M731V

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

Methionine → Valine at position 731 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Met→Val p731 lumenal AM=0.11 ddg=-0.86 pLDDT=85. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type M731 — hydrogen bond to Y735

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DynaMut2 mutant · M731V

Mutant V731 — hydrogen bond to G728 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost1 gained14 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	I727	I727	Preserved
Hydrogen bond	G728	—	Lost
Hydrogen bond	L734	L734	Preserved
Hydrogen bond	Y735	Y735	Preserved
Polar contact	I727	I727	Preserved
Polar contact	G728	G728	Preserved
Polar contact	D729	D729	Preserved
Polar contact	C733	C733	Preserved
Polar contact	L734	L734	Preserved
Polar contact	Y735	Y735	Preserved
Van der Waals	—	I720	Gained
Van der Waals	D729	—	Lost
Van der Waals	C733	C733	Preserved
Van der Waals	Y735	—	Lost
Hydrophobic	I720	I720	Preserved
Hydrophobic	L723	L723	Preserved
Hydrophobic	I727	I727	Preserved
Hydrophobic	L734	—	Lost
Hydrophobic	Y735	Y735	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

-0.86kcal/mol

Destabilising — mild

AlphaMissense

0.113

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 0.0052%

cDNA changec.2191A>G

ClinVar accessionVCV000374399

Last evaluated2025/05/04 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: TRP730 (2.5 Å), ARG732 (2.5 Å — R732C/H!), GLY728 (3.7 Å). Adjacent to R732 multi-variant position and C733-C765 disulfide region. The Atlas's neighbor extraction surfaces this variant's contacts.

Amino-acid chemistry

methionine chemistry lost

Position in the protein

C-terminal lumenal domain

Druggability Assessment

Cat 3/4 — 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

Adjacent to C733-C765 disulfide region.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the M731V 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 M731V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal