V601M

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Valine → Methionine at position 601 · TM9 (589-609), helical transmembrane · WFS1 (Wolframin)

Val→Met p601 TM9 AM=0.07 ddg=-0.14 pLDDT=75. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type V601 — hydrogen bond to I597

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DynaMut2 mutant · V601M

Mutant M601 — polar contact to I597 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost2 gained5 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	I597	I597	Preserved
Hydrogen bond	—	A598	Gained
Hydrogen bond	S605	S605	Preserved
Polar contact	I597	I597	Preserved
Polar contact	—	A598	Gained
Polar contact	C604	—	Lost
Polar contact	S605	S605	Preserved
Van der Waals	I597	I597	Preserved
Van der Waals	S605	—	Lost
Hydrophobic	I597	—	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

-0.14kcal/mol

Destabilising — mild

AlphaMissense

0.069

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 0.0032%

cDNA changec.1801G>A

ClinVar accessionVCV000215363

Last evaluated2025/11/19 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: ALA602 (2.5 Å), THR600 (2.5 Å), ILE597 (3.8 Å — A598T region). TM9 cluster. The Atlas's neighbor extraction surfaces this variant's contacts and connects them to the broader multi-variant target landscape.

Amino-acid chemistry

methionine chemistry

Position in the protein

TM9 (589-609)

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

TM9 multi-variant cluster.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the V601M 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 V601M PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane589–609 · Helical