R685C

Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorial

Arginine → Cysteine at position 685 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Arginine → Cysteine at position 685. ClinVar Conflicting including monogenic diabetes + DFNA6. AlphaMissense 0.581, ΔΔG +0.10. Same position as R685P (Atlas card). R→C class with disulfide-pair partner CYS673 visible nearby in the broader region.

Interactive 3D Structure

Wild-type reference

Wild-type R685 — hydrogen bond to L689

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DynaMut2 mutant · R685C

Mutant C685 — energy-minimized; 2 new contacts formed

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Bond changes · DynaMut2 interaction analysis

0 lost2 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	N682	N682	Preserved
Hydrogen bond	I688	I688	Preserved
Hydrogen bond	L689	L689	Preserved
Polar contact	N682	N682	Preserved
Polar contact	M683	M683	Preserved
Polar contact	I688	I688	Preserved
Polar contact	L689	L689	Preserved
Van der Waals	—	N682	Gained
Van der Waals	M683	M683	Preserved
Hydrophobic	—	N682	Gained

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

0.10kcal/mol

Stabilising — mild

AlphaMissense

0.581

LPath

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditionsMonogenic diabetes; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

InheritanceMonogenic diabetes + DFNA6.

Population frequency (gnomAD v4)Low frequency · AF 0.018%

cDNA changec.2053C>T

ClinVar accessionVCV000393391

Last evaluated2026/02/17 00:00

Observed in the general population.

Structural Context

Position 685 same neighbors as R685P: THR686 (2.5 Å), ALA684 (2.5 Å — A684T/V/G cluster), ASN682 (3.5 Å), MET683 (4.3 Å), GLN687 (4.4 Å — Q687H).

R685C is a second pathogenic substitution at 685. Where R685P removed charge + introduced backbone kink, R685C removes charge + introduces free thiol. The new C685 sits in the dense 684-688 cluster — its thiol could engage in disulfide chemistry with other lumenal cysteines.

ΔΔG essentially neutral; AM 0.581 borderline + monogenic diabetes + DFNA6 confirm severe consequence.

Amino-acid chemistry

Arginine (R) → Cysteine (C) — long positively-charged guanidinium replaced by thiol.

Position in the protein

C-terminal lumenal domain · position 685 (pLDDT 90). Same as R685P.

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted. ΔΔG ≈ 0. AlphaMissense 0.581 borderline + multi-phenotype confirm pathogenicity.

Mechanism: charge loss + free thiol introduction in dense 684-688 cluster. Therapeutic: same cluster target.

Why this matters

R685C is the FIFTH variant at position 685's microregion (R685P, R685C, A684T/V/G, Q687H). Densest multi-substitution hub in the Atlas.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the R685C 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 R685C PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal

Natural variant685–685 · in DFNA6; dbSNP:rs142668478