V644L

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Valine → Leucine at position 644 · TM10 (632-652), helical transmembrane · WFS1 (Wolframin)

Val→Leu p644 TM10 AM=0.10 ddg=-0.35 pLDDT=82. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type V644 — hydrogen bond to L640

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DynaMut2 mutant · V644L

Mutant L644 — polar contact to L640 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost1 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L640	L640	Preserved
Hydrogen bond	—	T641	Gained
Hydrogen bond	C647	C647	Preserved
Hydrogen bond	W648	W648	Preserved
Polar contact	L640	L640	Preserved
Polar contact	T641	T641	Preserved
Polar contact	C647	C647	Preserved
Polar contact	W648	W648	Preserved
Van der Waals	L640	—	Lost
Van der Waals	W648	W648	Preserved
Hydrophobic	I349	—	Lost
Hydrophobic	F414	F414	Preserved

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

-0.35kcal/mol

Destabilising — mild

AlphaMissense

0.096

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 0.00037%

cDNA changec.1930G>T

ClinVar accessionVCV000215364

Last evaluated2025/07/06 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: ILE643 (2.5 Å), LEU645 (2.5 Å), LEU640 (3.7 Å). Conservative TM10 substitution. The Atlas's neighbor extraction surfaces this variant's contacts.

Amino-acid chemistry

conservative volume increase

Position in the protein

TM10 (632-652)

Druggability Assessment

Cat 4 — see structural prose. AlphaMissense below threshold (AM under-call class) but mechanism is structurally clear from neighbor analysis. Therapeutic strategy: site-directed at the contacts identified above.

Why this matters

TM10 conservative variant.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the V644L 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 V644L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane632–652 · Helical