F439C

Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorial

Phenylalanine → Cysteine at position 439 · TM4 (427-447), helical transmembrane · WFS1 (Wolframin)

Phenylalanine → Cysteine at position 439 inside TM4. ClinVar Conflicting including DFNA6 and Wolfram. AlphaMissense 0.886, ΔΔG +0.51 STABILISING.

Interactive 3D Structure

Wild-type reference

Wild-type F439 — hydrogen bond to S443

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DynaMut2 mutant · F439C

Mutant C439 — polar contact to I435 lost (5 contacts lost)

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Bond changes · DynaMut2 interaction analysis

5 lost3 gained10 preserved

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

DynaMut2 ΔΔG

0.51kcal/mol

Stabilising — mild

AlphaMissense

0.886

LPath

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditionsAutosomal dominant nonsyndromic hearing loss 6 (DFNA6); Wolfram-like syndrome

InheritanceDFNA6 hearing loss + WFS1-related disorder documented.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0098%

cDNA changec.1316T>G

ClinVar accessionVCV000215388

Last evaluated2025/08/18 00:00

Observed at very low frequency in gnomAD.

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.

Amino-acid chemistry

Phenylalanine (F) → Cysteine (C) — aromatic hydrophobic replaced by thiol-bearing residue.

Position in the protein

TM4 (residues 427–447) · position 439 mid-helix (pLDDT 93).

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted. ΔΔG = +0.51 stabilising. AlphaMissense 0.886 + DFNA6 confirm severe consequence.

Mechanism: lost aromatic packing in TM4 + thiol introduction. Therapeutic: TM4 site-directed.

Why this matters

F439C joins the F-to-C class (with F882C) — both stabilising or near-neutral ΔΔG but pathogenic by AlphaMissense + clinical.

Therapeutic Strategy Handoff · prediction

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.

Download F439C PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane427–447 · Helical