R177C
Category 3/4 — Most DruggableConflictingCytoplasmic · predictedEditorialArginine → Cysteine at position 177 in N-terminal cytoplasmic domain. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.902, ΔΔG -0.88. Charge loss + thiol introduction.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | E169 | — | Lost |
| Hydrogen bond | A134 | — | Lost |
| Hydrogen bond | K135 | — | Lost |
| Hydrogen bond | E173 | E173 | Preserved |
| Hydrogen bond | R174 | R174 | Preserved |
| Hydrogen bond | A180 | A180 | Preserved |
| Hydrogen bond | L181 | L181 | Preserved |
| Hydrogen bond | — | K252 | Gained |
| Polar contact | A134 | — | Lost |
| Polar contact | K135 | — | Lost |
| Polar contact | E169 | — | Lost |
| Polar contact | E173 | E173 | Preserved |
| Polar contact | R174 | R174 | Preserved |
| Polar contact | A175 | A175 | Preserved |
| Polar contact | A179 | — | Lost |
| Polar contact | A180 | A180 | Preserved |
| Polar contact | L181 | L181 | Preserved |
| Van der Waals | L166 | — | Lost |
| Van der Waals | E169 | — | Lost |
| Van der Waals | A175 | A175 | Preserved |
| Van der Waals | A179 | — | Lost |
| Van der Waals | L181 | L181 | Preserved |
| Van der Waals | — | K252 | Gained |
| Hydrophobic | L181 | — | Lost |
| Hydrophobic | V248 | V248 | 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
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 Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- 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 European (non-Finnish): AF 0.00081% (9 of 1,112,006 alleles), in line with the global figure.
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 · under-sampled | 0.0025% | 1 / 39,700 | 0 | — |
| Admixed American · under-sampled | 0.0022% | 1 / 44,724 | 0 | — |
| Remaining individuals · under-sampled | 0.0017% | 1 / 60,392 | 0 | — |
| European (non-Finnish) | 0.00081% | 9 / 1,112,006 | 0 | ~1 in 61780 |
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 177 sits in the N-terminal cytoplasmic domain. Neighbors: LYS178 (2.5 Å — adjacent existing lysine), VAL176 (2.5 Å), GLU173 (3.7 Å — likely wild-type salt-bridge partner with R177), ARG174 (3.8 Å — second nearby arginine).
The wild-type R177 contributes to a positively-charged surface patch (with K178, R174) and likely salt-bridges with E173. Replacing R177 with cysteine eliminates the positive charge contribution and introduces a free thiol in the cytosol (less prone to aberrant disulfide than ER lumen but still a misfolding consideration).
|ΔΔG| 0.88 + AlphaMissense 0.902 + Wolfram 1 confirm severe consequence.
Druggability Assessment
Mechanism: loss of R177-E173 salt bridge plus charge loss from cytoplasmic surface patch. Therapeutic: site-directed at the R174-R177-E173 cluster.
Why this matters
Feed this card to Wolfram Intelligence
Download the R177C 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.