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
Clinical Evidence
Observed at very low frequency in gnomAD.
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.