E680A

Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorial

Glutamate → Alanine at position 680 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Glutamate → 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

Wild-type reference

Wild-type E680 — hydrogen bond to R676

Fullscreen ↗

DynaMut2 mutant · E680A

Mutant A680 — energy-minimized; local contact network preserved

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

0 lost0 gained3 preserved

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

DynaMut2 ΔΔG

-0.23kcal/mol

Destabilising — mild

AlphaMissense

0.342

Amb

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditionsMonogenic diabetes; Wolfram syndrome 1

InheritanceMulti-phenotype.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0094%

cDNA changec.2039A>C

ClinVar accessionVCV000286507

Last evaluated2026/01/30 00:00

Observed at very low frequency in gnomAD.

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.

Amino-acid chemistry

Glutamate (E) → Alanine (A) — small negatively-charged carboxylate replaced by small methyl-bearing hydrophobic. Charge lost + side chain reduced.

Position in the protein

C-terminal lumenal domain · position 680 (pLDDT 84).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| = 0.23. AlphaMissense 0.34 below threshold but monogenic diabetes + Wolfram confirm pathogenicity.

Mechanism: complete loss of E680-K679 salt bridge plus side-chain volume reduction. Therapeutic strategy: same K679 microregion as E680Q.

Why this matters

E680A + E680Q at same position — both pathogenic at the K679 salt-bridge partner site.

Therapeutic Strategy Handoff · prediction

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.

Download E680A PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal

Natural variant680–680 · in DFNA6; uncertain significance