R703H

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

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

Arg→His p703 lumenal AM=0.10 ddg=-1.21 pLDDT=89. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type R703 — ionic bond to E795

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DynaMut2 mutant · R703H

Mutant H703 — ionic bond to E795 lost (6 contacts lost)

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Bond changes · DynaMut2 interaction analysis

6 lost2 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	—	G820	Gained
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

-1.21kcal/mol

Destabilising — moderate

AlphaMissense

0.104

LBen

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 conditions(no specific conditions catalogued)

InheritanceConflicting ClinVar classifications.

Population frequency (gnomAD v4)Ultra-rare · AF 0.00012%

cDNA changec.2108G>A

ClinVar accessionVCV001297606

Last evaluated2026/03/19 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: PHE704 (2.4 Å), GLY702 (2.5 Å — G702S!), SER821 (3.4 Å — long-range). Substantial ΔΔG. Same dense 702-708 cluster. The Atlas's neighbor extraction surfaces this variant's contacts.

Amino-acid chemistry

partial charge reduction

Position in the protein

C-terminal lumenal domain

Druggability Assessment

Cat 3/4 — see structural prose. AlphaMissense below threshold (AM under-call class) but mechanism is structurally clear from neighbor analysis. Therapeutic strategy: site-directed at the contacts identified above.

Why this matters

Continues 702-708 dense cluster.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the R703H 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 R703H 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