E593D

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Glutamate → Aspartate at position 593 · TM9 (589-609), helical transmembrane · WFS1 (Wolframin)

Glu→Asp p593 TM9 AM=0.11 ddg=+0.03 pLDDT=70. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.

Interactive 3D Structure

Wild-type reference

Wild-type E593 — hydrogen bond to K596

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DynaMut2 mutant · E593D

Mutant D593 — polar contact contact to K596 lost

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Bond changes · DynaMut2 interaction analysis

1 lost2 gained5 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	K596	K596	Preserved
Hydrogen bond	I597	I597	Preserved
Polar contact	S591	—	Lost
Polar contact	T595	T595	Preserved
Polar contact	K596	K596	Preserved
Polar contact	I597	I597	Preserved
Van der Waals	—	T595	Gained
Van der Waals	—	K596	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

0.03kcal/mol

Stabilising — mild

AlphaMissense

0.110

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 0.011%

cDNA changec.1779G>C

ClinVar accessionVCV000215362

Last evaluated2025/12/29 00:00

Observed in the general population.

Structural Context

Position analysis: LEU592 (2.5 Å — L592V!), LEU594 (2.5 Å), THR595 (4.5 Å — A598T region). Adjacent to L592V in TM9 cluster. The Atlas's neighbor extraction surfaces this variant's contacts.

Amino-acid chemistry

conservative carboxylate swap

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 cluster adjacent to L592V/P607L/R/A598T.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the E593D 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 E593D PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane589–609 · Helical