R456H
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialArginine → Histidine at position 456 in connecting loop. ClinVar Conflicting including WFS1 spectrum. AlphaMissense 0.16 (below threshold) — AM under-call. DynaMut2 ΔΔG -1.26 (substantial). Adjacent to R457S.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | E452 | E452 | Preserved |
| Hydrogen bond | A460 | A460 | Preserved |
| Polar contact | E452 | E452 | Preserved |
| Polar contact | A460 | A460 | Preserved |
| Van der Waals | — | A460 | Gained |
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
Population frequency too high for a penetrant Wolfram allele — stand-alone benign evidence (ACMG BA1).
Structural Context
Position 456 in connecting loop. Neighbors: ARG457 (2.5 Å — R457S partner!), THR455 (2.5 Å), GLU452 (3.6 Å — likely salt-bridge).
R456H + R457S both at the R456-R457 double-arginine cluster. Partial charge reduction + perturbed E452 salt bridge. |ΔΔG| 1.26 substantial; AM 0.16 under-call; multi-phenotype confirms.
Druggability Assessment
Mechanism: partial charge loss from R456-R457 cluster + E452 salt-bridge disruption. Therapeutic: same loop as R457S.
Why this matters
Feed this card to Wolfram Intelligence
Download the R456H 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.