V288M

Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorial

Valine → Methionine at position 288 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)

Valine → Methionine at position 288 in N-terminal cytoplasmic domain. ClinVar Conflicting including DFNA6. AlphaMissense 0.13 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.23. Same position as V288G.

Interactive 3D Structure

Wild-type reference

Wild-type V288 — hydrogen bond to L284

Fullscreen ↗

DynaMut2 mutant · V288M

Mutant M288 — hydrogen bond contact to L284 lost

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

0 lost1 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L284	L284	Preserved
Polar contact	L284	L284	Preserved
Polar contact	—	P292	Gained
Van der Waals	L284	L284	Preserved
Hydrophobic	A295	A295	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

-0.23kcal/mol

Destabilising — mild

AlphaMissense

0.132

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 hearing loss.

Population frequency (gnomAD v4)Ultra-rare · AF 0.00062%

cDNA changec.862G>A

ClinVar accessionVCV000191322

Last evaluated2025/11/24 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 288 same neighbors as V288G: VAL289 (2.5 Å), LYS287 (2.5 Å), LEU284 (4.0 Å). Borderline pLDDT.

V288M is the second pathogenic substitution at 288 (with V288G). Conservative chemistry shift. AM 0.13 under-call; DFNA6 confirms.

Amino-acid chemistry

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

Position in the protein

N-terminal cytoplasmic domain · position 288 (pLDDT 58 borderline). Same as V288G.

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted (AM under-call, pLDDT borderline). |ΔΔG| 0.23. AlphaMissense 0.13 below threshold but DFNA6 confirms.

Mechanism: conservative chemistry shift in borderline-confidence region. Therapeutic: same target as V288G.

Why this matters

V288M + V288G at same position — borderline-region variants both pathogenic.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the V288M 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 V288M PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Region1–321 · Interaction with ATP6V1A