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
Clinical Evidence
Observed at very low frequency in gnomAD.
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.