R685P
Category 3/4 — Most DruggablePathogenicLumenal · predictedσ-1 candidateEditorialArginine → Proline at position 685 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic, associated with rare genetic deafness. AlphaMissense 0.954, DynaMut2 ΔΔG +0.33 kcal/mol — a STABILIZING substitution. A charge-loss-plus-helix-break variant.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | N682 | — | Lost |
| Hydrogen bond | I688 | — | Lost |
| Hydrogen bond | L689 | L689 | Preserved |
| Polar contact | N682 | N682 | Preserved |
| Polar contact | M683 | — | Lost |
| Polar contact | I688 | — | Lost |
| Polar contact | L689 | L689 | Preserved |
| Van der Waals | — | N682 | Gained |
| Van der Waals | M683 | — | Lost |
| Hydrophobic | — | N682 | 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
Observed at very low frequency in gnomAD.
Structural Context
Position 685 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places R685 within 5 Å of THR686 (2.5 Å), ALA684 (2.5 Å — the partner residue in the A684T atlas card), ASN682 (3.5 Å), MET683 (4.3 Å), and GLN687 (4.4 Å). The wild-type arginine's long, positively-charged side chain likely makes H-bond contacts with the nearby polar residues (N682, T686, Q687).
Replacing arginine with proline at 685 removes the long side chain and introduces a rigid ring-locked residue. The H-bond network the wild-type R685 maintained is gone; the local backbone gains a forced kink from the proline. The DynaMut2 ΔΔG of +0.33 (stabilising) reflects that the tighter local packing achievable with proline outweighs the lost H-bonding in pure energetic terms.
Yet the variant is pathogenic — AlphaMissense 0.954, ClinVar Pathogenic, associated with rare genetic deafness. The pathogenic mechanism is functional: the lost R685 H-bond network is required for wolframin's lumenal function (likely partner protein recognition), even though the fold accommodates the substitution structurally.
Notably, A684T sits at the adjacent position with its own Atlas card — a second variant in the same microregion. Both R685P and A684T perturb the M683-A684-R685-T686 loop geometry, just from different sides.
Druggability Assessment
The mechanism is functional rather than structural: lost R685 H-bond network with N682, T686, Q687, plus introduction of a backbone kink from proline. Drug discovery here aims at the functional contact, not at fold rescue.
Combined with A684T (Atlas card adjacent), drug discovery in the 683-687 microregion has two convergent variant targets.
Why this matters
Feed this card to Wolfram Intelligence
Download the R685P 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.