M474L

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Methionine → Leucine at position 474 · TM5 (465-485), helical transmembrane · WFS1 (Wolframin)

Met→Leu p474 TM5 AM=0.07 ddg=-0.21 pLDDT=65. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type M474 — hydrogen bond to L470

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DynaMut2 mutant · M474L

Mutant L474 — hydrogen bond contact to L471 lost

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Bond changes · DynaMut2 interaction analysis

0 lost0 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L470	L470	Preserved
Hydrogen bond	L471	L471	Preserved
Polar contact	L470	L470	Preserved
Polar contact	L476	L476	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

-0.21kcal/mol

Destabilising — mild

AlphaMissense

0.068

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 0.00019%

cDNA changec.1420A>C

ClinVar accessionVCV003590694

Last evaluated2024/12/20 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: SER473 (2.5 Å — partner of S469L region), PRO475 (2.5 Å), LEU471 (4.1 Å). Second TM5 variant. 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 lost

Position in the protein

TM5 (465-485)

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

TM5 cluster (with S469L).

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the M474L 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 M474L PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane465–485 · Helical