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
Clinical Evidence
Observed in the general population.
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.