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
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Pathogenic for Hearing loss, inheritance unstated (inheritance not specified).
- Hearing loss, inheritance unstatedinheritance not specifiedsubmitted as: Rare genetic deafness
- This rests on a single submitter (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ single submitter. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Every ancestry group with observed alleles falls below the reporting threshold (min 2 alleles, min 500 sampled) — too sparse to name a highest-frequency population.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| European (non-Finnish) · under-sampled | 0.000090% | 1 / 1,111,900 | 0 | — |
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
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.