F439C
Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorialPhenylalanine → Cysteine at position 439 inside TM4. ClinVar Conflicting including DFNA6 and Wolfram. AlphaMissense 0.886, ΔΔG +0.51 STABILISING.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | I435 | I435 | Preserved |
| Hydrogen bond | T436 | T436 | Preserved |
| Hydrogen bond | T442 | T442 | Preserved |
| Hydrogen bond | S443 | S443 | Preserved |
| Polar contact | I435 | I435 | Preserved |
| Polar contact | T436 | T436 | Preserved |
| Polar contact | T442 | T442 | Preserved |
| Polar contact | S443 | S443 | Preserved |
| Aromatic / π | W540 | — | Lost |
| Carbonyl | — | T436 | Gained |
| Van der Waals | I435 | I435 | Preserved |
| Van der Waals | — | T436 | Gained |
| Van der Waals | — | W540 | Gained |
| Hydrophobic | V358 | — | Lost |
| Hydrophobic | L362 | — | Lost |
| Hydrophobic | F365 | — | Lost |
| Hydrophobic | I435 | — | Lost |
| Hydrophobic | W540 | W540 | 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
- 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 Conflicting classifications of pathogenicity for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Cataract 41 (autosomal dominant, OMIM 116400); WFS1-related diabetes (autosomal dominant); Hearing loss, inheritance unstated (inheritance not specified). 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.
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6; Autosomal dominant nonsyndromic hearing loss 6
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1; Wolfram syndrome 1
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome; Wolfram-like syndrome
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Hearing loss, inheritance unstatedinheritance not specifiedsubmitted as: Hearing impairment
- 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 0.012% (143 of 1,180,018 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. |
|---|---|---|---|---|
| Middle Eastern · under-sampled | 0.016% | 1 / 6,062 | 0 | — |
| European (non-Finnish) | 0.012% | 143 / 1,180,018 | 0 | ~1 in 4130 |
| Admixed American | 0.012% | 7 / 60,016 | 0 | ~1 in 4290 |
| Remaining individuals | 0.0096% | 6 / 62,502 | 0 | ~1 in 5210 |
| Finnish · under-sampled | 0.0016% | 1 / 63,708 | 0 | — |
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 439 sits in TM4. Neighbors: PHE438 (2.5 Å — second aromatic), THR440 (2.5 Å), THR442 (3.4 Å), THR436 (3.6 Å). Multiple threonines suggest polar packing in the local TM environment.
Replacing F439 with cysteine eliminates aromatic packing. The fold actually stabilises (+0.51) — the local pocket likely accommodates the smaller cysteine more efficiently than the aromatic ring. But AlphaMissense 0.886 + DFNA6 + Wolfram-related clinical evidence confirm severe consequence.
Mechanism is loss of aromatic packing with adjacent F438 plus free-thiol introduction in TM4.
Druggability Assessment
Mechanism: lost aromatic packing in TM4 + thiol introduction. Therapeutic: TM4 site-directed.
Why this matters
Feed this card to Wolfram Intelligence
Download the F439C 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.