T590M

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Threonine → Methionine at position 590 · TM9 (589-609), helical transmembrane · WFS1 (Wolframin)

Thr→Met p590 TM9 AM=0.06 ddg=+0.09 pLDDT=73. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type T590 — hydrogen bond to R587

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DynaMut2 mutant · T590M

Mutant M590 — hydrogen bond contact to R587 lost

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Bond changes · DynaMut2 interaction analysis

1 lost1 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	A586	A586	Preserved
Hydrogen bond	R587	—	Lost
Polar contact	A586	A586	Preserved
Polar contact	R587	R587	Preserved
Polar contact	W588	W588	Preserved
Polar contact	—	L592	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

0.09kcal/mol

Stabilising — mild

AlphaMissense

0.063

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 0.0037%

cDNA changec.1769C>T

ClinVar accessionVCV000505398

Last evaluated2023/04/17 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position analysis: SER591 (2.5 Å), PHE589 (2.5 Å — TM9 start), ARG587 (3.8 Å — R587W/Q!). TM9 cluster + loop boundary. The Atlas's neighbor extraction surfaces this variant's contacts and connects them to the broader multi-variant target landscape.

Amino-acid chemistry

polar→hydrophobic

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 identified. Therapeutic strategy: site-directed at contacts identified above, or wet-lab validation if pLDDT borderline/below 50.

Why this matters

TM9 cluster + R587 loop boundary.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the T590M 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 T590M PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane589–609 · Helical