R708C
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialArginine → Cysteine at position 708. ClinVar Conflicting (monogenic diabetes, inborn genetic diseases, retinal). AlphaMissense 0.973, ΔΔG -0.36. R→C charge loss + free thiol in ER lumen.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | E776 | — | Lost |
| Hydrogen bond | F775 | — | Lost |
| Hydrogen bond | E776 | E776 | Preserved |
| Polar contact | — | T710 | Gained |
| Polar contact | F775 | — | Lost |
| Polar contact | E776 | E776 | Preserved |
| Carbonyl | F775 | — | Lost |
| Van der Waals | F775 | — | Lost |
| Van der Waals | E776 | — | Lost |
| Hydrophobic | T710 | — | Lost |
| Hydrophobic | E776 | — | Lost |
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 Conflicting classifications of pathogenicity for WFS1-related diabetes (autosomal dominant); Retinal dystrophy (inheritance not specified); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Cataract 41 (autosomal dominant, OMIM 116400). 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
- Retinal dystrophyinheritance not specifiedsubmitted as: Retinal dystrophy
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- 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 East Asian: AF 0.018% (8 of 44,888 alleles), 2.0x 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. |
|---|---|---|---|---|
| East Asian | 0.018% | 8 / 44,888 | 0 | ~1 in 2810 |
| Admixed American | 0.013% | 8 / 59,994 | 0 | ~1 in 3750 |
| European (non-Finnish) | 0.0097% | 114 / 1,179,924 | 0 | ~1 in 5180 |
| African / African American | 0.0093% | 7 / 74,924 | 0 | ~1 in 5350 |
| Remaining individuals | 0.0048% | 3 / 62,474 | 0 | ~1 in 10410 |
| South Asian | 0.0022% | 2 / 91,080 | 0 | ~1 in 22770 |
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 708 sits in the lumenal domain. Neighbors: VAL709 (2.4 Å), VAL707 (2.5 Å — partner of V707F), GLU776 (3.8 Å — likely wild-type salt-bridge partner).
R708C is the second pathogenic substitution at position 708 (with R708L). The mechanism overlaps but differs: R708L removes the charge cleanly with hydrophobic replacement; R708C removes the charge AND introduces a free thiol into the oxidizing ER lumen. The new C708 could engage in aberrant disulfide formation with nearby cysteines, creating misfolding pressure that DynaMut2's |ΔΔG| of 0.36 does not capture.
AlphaMissense 0.973 + monogenic diabetes + retinal phenotype confirm severe functional consequence across tissues.
Druggability Assessment
Mechanism: loss of R708-E776 salt bridge plus free-thiol misfolding pressure. Therapeutic: site-directed at the E776 microregion, with attention to oxidative chemistry risk.
Why this matters
Feed this card to Wolfram Intelligence
Download the R708C 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.