L734H
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialLeucine → Histidine at position 734 in lumenal domain. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.461 (below threshold), ΔΔG -0.47.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| 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
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
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 and Wolfram 1 does not resolve it (ClinVar: conflicting submissions).
Druggability Assessment
Mechanism: perturbation of C733-C765 disulfide region from adjacent position. Therapeutic: same C733-C765 microregion.
Why this matters
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.