A243V

Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorial

Alanine → Valine at position 243 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)

Alanine → Valine at position 243 in N-terminal cytoplasmic domain. ClinVar Conflicting including monogenic diabetes. AlphaMissense 0.27 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.93.

Interactive 3D Structure

Wild-type reference

Wild-type A243 — hydrogen bond to D246

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DynaMut2 mutant · A243V

Mutant V243 — hydrogen bond to D246 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost2 gained5 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	D246	D246	Preserved
Hydrogen bond	F247	F247	Preserved
Polar contact	D245	—	Lost
Polar contact	D246	D246	Preserved
Polar contact	F247	F247	Preserved
Van der Waals	D245	—	Lost
Van der Waals	—	F247	Gained
Hydrophobic	Q194	Q194	Preserved
Hydrophobic	—	D246	Gained

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

-0.93kcal/mol

Destabilising — mild

AlphaMissense

0.269

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 conditionsMonogenic diabetes; Inborn genetic diseases

InheritanceMonogenic diabetes.

Population frequency (gnomAD v4)Low frequency · AF 0.040%

cDNA changec.728C>T

ClinVar accessionVCV000215381

Last evaluated2025/11/16 00:00

Observed in the general population.

Structural Context

Position 243 in cytoplasmic domain. Neighbors: LEU244 (2.5 Å), ILE242 (2.5 Å), LYS193 (4.0 Å — long-range contact!). The K193 long-range contact suggests A243 sits in a structural element bringing distant sequence positions into contact.

|ΔΔG| 0.93 substantial for conservative substitution. AM 0.27 under-call; monogenic diabetes confirms pathogenicity.

Amino-acid chemistry

Alanine (A) → Valine (V) — small replaced by branched aliphatic. Conservative volume increase.

Position in the protein

N-terminal cytoplasmic domain · position 243 (pLDDT 86).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| 0.93. AlphaMissense 0.27 below threshold but monogenic diabetes confirms pathogenicity.

Mechanism: volume mismatch perturbing K193 long-range contact. Therapeutic: site-directed at the 193-243 cross-fold geometry.

Why this matters

A243V demonstrates a long-range 50-residue contact (K193). The Atlas's neighbor analysis surfaces these cross-domain interactions.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the A243V 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 A243V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Region1–321 · Interaction with ATP6V1A