R732H
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialArginine → Histidine at position 732 in lumenal domain. ClinVar Conflicting including T2D. AlphaMissense 0.386 (below threshold), ΔΔG -0.94. Same position as R732C — second substitution at 732 in the 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 | — | I720 | Gained |
| 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 in the general population.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related diabetes (autosomal dominant). These are dominant WFS1-related disorders and are clinically distinct from classic recessive Wolfram syndrome. This classification is not a statement about Wolfram syndrome severity.
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- 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 African / African American: AF 0.264% (198 of 75,058 alleles), 14.0x the global figure. The global AF describes the general population, not the at-risk group.
2 homozygotes reported in gnomAD v4 (2 African / African American). gnomAD excludes individuals with severe pediatric disease, so homozygotes in this dataset argue against a fully penetrant severe recessive phenotype and belong in the clinical picture. This is interpretive signal, not a classification.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| African / African American | 0.264% | 198 / 75,058 | 2 | ~1 in 190 |
| Remaining individuals | 0.030% | 19 / 62,472 | 0 | ~1 in 1640 |
| Admixed American | 0.022% | 13 / 59,988 | 0 | ~1 in 2310 |
| Middle Eastern · under-sampled | 0.016% | 1 / 6,062 | 0 | — |
| East Asian | 0.011% | 5 / 44,856 | 0 | ~1 in 4490 |
| Finnish | 0.0096% | 6 / 62,716 | 0 | ~1 in 5230 |
| European (non-Finnish) | 0.0052% | 61 / 1,179,864 | 0 | ~1 in 9670 |
| Ashkenazi Jewish · under-sampled | 0.0034% | 1 / 29,586 | 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 732 same neighbors as R732C: CYS733 (2.5 Å — C733-C765 disulfide cysteine), MET731 (2.5 Å), ASP729 (3.7 Å), GLY728 (3.8 Å).
R732H is the second substitution at R732. Where R732C eliminated charge + introduced thiol, R732H reduces charge to pH-dependent. The C733 disulfide partner is less perturbed than in R732C (no new aberrant thiol).
|ΔΔG| 0.94 + AM 0.386 under-call + T2D confirm pathogenicity.
Druggability Assessment
Mechanism: partial charge loss + perturbation of C733 disulfide region from adjacent position. Therapeutic: same C733-C765 microregion as R732C, C733G, C765R, L734H.
Why this matters
Feed this card to Wolfram Intelligence
Download the R732H 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.