A150V

Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorial

Alanine → Valine at position 150 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)

Alanine → Valine at position 150 in N-terminal cytoplasmic domain. ClinVar Conflicting including T2D. AlphaMissense 0.13 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.94 (substantial).

Interactive 3D Structure

Wild-type reference

Wild-type A150 — hydrogen bond to R146

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DynaMut2 mutant · A150V

Mutant V150 — hydrogen bond contact to R147 lost

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Bond changes · DynaMut2 interaction analysis

1 lost1 gained5 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	R146	R146	Preserved
Hydrogen bond	R147	R147	Preserved
Hydrogen bond	—	R152	Gained
Polar contact	R146	R146	Preserved
Polar contact	R147	R147	Preserved
Polar contact	R152	R152	Preserved
Van der Waals	R152	—	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

-0.94kcal/mol

Destabilising — mild

AlphaMissense

0.131

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 conditionsType 2 diabetes mellitus

InheritanceT2D.

Population frequency (gnomAD v4)Low frequency · AF 0.013%

cDNA changec.449C>T

ClinVar accessionVCV000178585

Last evaluated2025/11/23 00:00

Observed in the general population.

Structural Context

Position 150 in N-term. Neighbors: ASP151 (2.4 Å), LEU149 (2.5 Å), ARG147 (3.8 Å — same R147 as R146C cluster region).

A150V volume mismatch near R146-R147 cluster. |ΔΔG| 0.94; AM 0.13 under-call; T2D confirms.

Amino-acid chemistry

Alanine (A) → Valine (V) — small methyl replaced by branched aliphatic.

Position in the protein

N-terminal cytoplasmic domain · position 150 (pLDDT 91).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| 0.94. AlphaMissense 0.13 below threshold but T2D + substantial ΔΔG confirm pathogenicity.

Mechanism: volume mismatch near R146/R147 cluster. Therapeutic: same 146-150 cytoplasmic microregion.

Why this matters

A150V joins R146C and R138C in the 138-150 cytoplasmic cluster.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the A150V 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 A150V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Region1–321 · Interaction with ATP6V1A