A569V

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Alanine → Valine at position 569 · TM8 (563-583), helical transmembrane · WFS1 (Wolframin)

Alanine → Valine at position 569 inside TM8. ClinVar Conflicting including Wolfram-like + Cataract 41 + DFNA6. AlphaMissense 0.481 (below threshold), ΔΔG +0.02. AM under-call.

Interactive 3D Structure

Wild-type reference

Wild-type A569 — hydrogen bond to L565

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DynaMut2 mutant · A569V

Mutant V569 — energy-minimized; 1 new contact formed

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Bond changes · DynaMut2 interaction analysis

0 lost1 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L565	L565	Preserved
Hydrogen bond	I572	I572	Preserved
Hydrogen bond	L573	L573	Preserved
Polar contact	L565	L565	Preserved
Polar contact	I572	I572	Preserved
Polar contact	L573	L573	Preserved
Carbonyl	I572	I572	Preserved
Van der Waals	L565	L565	Preserved
Van der Waals	I572	I572	Preserved
Hydrophobic	L565	L565	Preserved
Hydrophobic	—	L573	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

0.02kcal/mol

Stabilising — mild

AlphaMissense

0.481

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 conditionsWolfram-like syndrome; Cataract 41; Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

InheritanceMulti-phenotype AD.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0076%

cDNA changec.1706C>T

ClinVar accessionVCV000504710

Last evaluated2025/12/24 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 569 in TM8. Neighbors: PHE568 (2.5 Å), LEU570 (2.5 Å), LEU565 (3.3 Å), ILE572 (4.2 Å). Hydrophobic TM environment.

A569V is a conservative volume increase. ΔΔG essentially neutral. AM 0.481 below threshold — under-call. Multi-phenotype (Wolfram-like + Cataract + DFNA6) confirms clinical pathogenicity.

Amino-acid chemistry

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

Position in the protein

TM8 (residues 563–583) · position 569 mid-helix (pLDDT 73).

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted (AM under-call). ΔΔG ≈ 0. AlphaMissense 0.481 below threshold but three documented phenotypes confirm pathogenicity.

Mechanism: subtle volume mismatch in TM8 hydrophobic packing. Therapeutic: TM8 site-directed.

Why this matters

A569V is the first TM8 variant at full v3 depth in the Atlas — new helix target identified.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the A569V 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 A569V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane563–583 · Helical