V839A

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

Valine → Alanine at position 839 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Valine → Alanine at position 839 in lumenal domain. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.398 (below threshold), ΔΔG -1.37 (substantial destabilising).

Interactive 3D Structure

Wild-type reference

Wild-type V839 — hydrogen bond to W837

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DynaMut2 mutant · V839A

Mutant A839 — hydrogen bond to W837 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost0 gained5 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	V803	V803	Preserved
Hydrogen bond	W837	—	Lost
Polar contact	V803	V803	Preserved
Polar contact	W837	W837	Preserved
Carbonyl	V803	V803	Preserved
Van der Waals	V803	V803	Preserved
Hydrophobic	V803	—	Lost
Hydrophobic	R805	—	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

-1.37kcal/mol

Destabilising — moderate

AlphaMissense

0.398

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 conditionsWolfram syndrome 1

InheritanceWolfram syndrome 1.

Population frequency (gnomAD v4)Ultra-rare · AF 0.00041%

cDNA changec.2516T>C

ClinVar accessionVCV000505203

Last evaluated2024/02/24 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 839 in lumenal domain. Neighbors: PHE840 (2.4 Å — partner of L842F, L829P regions), PRO838 (2.5 Å), VAL803 (3.3 Å — long-range; L804P region), TRP837 (4.3 Å).

Replacing V839 with alanine reduces side-chain volume substantially, creating a cavity. The V803 long-range contact through the fold geometry is perturbed. |ΔΔG| 1.37 reflects substantial fold cost. AM 0.398 below threshold; Wolfram 1 confirms pathogenicity.

Amino-acid chemistry

Valine (V) → Alanine (A) — branched aliphatic replaced by small methyl-bearing. Volume decrease.

Position in the protein

C-terminal lumenal domain · position 839 (pLDDT 88).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| 1.37 substantial. AlphaMissense 0.398 below threshold but Wolfram 1 + ΔΔG confirm pathogenicity.

Mechanism: hydrophobic cavity creation + V839-V803 long-range contact perturbation. Therapeutic: lumenal hub region (with L842F, L829P, L804P targets).

Why this matters

V839A joins the 829-844 lumenal cluster — multiple variants converge.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the V839A 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 V839A PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal