T749M

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

Threonine → Methionine at position 749 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Thr→Met p749 lumenal AM=0.09 ddg=+0.33 pLDDT=71. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type T749 — hydrogen bond to E753

Fullscreen ↗

DynaMut2 mutant · T749M

Mutant M749 — energy-minimized; 1 new contact formed

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

0 lost1 gained2 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	E753	E753	Preserved
Polar contact	—	E752	Gained
Polar contact	E753	E753	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

0.33kcal/mol

Stabilising — mild

AlphaMissense

0.093

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 0.0014%

cDNA changec.2246C>T

ClinVar accessionVCV000906718

Last evaluated2025/07/16 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: ALA750 (2.5 Å), SER748 (2.5 Å), THR747 (4.4 Å). Loss of H-bonding in polar microregion. The Atlas's neighbor extraction surfaces this variant's contacts.

Amino-acid chemistry

polar→hydrophobic switch

Position in the protein

C-terminal lumenal domain

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

Lumenal polar→hydrophobic switch.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the T749M 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 T749M PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal