A598T

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Alanine → Threonine at position 598 · TM9 (589-609), helical transmembrane · WFS1 (Wolframin)

Ala→Thr p598 TM9 AM=0.09 ddg=+0.12 pLDDT=69. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type A598 — hydrogen bond to L594

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DynaMut2 mutant · A598T

Mutant T598 — hydrogen bond contact to T595 lost

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Bond changes · DynaMut2 interaction analysis

0 lost0 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L594	L594	Preserved
Hydrogen bond	T595	T595	Preserved
Hydrogen bond	A602	A602	Preserved
Polar contact	L594	L594	Preserved
Polar contact	T595	T595	Preserved
Polar contact	A602	A602	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

0.12kcal/mol

Stabilising — mild

AlphaMissense

0.085

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)Low frequency · AF 0.015%

cDNA changec.1792G>A

ClinVar accessionVCV000178596

Last evaluated2025/12/20 00:00

Observed in the general population.

Structural Context

Position analysis: ILE597 (2.5 Å), VAL599 (2.5 Å), THR595 (3.9 Å — A598T-T595 H-bond possible). TM9 cluster (with L592V/P607L/R, E593D, V601M). The Atlas's neighbor extraction surfaces this variant's contacts.

Amino-acid chemistry

polarity into bilayer

Position in the protein

TM9 (589-609)

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

TM9 multi-variant cluster.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the A598T 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 A598T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane589–609 · Helical