 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 0.926 | Likely Pathogenic | 4.00 | Destabilizing | 0.1 | 3.78 | Destabilizing | 3.89 | Destabilizing | 2.34 | Destabilizing | -4.63 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.44 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -1 | -2 | -5.3 | -26.08 | 201.4 | 45.9 | -0.4 | 0.2 | 0.0 | 0.3 | X | Potentially Pathogenic | Ile510 is located in the middle of an α-helix (res. Gly502-Tyr518) within the inter-helix space of three helices (res. Gly502-Tyr518, Ala533-Val560, and res. Glu582-Met603). In the WT simulations, the sec-butyl side chain of Ile510 hydrophobically packs with other residues in the inter-helix space (e.g., Leu506, Leu610, Ile514, Ile602, Leu598). In the variant simulations, the hydroxyl group of Ser510 forms a hydrogen bond with the backbone atoms of Leu506 and Gly511 in the same α-helix, which could further weaken the α-helix integrity. This α-helix already shows weakness in the WT simulations due to Gly511. Although the simulations do not show large-scale effects, the residue swap could have a substantial impact due to the fundamental role of hydrophobic packing during protein folding. | |||||||||||
| c.1789T>C | F597L 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant F597L is listed in ClinVar with an uncertain significance (ClinVar ID 3658115.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include only SIFT, whereas the remaining tools—SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. The high‑accuracy AlphaMissense‑Optimized score is 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, is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for F597L, 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 | Uncertain | 1 | -10.173 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.929 | Likely Pathogenic | 0.74 | Ambiguous | 0.1 | 2.12 | Destabilizing | 1.43 | Ambiguous | 1.20 | Destabilizing | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -2.06 | Pathogenic | 0.13 | Tolerated | 2 | 0 | 1.0 | -34.02 | ||||||||||||||||||||||
| c.1763T>C | L588P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L588P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset 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. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Uncertain | 1 | -14.771 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.932 | Likely Pathogenic | 5.61 | Destabilizing | 0.5 | 12.91 | Destabilizing | 9.26 | Destabilizing | 2.33 | Destabilizing | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.42 | Pathogenic | 0.00 | Affected | 3.38 | 34 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||
| c.1763T>A | L588H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L588H is listed in ClinVar (ID 422233.0) as Pathogenic and is not reported in gnomAD. All available in silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -16.947 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.939 | Likely Pathogenic | 4.20 | Destabilizing | 0.2 | 3.69 | Destabilizing | 3.95 | Destabilizing | 2.26 | Destabilizing | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.42 | Pathogenic | 0.00 | Affected | 3.38 | 34 | -2 | -3 | -7.0 | 23.98 | 214.3 | 20.9 | 0.0 | 0.0 | 0.0 | 0.2 | X | X | X | Potentially Pathogenic | The isobutyl group of the Leu588 side chain, located in an α helix (res. Glu582-Met603), packs against hydrophobic residues in the inter-helix hydrophobic space (e.g., Ile584, Trp572, Phe484, Met470, Val473, Ile483).In the variant simulations, the imidazole ring of His588 is aromatic but contains polar delta and epsilon nitrogen atoms that are not suited for the hydrophobic niche. The protonated epsilon nitrogen forms a hydrogen bond with the backbone carbonyl group of Ala469, which can disrupt the continuity of the opposing α helix (res. Phe476-Lys460).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.1466T>C | L489P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All evaluated in‑silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Overall, the variant is most likely pathogenic based on the consensus of predictive tools, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Conflicting | 2 | -13.520 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.939 | Likely Pathogenic | 2.50 | Destabilizing | 0.1 | 4.69 | Destabilizing | 3.60 | Destabilizing | 1.73 | Destabilizing | -6.74 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.56 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -3 | -3 | -5.4 | -16.04 | 209.9 | 61.9 | 0.1 | 0.0 | 0.6 | 0.1 | X | Potentially Pathogenic | The iso-butyl side chain of Leu489, located in the α-helix (res. Leu489-Glu519) within an inter-helix space of four helices (res. Ala461-Phe476, res. Val441-Ser457, and res. Met414-Glu436), packs with hydrophobic residues (e.g., Cys432, Ala448, Lys444, Ala493, Val447, Met468). In the variant simulations, Pro489 is located near the beginning of the α-helix, so the residue swap with Leu489 does not affect the continuity of the secondary structure element. However, the side chain of proline is not as optimal as that of leucine for maintaining hydrophobic packing with nearby residues (e.g., Ala448, Lys444). Additionally, the consistently maintained hydrogen bond interaction between the backbone amide group of Leu489 and the carbonyl of Glu436 is lost due to the residue swap, potentially affecting the tertiary structure integrity. | |||||||||||
| c.1652T>C | L551P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L551P (ClinVar ID 547942.0) is classified as Pathogenic in ClinVar and is not reported in gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign outcome. High‑accuracy assessments 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 stability predictions, is Pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | Likely Pathogenic | 1 | -14.620 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.953 | Likely Pathogenic | 6.66 | Destabilizing | 0.1 | 6.58 | Destabilizing | 6.62 | Destabilizing | 2.66 | Destabilizing | -4.70 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.60 | Pathogenic | 0.01 | Affected | 3.37 | 35 | -3 | -3 | -5.4 | -16.04 | 208.6 | 60.9 | 0.1 | 0.0 | -0.3 | 0.0 | X | Potentially Pathogenic | L551 is located on an α-helix (res. Ala533-Val560). The iso-butyl side chain of Leu551 hydrophobically packs with nearby hydrophobic residues such as Cys547, Phe652, Leu633, and Ile630 in the inter-helix space. In the variant simulations, the pyrrolidine side chain of Pro551 is not as optimal as leucine for hydrophobic packing with the nearby residues. Moreover, Pro551 lacks the amide group, and thus, it cannot form a hydrogen bond with the backbone carbonyl group of Cys547, which disrupts the continuity of the secondary structure element. | |||||||||||
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