R859Q

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

Arginine → Glutamine at position 859 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Arginine → Glutamine at position 859 in lumenal C-terminal region. ClinVar Conflicting including optic atrophy + DFNA6. AlphaMissense 0.11 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.22. pLDDT 56 borderline.

Interactive 3D Structure

Wild-type reference

Wild-type R859 — hydrogen bond to C847

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DynaMut2 mutant · R859Q

Mutant Q859 — polar contact to C847 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost1 gained3 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	S846	S846	Preserved
Hydrogen bond	C847	C847	Preserved
Polar contact	S846	—	Lost
Polar contact	C847	—	Lost
Polar contact	T857	T857	Preserved
Van der Waals	A852	—	Lost
Van der Waals	—	T857	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

0.22kcal/mol

Stabilising — mild

AlphaMissense

0.106

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 conditionsWFS1-related disorder; Optic atrophy; Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

InheritanceMulti-phenotype AD.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0027%

cDNA changec.2576G>A

ClinVar accessionVCV000004529

Last evaluated2026/02/01 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 859 in lumenal C-terminus. Neighbors: HIS860 (2.4 Å), ARG858 (2.5 Å — adjacent existing arginine), THR857 (4.1 Å).

R859Q charge loss in R858-R859 adjacent arginine cluster. AM 0.11 under-call; optic atrophy + DFNA6 confirm.

Amino-acid chemistry

Arginine (R) → Glutamine (Q) — long positively-charged amine replaced by neutral polar amide.

Position in the protein

C-terminal lumenal domain · position 859 (pLDDT 56 borderline).

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted (AM under-call, pLDDT borderline). ΔΔG +0.22. AlphaMissense 0.11 below threshold but optic atrophy + DFNA6 confirm.

Mechanism: charge loss from R858-R859 cluster. Therapeutic: C-terminal microregion.

Why this matters

R859Q joins the C-terminal cluster — connecting the K843-V861 region with 859-868.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the R859Q 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 R859Q PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal

Natural variant859–859 · in DFNA6; dbSNP:rs121912618