M632I

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Methionine → Isoleucine at position 632 · TM10 (632-652), helical transmembrane · WFS1 (Wolframin)

Met→Ile p632 TM10 AM=0.10 ddg=-0.44 pLDDT=74. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type M632 — hydrogen bond to I636

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DynaMut2 mutant · M632I

Mutant I632 — hydrogen bond to L635 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost4 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	R629	R629	Preserved
Hydrogen bond	L635	L635	Preserved
Hydrogen bond	I636	I636	Preserved
Polar contact	S626	S626	Preserved
Polar contact	R629	R629	Preserved
Polar contact	S630	S630	Preserved
Polar contact	K634	—	Lost
Polar contact	L635	L635	Preserved
Polar contact	I636	I636	Preserved
Van der Waals	S626	—	Lost
Van der Waals	S630	S630	Preserved
Van der Waals	K634	K634	Preserved
Van der Waals	L635	—	Lost
Van der Waals	—	I636	Gained
Hydrophobic	—	L627	Gained
Hydrophobic	—	R629	Gained
Hydrophobic	L635	—	Lost
Hydrophobic	—	I636	Gained

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

-0.44kcal/mol

Destabilising — mild

AlphaMissense

0.101

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 0.00043%

cDNA changec.1896G>T

ClinVar accessionVCV000393390

Last evaluated2025/10/13 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: SER631 (2.5 Å), VAL633 (2.5 Å), ARG629 (3.7 Å — R629W/Q neighbors!). TM10 start, adjacent to R629 multi-variant region. The Atlas's neighbor extraction surfaces this variant's contacts.

Amino-acid chemistry

methionine chemistry lost

Position in the protein

TM10 (632-652)

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

TM10 start adjacent to R629 cluster.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the M632I 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 M632I PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane632–652 · Helical