F882C
Category 4 — Stable Fold, Function DisruptedLikely pathogenicTransmembrane · predictedEditorialPhenylalanine → 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
- transmembrane position; predictor benchmarked on soluble proteins
This variant sits in the transmembrane band. The stability value was computed with a predictor benchmarked on water-soluble proteins. Published benchmarks of ddG predictors on membrane proteins report correlation below 0.4. Treat the magnitude as unreliable and the sign as weak evidence only.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Likely pathogenic for Hearing loss, inheritance unstated (inheritance not specified).
- Hearing loss, inheritance unstatedinheritance not specifiedsubmitted as: Auditory neuropathy
- This rests on a single submitter (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★ single submitter. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in East Asian: AF 0.0045% (2 of 44,890 alleles), 35.9x 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 | 0.0045% | 2 / 44,890 | 0 | ~1 in 11220 |
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 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.