V779M

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

Valine → Methionine at position 779 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Valine → Methionine at position 779 in lumenal domain. ClinVar Conflicting including monogenic diabetes. AlphaMissense 0.399 (below threshold), ΔΔG -0.19. Same position as V779G (Cat 2 outlier)!

Interactive 3D Structure

Wild-type reference

Wild-type V779 — hydrogen bond to I802

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DynaMut2 mutant · V779M

Mutant M779 — hydrogen bond to R703 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost6 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	R703	—	Lost
Hydrogen bond	D801	—	Lost
Hydrogen bond	I802	I802	Preserved
Hydrogen bond	—	I823	Gained
Polar contact	D801	D801	Preserved
Polar contact	I802	I802	Preserved
Polar contact	—	I823	Gained
Carbonyl	—	D801	Gained
Van der Waals	G702	—	Lost
Van der Waals	—	D801	Gained
Van der Waals	—	L804	Gained
Hydrophobic	I777	I777	Preserved
Hydrophobic	M781	M781	Preserved
Hydrophobic	—	I802	Gained
Hydrophobic	L804	L804	Preserved
Hydrophobic	I823	I823	Preserved
Hydrophobic	F825	F825	Preserved

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

-0.19kcal/mol

Destabilising — mild

AlphaMissense

0.399

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 conditionsWFS1-Related Spectrum Disorders; Monogenic diabetes

InheritanceMulti-phenotype.

Population frequency (gnomAD v4)Low frequency · AF 0.152%

cDNA changec.2335G>A

ClinVar accessionVCV000045453

Last evaluated2026/01/27 00:00

Observed in the general population.

Structural Context

Position 779 same neighbors as V779G: GLY780 (2.4 Å), THR778 (2.5 Å), ARG703 (3.6 Å — R703C!), ILE802 (3.8 Å — I802T!).

V779M is the second pathogenic substitution at the V779 Cat 2 outlier position (with V779G). Where V779G eliminated the side chain entirely (Cat 2), V779M is conservative hydrophobic-to-hydrophobic — fold accommodates more easily (|ΔΔG| 0.19).

AM 0.399 below threshold; multi-phenotype confirms pathogenicity. V779 is structurally critical regardless of substitution.

Amino-acid chemistry

Valine (V) → Methionine (M) — branched aliphatic replaced by flexible sulfur-containing hydrophobic.

Position in the protein

C-terminal lumenal domain · position 779 (pLDDT 90). Same as V779G.

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| 0.19. AlphaMissense 0.399 below threshold.

Mechanism: subtle hydrophobic chemistry shift at V779 outlier position. Therapeutic: same V779 microregion as V779G.

Why this matters

V779M + V779G at the Atlas's most-discussed Cat 2 outlier position. Two variants demonstrate V779's structural importance regardless of substitution chemistry.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the V779M 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 V779M PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal

Natural variant779–779 · in DFNA6; benign; dbSNP:rs141328044