L734H

Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorial

Leucine → Histidine at position 734 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Leucine → Histidine at position 734 in lumenal domain. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.461 (below threshold), ΔΔG -0.47.

Interactive 3D Structure

Wild-type reference

Wild-type L734 — hydrogen bond to W730

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DynaMut2 mutant · L734H

Mutant H734 — polar contact to W730 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost0 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	W730	W730	Preserved
Hydrogen bond	M731	M731	Preserved
Polar contact	W730	W730	Preserved
Polar contact	M731	M731	Preserved
Hydrophobic	W730	—	Lost
Hydrophobic	M731	—	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

-0.47kcal/mol

Destabilising — mild

AlphaMissense

0.461

Amb

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 conditionsWolfram syndrome 1

InheritanceWolfram syndrome 1.

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.2201T>A

ClinVar accessionVCV000593953

Last evaluated2017/09/26 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Structural Context

Position 734 in lumenal domain — same C733-C765 disulfide region (R732C, C733G, C765R). Neighbors: TYR735 (2.5 Å — Y735 partner of G736 environment), CYS733 (2.5 Å — the C733 disulfide cysteine!), MET731 (3.8 Å), TRP730 (3.8 Å).

L734H sits immediately downstream of C733 — perturbing the C733-C765 disulfide region from the adjacent position. AM 0.461 below threshold but Wolfram 1 confirms pathogenicity.

Amino-acid chemistry

Leucine (L) → Histidine (H) — branched aliphatic replaced by aromatic titratable basic.

Position in the protein

C-terminal lumenal domain · position 734 (pLDDT 88).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| 0.47. AlphaMissense 0.461 below threshold but Wolfram 1 confirms pathogenicity.

Mechanism: perturbation of C733-C765 disulfide region from adjacent position. Therapeutic: same C733-C765 microregion.

Why this matters

L734H is in the same C733-C765 disulfide microregion as R732C, C733G, C765R.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the L734H 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 L734H PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal