M306T

Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorial

Methionine → Threonine at position 306 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)

Methionine → Threonine at position 306 in N-terminal cytoplasmic domain. ClinVar Conflicting including monogenic diabetes + WFS1 spectrum. AlphaMissense 0.14 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.03 (neutral).

Interactive 3D Structure

Wild-type reference

Wild-type M306 — hydrogen bond to Y302

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DynaMut2 mutant · M306T

Mutant T306 — hydrogen bond to L303 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost0 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	Y302	Y302	Preserved
Hydrogen bond	L303	—	Lost
Hydrogen bond	A310	A310	Preserved
Polar contact	Y302	Y302	Preserved
Polar contact	L303	L303	Preserved
Polar contact	I304	I304	Preserved
Polar contact	A310	A310	Preserved
Van der Waals	Y302	Y302	Preserved
Van der Waals	I304	I304	Preserved
Hydrophobic	Y302	—	Lost

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

-0.03kcal/mol

Destabilising — mild

AlphaMissense

0.144

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 conditionsMonogenic diabetes; WFS1-Related Spectrum Disorders

InheritanceMulti-phenotype.

Population frequency (gnomAD v4)Low frequency · AF 0.068%

cDNA changec.917T>C

ClinVar accessionVCV000167850

Last evaluated2026/01/27 00:00

Observed in the general population.

Structural Context

Position 306 near TM1 boundary. Neighbors: ASP305 (2.5 Å), ALA307 (2.5 Å — partner of S308C!), LEU303 (3.9 Å).

M306T near the S308C variant region. Loss of methionine-specific chemistry + introduced polarity. AM 0.14 under-call; multi-phenotype confirms.

Amino-acid chemistry

Methionine (M) → Threonine (T) — flexible sulfur-containing hydrophobic replaced by small polar hydroxyl.

Position in the protein

N-terminal cytoplasmic domain · position 306 near TM1 boundary (pLDDT 66).

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted (AM under-call). ΔΔG ≈ 0. AlphaMissense 0.14 below threshold but multi-phenotype confirms.

Mechanism: lost methionine chemistry near TM1 boundary. Therapeutic: same 305-308 microregion as S308C.

Why this matters

M306T + S308C in same TM1-boundary region.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the M306T 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 M306T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Region1–321 · Interaction with ATP6V1A