F882C
Category 4 — Stable Fold, Function DisruptedLikely pathogenicLumenal · predictedσ-1 candidateEditorialPhenylalanine → Cysteine at position 882 inside TM11. ClinVar Likely pathogenic, auditory neuropathy. AlphaMissense 0.496 (below threshold) — AM under-call. DynaMut2 ΔΔG -1.59 kcal/mol (destabilising). Volume loss in the TM11 aromatic cluster.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | Y508 | Gained |
| Hydrogen bond | A878 | A878 | Preserved |
| Hydrogen bond | F879 | F879 | Preserved |
| Polar contact | Y508 | Y508 | Preserved |
| Polar contact | A878 | A878 | Preserved |
| Polar contact | F879 | F879 | Preserved |
| Polar contact | D880 | D880 | Preserved |
| Van der Waals | I416 | — | Lost |
| Van der Waals | A878 | — | Lost |
| Van der Waals | — | D880 | Gained |
| Hydrophobic | I416 | — | Lost |
| Hydrophobic | M539 | — | 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
Clinical Evidence
Observed at very low frequency in gnomAD.
Structural Context
Position 882 sits inside TM11. The AlphaFold model places F882 within 5 Å of PHE881 (2.5 Å), PHE883 (2.5 Å), PHE879 (3.9 Å), ASP880 (4.2 Å), and ALA878 (4.4 Å). The local environment is a dense aromatic cluster — four phenylalanines (F879, F881, F882, F883) plus the nearby P885 (P885L Atlas card) and F884/F886 (in the broader cluster).
Replacing F882 with cysteine eliminates one of the four aromatics in this cluster. The π-stacking network reorganizes; the introduced thiol can engage in oxidative disulfide chemistry if a partner cysteine is nearby (none within 5 Å here). The |ΔΔG| of 1.59 reflects substantial structural cost from the lost aromatic.
AlphaMissense's 0.496 is below the 0.564 likely-pathogenic threshold — another AM under-call case. ClinVar Likely Pathogenic + auditory neuropathy + the substantial ΔΔG argue for genuine pathogenicity despite the AM signal.
Druggability Assessment
Mechanism is loss of one aromatic from the dense TM11 phenylalanine cluster (F879-F881-F882-F883). Therapeutic strategy: site-directed at the TM11 aromatic cluster — same broader region as P885L.
Why this matters
Feed this card to Wolfram Intelligence
Download the F882C 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.