E680Q
Category 4 — Stable Fold, Function DisruptedLikely pathogenicLumenal · predictedσ-1 candidateEditorialGlutamate → Glutamine at position 680 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic, optic atrophy. AlphaMissense 0.321 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.12 kcal/mol — essentially neutral. Conservative charge-to-amide swap.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | R676 | R676 | Preserved |
| Polar contact | R676 | R676 | Preserved |
| Van der Waals | R676 | R676 | 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
Clinical Evidence
Observed at very low frequency in gnomAD.
Structural Context
Position 680 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places E680 within 5 Å of THR681 (2.5 Å), LYS679 (2.5 Å — likely salt-bridge partner), ALA677 (4.0 Å), ARG676 (4.1 Å — second nearby basic), and TRP678 (4.7 Å).
The wild-type glutamate likely forms a salt bridge with K679 and contributes to the local electrostatic surface that includes R676 nearby. Replacing E680 with glutamine eliminates the negative charge while preserving similar volume and H-bonding capacity.
The |ΔΔG| of essentially zero (+0.12) indicates fold accommodates the conservative swap. AlphaMissense's 0.321 is below threshold — AM under-call. ClinVar Pathogenic + optic atrophy confirm clinical relevance.
Druggability Assessment
Mechanism is loss of E680-K679 salt bridge. Therapeutic strategy: site-directed at the K679 microregion.
Why this matters
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