R685C
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialArginine → Cysteine at position 685. ClinVar Conflicting including monogenic diabetes + DFNA6. AlphaMissense 0.581, ΔΔG +0.10. Same position as R685P (Atlas card). R→C class with disulfide-pair partner CYS673 visible nearby in the broader region.
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 | — | N682 | Gained |
| Van der Waals | M683 | M683 | Preserved |
| 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 in the general population.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Optic atrophy / optic neuropathy (autosomal dominant). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- WFS1-related diabetesautosomal dominantsubmitted as: Monogenic diabetes; Type 2 diabetes mellitus
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1; Wolfram syndrome 1
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6; Autosomal dominant nonsyndromic hearing loss 6
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Optic atrophy / optic neuropathyautosomal dominantsubmitted as: Optic atrophy
- Submitters conflict on this classification (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★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in Middle Eastern: AF 0.082% (5 of 6,062 alleles), 4.6x the global figure. The global AF describes the general population, not the at-risk group.
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. |
|---|---|---|---|---|
| Middle Eastern | 0.082% | 5 / 6,062 | 0 | ~1 in 610 |
| East Asian | 0.056% | 25 / 44,868 | 0 | ~1 in 900 |
| Remaining individuals | 0.038% | 24 / 62,484 | 0 | ~1 in 1300 |
| South Asian | 0.036% | 33 / 91,076 | 0 | ~1 in 1380 |
| African / African American | 0.027% | 20 / 75,028 | 0 | ~1 in 1880 |
| Admixed American | 0.017% | 10 / 60,032 | 0 | ~1 in 3000 |
| European (non-Finnish) | 0.014% | 171 / 1,179,944 | 0 | ~1 in 3450 |
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 same neighbors as R685P: THR686 (2.5 Å), ALA684 (2.5 Å — A684T/V/G cluster), ASN682 (3.5 Å), MET683 (4.3 Å), GLN687 (4.4 Å — Q687H).
R685C is a second pathogenic substitution at 685. Where R685P removed charge + introduced backbone kink, R685C removes charge + introduces free thiol. The new C685 sits in the dense 684-688 cluster — its thiol could engage in disulfide chemistry with other lumenal cysteines.
ΔΔG essentially neutral; AM 0.581 borderline + monogenic diabetes + DFNA6 confirm severe consequence.
Druggability Assessment
Mechanism: charge loss + free thiol introduction in dense 684-688 cluster. Therapeutic: same cluster target.
Why this matters
Feed this card to Wolfram Intelligence
Download the R685C 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.