V875M

Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorial

Valine → Methionine at position 875 · TM11 (870-890), helical transmembrane · WFS1 (Wolframin)

Val→Met p875 TM11 AM=0.08 ddg=-0.11 pLDDT=82. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type V875 — hydrogen bond to F879

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DynaMut2 mutant · V875M

Mutant M875 — hydrogen bond contact to V871 lost

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Bond changes · DynaMut2 interaction analysis

1 lost0 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	V871	V871	Preserved
Hydrogen bond	H872	H872	Preserved
Hydrogen bond	A878	A878	Preserved
Hydrogen bond	F879	F879	Preserved
Polar contact	V871	V871	Preserved
Polar contact	H872	H872	Preserved
Polar contact	A878	A878	Preserved
Polar contact	F879	F879	Preserved
Hydrophobic	F417	—	Lost
Hydrophobic	V871	V871	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

-0.11kcal/mol

Destabilising — mild

AlphaMissense

0.084

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 0.0029%

cDNA changec.2623G>A

ClinVar accessionVCV000259899

Last evaluated2026/01/26 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: LYS876 (2.5 Å — K876T!), ALA874 (2.5 Å — A874T!), HIS872 (3.8 Å — V871G region). TM11 dense 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

TM11 (870-890)

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

TM11 cluster (now 7+ converging variants).

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the V875M 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 V875M PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane870–890 · Helical