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
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 Likely pathogenic for Optic atrophy / optic neuropathy (autosomal dominant). These are dominant WFS1-related disorders and are clinically distinct from classic recessive Wolfram syndrome. This classification is not a statement about Wolfram syndrome severity.
- Optic atrophy / optic neuropathyautosomal dominantsubmitted as: Optic atrophy
- No assertion criteria were provided (0★). Treat the conditions above as unverified submissions, not as documented phenotypes.
- 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: 0★ no assertion criteria provided. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.00045% (5 of 1,111,970 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) | 0.00045% | 5 / 1,111,970 | 0 | ~1 in 111200 |
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
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
Feed this card to Wolfram Intelligence
Download the E680Q 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.