L592V

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Leucine → Valine at position 592 · TM9 (589-609), helical transmembrane · WFS1 (Wolframin)

Leucine → Valine at position 592 inside TM9. ClinVar Conflicting. AlphaMissense 0.13 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.52. pLDDT 63 borderline.

Interactive 3D Structure

Wild-type reference

Wild-type L592 — hydrogen bond to F589

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DynaMut2 mutant · L592V

Mutant V592 — hydrogen bond to W588 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost2 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	W588	W588	Preserved
Hydrogen bond	F589	F589	Preserved
Polar contact	W588	W588	Preserved
Polar contact	F589	F589	Preserved
Van der Waals	W588	—	Lost
Van der Waals	—	T590	Gained
Van der Waals	—	K596	Gained
Hydrophobic	W588	W588	Preserved
Hydrophobic	K596	K596	Preserved
Hydrophobic	I597	I597	Preserved
Hydrophobic	T600	—	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

-0.52kcal/mol

Destabilising — mild

AlphaMissense

0.128

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)

InheritanceNot specified.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0087%

cDNA changec.1774C>G

ClinVar accessionVCV001320760

Last evaluated2025/06/24 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 592 in TM9. Neighbors: GLU593 (2.4 Å), SER591 (2.5 Å), PHE589 (4.0 Å — TM9 start).

L592V conservative volume reduction in TM9. AM 0.13 under-call; Conflicting clinical evidence.

Amino-acid chemistry

Leucine (L) → Valine (V) — branched aliphatic to smaller branched aliphatic. Conservative volume reduction.

Position in the protein

TM9 (residues 589–609) · position 592 (pLDDT 63 borderline).

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted (AM under-call, pLDDT borderline). |ΔΔG| 0.52. AlphaMissense 0.13 below threshold.

Mechanism: conservative TM9 volume reduction. Therapeutic: TM9 site-directed.

Why this matters

L592V is TM9 — same helix as P607L/P607R. TM9 cluster grows.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the L592V 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 L592V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane589–609 · Helical