R676H

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

Arginine → Histidine at position 676 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Arginine → Histidine at position 676 in lumenal domain. ClinVar Conflicting including DFNA6. AlphaMissense 0.12 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.54.

Interactive 3D Structure

Wild-type reference

Wild-type R676 — hydrogen bond to E680

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DynaMut2 mutant · R676H

Mutant H676 — van der waals to E680 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost0 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	K679	K679	Preserved
Hydrogen bond	E680	E680	Preserved
Polar contact	G674	G674	Preserved
Polar contact	W678	W678	Preserved
Polar contact	K679	K679	Preserved
Polar contact	E680	E680	Preserved
Van der Waals	W678	W678	Preserved
Van der Waals	K679	—	Lost
Van der Waals	E680	—	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

-0.54kcal/mol

Destabilising — mild

AlphaMissense

0.122

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 conditionsAutosomal dominant nonsyndromic hearing loss 6 (DFNA6)

InheritanceDFNA6.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0043%

cDNA changec.2027G>A

ClinVar accessionVCV000426907

Last evaluated2025/09/07 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 676 in lumenal domain. Neighbors: ALA677 (2.5 Å), PRO675 (2.5 Å — adjacent to G674 cluster!), GLY674 (4.0 Å — G674 multi-variant position!).

R676H sits in the dense G674 cluster region. |ΔΔG| 0.54; AM 0.12 under-call; DFNA6 confirms.

Amino-acid chemistry

Arginine (R) → Histidine (H) — charge partial-reduction.

Position in the protein

C-terminal lumenal domain · position 676 (pLDDT 81).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| 0.54. AlphaMissense 0.12 below threshold but DFNA6 confirms.

Mechanism: partial charge loss adjacent to G674 cluster. Therapeutic: same G674-R676 microregion.

Why this matters

R676H extends the G674 cluster region — now 5+ variants converge on position 674 ± neighbors.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the R676H 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 R676H PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal