R685H
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialArginine → Histidine at position 685 — SAME position as R685P (Atlas card flagship pathogenic-stabilising variant) and R685C. ClinVar Conflicting with broad spectrum — Wolfram, Cataract 41, DFNA6. AlphaMissense 0.12 (below threshold) — AM under-call. DynaMut2 ΔΔG -1.18 (substantial).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | N682 | N682 | Preserved |
| Hydrogen bond | I688 | I688 | Preserved |
| Hydrogen bond | L689 | L689 | Preserved |
| Polar contact | N682 | N682 | Preserved |
| Polar contact | M683 | M683 | Preserved |
| Polar contact | I688 | I688 | Preserved |
| Polar contact | L689 | L689 | Preserved |
| Van der Waals | M683 | M683 | 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 685 same neighbors as R685P/R685C: THR686 (2.5 Å), ALA684 (2.5 Å — A684T/V/G), ASN682 (3.5 Å), MET683 (4.3 Å), GLN687 (4.4 Å — Q687H).
R685H is the THIRD substitution at position 685 (with R685P, R685C). Partial charge reduction. |ΔΔG| 1.18 substantial; AM 0.12 under-call; multi-phenotype confirms.
Druggability Assessment
Mechanism: partial charge loss in the dense 684-688 cluster. Therapeutic: same cluster target as R685P, R685C, A684T/V/G, Q687H.
Why this matters
Feed this card to Wolfram Intelligence
Download the R685H 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.