C765R
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialCysteine → Arginine at position 765 in wolframin's C-terminal lumenal domain. ClinVar Conflicting classifications including Wolfram syndrome 1. AlphaMissense 0.991 (near-maximum), DynaMut2 ΔΔG -1.06 kcal/mol (destabilising). The C765 partner residue of the C733 inferred disulfide.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | C733 | Gained |
| Hydrogen bond | A738 | — | Lost |
| Polar contact | C733 | C733 | Preserved |
| Polar contact | E737 | E737 | Preserved |
| Carbonyl | E737 | E737 | Preserved |
| Van der Waals | E737 | E737 | Preserved |
| Van der Waals | — | A738 | Gained |
| Van der Waals | H763 | H763 | Preserved |
| Hydrophobic | R732 | — | Lost |
| Hydrophobic | C733 | C733 | Preserved |
| Hydrophobic | — | A738 | 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
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
Observed at very low frequency in gnomAD.
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.
Every ancestry group with observed alleles falls below the reporting threshold (min 2 alleles, min 500 sampled) — too sparse to name a highest-frequency population.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| European (non-Finnish) · under-sampled | 0.000090% | 1 / 1,111,986 | 0 | — |
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 765 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places C765 within 5 Å of HIS766 (2.4 Å — partner of D771H Atlas card region), PRO764 (2.5 Å), GLU737 (3.2 Å — same E737 as G736R/G736S neighbor), ALA738 (4.0 Å), and TYR739 (4.2 Å).
C765 was the partner residue identified in the C733G Atlas card (3.5 Å distance — possible disulfide). C765R replaces the cysteine at the OTHER end of this potential disulfide. The combination of C733G (cysteine removed) + C765R (cysteine replaced by arginine) at the inferred disulfide pair confirms both cysteines are pathogenic when mutated.
The |ΔΔG| of 1.06 reflects substantial fold cost. AlphaMissense's 0.991 (near-maximum) confirms severe functional consequence.
Druggability Assessment
Mechanism is loss of the inferred C733-C765 disulfide bond plus charge introduction. Therapeutic strategy: site-directed at the C733-C765 microregion (same target as C733G).
Why this matters
Feed this card to Wolfram Intelligence
Download the C765R 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.