E202G
Category 4 — Stable Fold, Function DisruptedPathogenic/Likely pathogenicCytoplasmic · predictedEditorialGlutamate-to-glycine substitution in wolframin's N-terminal cytoplasmic ATP6V1A-interaction region — a low AlphaMissense score (0.283, Likely Benign) sits in tension with the ClinVar Pathogenic/Likely pathogenic classification, requiring careful interpretation.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | A198 | A198 | Preserved |
| Polar contact | A198 | A198 | Preserved |
| Polar contact | E199 | E199 | Preserved |
| Polar contact | V204 | V204 | Preserved |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Pathogenic/Likely pathogenic for Optic atrophy / optic neuropathy (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- Optic atrophy / optic neuropathyautosomal dominantsubmitted as: Optic atrophy
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 2★ multiple submitters, no conflicts. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.0056% (62 of 1,112,004 alleles), in line with the global figure.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| European (non-Finnish) | 0.0056% | 62 / 1,112,004 | 0 | ~1 in 8970 |
| Remaining individuals | 0.0033% | 2 / 60,390 | 0 | ~1 in 15100 |
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
Structural Context
E202 is held between Asn203 (2.46 Angstrom) and Leu201 (2.46 Angstrom) covalently, with through-space contacts to Ala198 (3.93 Angstrom), Glu199 (3.96 Angstrom), Val204 (4.36 Angstrom), and Leu200 (4.57 Angstrom). The local environment is mixed polar-aliphatic: two leucines, an alanine, a valine, an asparagine, and another glutamate (E199) within 4.5 Angstrom. The Glu199-Glu202 pair is interesting — two negatively charged carboxylates within 4 Angstrom likely participate in a coordinated electrostatic feature, either repelling each other to maintain extended conformation or both coordinating a divalent metal cation or a positively charged binding partner.
The E202G substitution removes the side chain entirely. Glycine introduces backbone freedom where the wild-type maintained a side-chain-rigidified conformation. The Glu199-Glu202 coordinated electrostatic feature is destroyed — only Glu199 remains. If the wild-type pair coordinated a cation or formed part of an ATP6V1A-binding salt-bridge interface, that functionality is now lost.
DynaMut2 reports DeltaDeltaG = -0.19 kcal/mol — essentially unchanged. AlphaMissense, however, scores E202G at 0.283 (Likely Benign by the AM classifier). This is a notable discordance with ClinVar's Pathogenic/Likely pathogenic classification. Three possible reconciliations: (a) the AM model under-weighs charge-removal mutations in surface-exposed regions; (b) ClinVar evidence for E202G derives from a small number of affected families and may include linkage to a separate causal variant; (c) the variant is genuinely a partial loss-of-function with subtle cellular consequences that AM does not detect.
The structural signature — a Glu pair at the ATP6V1A-binding interface, broken by removal of one Glu — is functionally plausible. The Atlas should flag E202G as a discordant-metric variant requiring careful clinical follow-up rather than confident druggability assignment.
Druggability Assessment
Why this matters
Feed this card to Wolfram Intelligence
Download the E202G PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.