E202G

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.