R732C
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialArginine → Cysteine at position 732 in lumenal domain. ClinVar Conflicting including monogenic diabetes, Wolfram, T2D. AlphaMissense 0.637, ΔΔG -0.83. Charge loss + thiol near C733-C765 disulfide region.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | D729 | — | Lost |
| Hydrogen bond | — | I720 | Gained |
| Hydrogen bond | N721 | — | Lost |
| Hydrogen bond | G728 | G728 | Preserved |
| Hydrogen bond | D729 | D729 | Preserved |
| Hydrogen bond | G736 | G736 | Preserved |
| Polar contact | N721 | — | Lost |
| Polar contact | G728 | G728 | Preserved |
| Polar contact | D729 | D729 | Preserved |
| Polar contact | — | W730 | Gained |
| Polar contact | G736 | G736 | Preserved |
| Van der Waals | — | G728 | Gained |
| Hydrophobic | I720 | — | Lost |
| Hydrophobic | C765 | C765 | Preserved |
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 WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- WFS1-related diabetesautosomal dominantsubmitted as: Monogenic diabetes; Type 2 diabetes mellitus
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1; Wolfram syndrome 1
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41; Myopia, high, with cataract and vitreoretinal degeneration
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- 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.
Highest in Middle Eastern: AF 0.066% (4 of 6,084 alleles), 14.1x the global figure. The global AF describes the general population, not the at-risk group.
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. |
|---|---|---|---|---|
| Middle Eastern | 0.066% | 4 / 6,084 | 0 | ~1 in 760 |
| East Asian | 0.0089% | 4 / 44,876 | 0 | ~1 in 5610 |
| South Asian | 0.0066% | 6 / 91,066 | 0 | ~1 in 7590 |
| Remaining individuals | 0.0064% | 4 / 62,454 | 0 | ~1 in 7810 |
| European (non-Finnish) | 0.0045% | 53 / 1,179,904 | 0 | ~1 in 11130 |
| Admixed American | 0.0033% | 2 / 59,978 | 0 | ~1 in 14990 |
| African / African American | 0.0027% | 2 / 74,946 | 0 | ~1 in 18740 |
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 732 sits next to C733 (3.5 Å from C765 in the inferred disulfide). Neighbors: CYS733 (2.5 Å), MET731 (2.5 Å), ASP729 (3.7 Å — partner of G728-D729 region), GLY728 (3.8 Å).
The wild-type R732 is the same R732 referenced as a partner in G736R Atlas card. R732C replaces this critical arginine with a free cysteine — adjacent to C733 (which forms a disulfide with C765). The new C732 could potentially form aberrant disulfide chemistry with C733 itself, disrupting the C733-C765 disulfide entirely.
|ΔΔG| 0.83 + AM 0.637 + multi-phenotype confirm severe consequence.
Druggability Assessment
Mechanism: loss of R732 charge + potential aberrant disulfide with C733 disrupting the C733-C765 structural disulfide. Therapeutic: site-directed at the R732-C733-C765 microregion.
Why this matters
Feed this card to Wolfram Intelligence
Download the R732C 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.