V258I

Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorial

Valine → Isoleucine at position 258 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)

Val→Ile p258 N-term AM=0.06 ddg=-0.39 pLDDT=71. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type V258 — hydrogen bond to K253

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DynaMut2 mutant · V258I

Mutant I258 — polar contact contact to K253 lost

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Bond changes · DynaMut2 interaction analysis

1 lost1 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	K253	K253	Preserved
Hydrogen bond	P260	P260	Preserved
Polar contact	K253	K253	Preserved
Carbonyl	—	K253	Gained
Hydrophobic	K253	K253	Preserved
Hydrophobic	K256	—	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

-0.39kcal/mol

Destabilising — mild

AlphaMissense

0.056

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 conditions(no specific conditions catalogued)

InheritanceConflicting ClinVar classifications.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0037%

cDNA changec.772G>A

ClinVar accessionVCV000732838

Last evaluated2025/06/26 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: ILE259 (2.4 Å), GLY257 (2.5 Å), LYS253 (3.5 Å — same K253 as K252E region). The Atlas's neighbor extraction surfaces this variant's contacts and connects them to the broader multi-variant target landscape.

Amino-acid chemistry

conservative branched-aliphatic

Position in the protein

N-terminal cytoplasmic domain

Druggability Assessment

Cat 4 — see structural prose. AlphaMissense below threshold (AM under-call class) but mechanism is structurally identified. Therapeutic strategy: site-directed at contacts identified above, or wet-lab validation if pLDDT borderline/below 50.

Why this matters

Adjacent to K252-K253 region.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the V258I 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 V258I PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Region1–321 · Interaction with ATP6V1A