R232H
Category 4 — Stable Fold, Function DisruptedConflictingCytoplasmic · predictedEditorialArginine → Histidine at position 232 in N-terminal cytoplasmic domain. ClinVar Conflicting including WFS1 spectrum + Wolfram. AlphaMissense 0.17 (below threshold) — AM under-call. DynaMut2 ΔΔG -1.27 (substantial destabilising).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | R228 | R228 | Preserved |
| Hydrogen bond | M229 | M229 | Preserved |
| Hydrogen bond | S235 | S235 | Preserved |
| Hydrogen bond | S236 | S236 | Preserved |
| Hydrogen bond | N373 | N373 | Preserved |
| Polar contact | R228 | R228 | Preserved |
| Polar contact | M229 | M229 | Preserved |
| Polar contact | L230 | L230 | Preserved |
| Polar contact | S235 | S235 | Preserved |
| Polar contact | S236 | S236 | Preserved |
| Polar contact | — | Y254 | Gained |
| Polar contact | L263 | — | Lost |
| Polar contact | N373 | — | Lost |
| Van der Waals | R228 | — | Lost |
| Van der Waals | L230 | — | Lost |
| Van der Waals | — | V234 | Gained |
| Van der Waals | — | Y254 | Gained |
| Hydrophobic | L263 | L263 | 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 232 in cytoplasmic domain. Neighbors: LEU233 (2.5 Å), GLU231 (2.5 Å — same E231 as R228H!), SER235 (3.5 Å). The R232-E231 salt bridge (with adjacent R228H Atlas card overlapping) creates a multi-variant cluster.
R232H + R228H both perturb the R227-R228-E231-R232 charged cluster. |ΔΔG| 1.27 substantial; AM 0.17 under-call; multi-phenotype confirms.
Druggability Assessment
Mechanism: charge partial-loss in R227-R228-E231-R232 cluster. Therapeutic: same cytoplasmic charged cluster as R228H.
Why this matters
Feed this card to Wolfram Intelligence
Download the R232H 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.