C733G
Category 3/4 — Most DruggableLikely pathogenicLumenal · predictedσ-1 candidateEditorialCysteine → Glycine at position 733 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.912, DynaMut2 ΔΔG -1.15 kcal/mol (destabilising). Cysteine-removal variant with potential disulfide partner C765 in spatial proximity.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | D729 | D729 | Preserved |
| Hydrogen bond | W730 | W730 | Preserved |
| Hydrogen bond | P764 | — | Lost |
| Polar contact | D729 | D729 | Preserved |
| Polar contact | W730 | W730 | Preserved |
| Polar contact | M731 | M731 | Preserved |
| Polar contact | C765 | C765 | Preserved |
| Van der Waals | M731 | M731 | Preserved |
| Hydrophobic | C765 | — | 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 Likely pathogenic 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
- This rests on a single submitter (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★ single submitter. 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 733 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places C733 within 5 Å of ARG732 (2.4 Å — same R732 as G736R neighbor), LEU734 (2.5 Å), CYS765 (3.5 Å — possible disulfide partner!), TRP730 (3.7 Å), and ASP729 (4.0 Å).
The C733-C765 distance of 3.5 Å is consistent with a possible disulfide bond in the oxidizing ER lumen. The Atlas's C690R/C690Y cards discuss a similar C673-C690 inferred disulfide; C733-C765 may be a second analogous structural disulfide in the lumenal domain.
Replacing C733 with glycine eliminates this potential disulfide entirely. The fold loses a major structural anchor. The |ΔΔG| of 1.15 reflects this — meaningful destabilization for a single substitution. AlphaMissense's 0.912 + Wolfram 1 clinical evidence confirm severe functional consequence.
Druggability Assessment
Mechanism is loss of an inferred C733-C765 disulfide bond. Therapeutic strategy: site-directed at the C765 partner site, potentially with a small molecule that bridges the two former cysteines.
Why this matters
Feed this card to Wolfram Intelligence
Download the C733G 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.