R703C

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

Arginine → Cysteine at position 703 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Arginine → Cysteine at position 703 in lumenal domain. ClinVar Conflicting including Cataract 41 + Wolfram + DFNA6. AlphaMissense 0.471 (below threshold), ΔΔG +0.02. AM under-call with multi-phenotype.

Interactive 3D Structure

Wild-type reference

Wild-type R703 — ionic bond to E795

Fullscreen ↗

DynaMut2 mutant · R703C

Mutant C703 — ionic bond to E795 lost (6 contacts lost)

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

6 lost1 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	E795	—	Lost
Hydrogen bond	V779	—	Lost
Hydrogen bond	G780	G780	Preserved
Hydrogen bond	E795	—	Lost
Hydrogen bond	S821	S821	Preserved
Polar contact	K705	K705	Preserved
Polar contact	G780	G780	Preserved
Polar contact	E795	—	Lost
Polar contact	S821	S821	Preserved
Carbonyl	S821	S821	Preserved
Van der Waals	E795	—	Lost
Van der Waals	—	S821	Gained
Hydrophobic	L822	—	Lost

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

0.02kcal/mol

Stabilising — mild

AlphaMissense

0.471

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 conditionsCataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

InheritanceMulti-phenotype AD.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0061%

cDNA changec.2107C>T

ClinVar accessionVCV001299576

Last evaluated2025/12/15 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 703 in lumenal domain near R708 region. Neighbors: PHE704 (2.4 Å — partner of V707F), GLY702 (2.5 Å — G702S!), SER821 (3.4 Å — long-range), GLY780 (3.6 Å — near V779/D801 region).

R703C sits in the dense 702-708 cluster (with G702S, F704, V707F, R708L, R708C). Loss of R703 charge + thiol introduction. ΔΔG essentially neutral; AM 0.471 below threshold; multi-phenotype confirms pathogenicity.

Amino-acid chemistry

Arginine (R) → Cysteine (C) — charge loss + thiol introduction.

Position in the protein

C-terminal lumenal domain · position 703 (pLDDT 89).

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted (AM under-call). ΔΔG ≈ 0. AlphaMissense 0.471 below threshold but three documented phenotypes confirm pathogenicity.

Mechanism: charge loss + thiol in the dense 702-708 cluster. Therapeutic: same multi-variant cluster.

Why this matters

R703C extends the 702-708 multi-variant cluster — six Atlas variants now converge here.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the R703C 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 R703C PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal

Natural variant703–703 · in DFNA6; dbSNP:rs1323852277