E680A
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialGlutamate → Alanine at position 680 in lumenal domain. ClinVar Conflicting including monogenic diabetes + Wolfram. AlphaMissense 0.34 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.23 kcal/mol. Same position as E680Q — second substitution at 680.
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 Conflicting classifications of pathogenicity for WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296). 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.
- WFS1-related diabetesautosomal dominantsubmitted as: Monogenic diabetes
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1; Wolfram syndrome 1
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, 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: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in African / African American: AF 0.180% (135 of 75,052 alleles), 19.2x the global figure. The global AF describes the general population, not the at-risk group.
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. |
|---|---|---|---|---|
| African / African American | 0.180% | 135 / 75,052 | 0 | ~1 in 280 |
| Middle Eastern · under-sampled | 0.016% | 1 / 6,062 | 0 | — |
| Remaining individuals | 0.014% | 9 / 62,498 | 0 | ~1 in 3470 |
| East Asian · under-sampled | 0.0022% | 1 / 44,872 | 0 | — |
| South Asian | 0.0022% | 2 / 91,076 | 0 | ~1 in 22770 |
| Admixed American · under-sampled | 0.0017% | 1 / 60,036 | 0 | — |
| European (non-Finnish) | 0.00017% | 2 / 1,179,984 | 0 | ~1 in 295000 |
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 same neighbors as E680Q: THR681 (2.5 Å), LYS679 (2.5 Å — wild-type salt-bridge partner), ALA677 (4.0 Å), ARG676 (4.1 Å — second nearby basic). E680A is more drastic than E680Q — eliminates the charge AND removes the side chain (compared to E680Q which kept H-bonding capacity through the amide).
The E680-K679 salt bridge is lost entirely. The R676 nearby basic loses its electrostatic counterpart through this position. AlphaMissense's 0.34 is below threshold (AM under-call); monogenic diabetes + Wolfram confirm pathogenicity.
Druggability Assessment
Mechanism: complete loss of E680-K679 salt bridge plus side-chain volume reduction. Therapeutic strategy: same K679 microregion as E680Q.
Why this matters
Feed this card to Wolfram Intelligence
Download the E680A 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.