M657L

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

Methionine → Leucine at position 657 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Methionine → Leucine at position 657 in lumenal domain. ClinVar Conflicting. AlphaMissense 0.15 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.29. pLDDT 52 borderline.

Interactive 3D Structure

Wild-type reference

Wild-type M657 — hydrogen bond to S654

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DynaMut2 mutant · M657L

Mutant L657 — hydrogen bond contact to V659 lost

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Bond changes · DynaMut2 interaction analysis

0 lost2 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	S654	S654	Preserved
Hydrogen bond	V659	V659	Preserved
Hydrogen bond	—	E830	Gained
Polar contact	S654	S654	Preserved
Polar contact	E655	E655	Preserved
Polar contact	V659	V659	Preserved
Carbonyl	E655	E655	Preserved
Van der Waals	S654	S654	Preserved
Van der Waals	E655	E655	Preserved
Hydrophobic	—	V659	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

0.29kcal/mol

Stabilising — mild

AlphaMissense

0.148

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)

InheritanceNot specified.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0016%

cDNA changec.1969A>T

ClinVar accessionVCV001673814

Last evaluated2025/07/15 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 657 at lumenal domain start. Neighbors: LYS658 (2.5 Å), GLY656 (2.5 Å), SER654 (3.8 Å). Borderline confidence region.

M657L loses methionine-specific chemistry (oxidative regulation, S-mediated contacts). AM 0.15 under-call; Conflicting evidence.

Amino-acid chemistry

Methionine (M) → Leucine (L) — flexible sulfur-containing hydrophobic replaced by branched aliphatic. Loss of methionine-specific chemistry.

Position in the protein

C-terminal lumenal domain · position 657 (pLDDT 52 borderline).

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted (AM under-call, pLDDT borderline). ΔΔG +0.29. AlphaMissense 0.15 below threshold.

Mechanism: lost methionine-specific chemistry. Therapeutic: wet-lab validation recommended.

Why this matters

M657L sits at pLDDT 52 borderline — Atlas flags for caution.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the M657L 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 M657L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal