F331I

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Phenylalanine → Isoleucine at position 331 · TM1 (314-334), helical transmembrane · WFS1 (Wolframin)

Phenylalanine → Isoleucine at position 331 inside TM1. ClinVar Conflicting including DFNA6. AlphaMissense 0.458 (below threshold), ΔΔG +0.56 STABILISING.

Interactive 3D Structure

Wild-type reference

Wild-type F331 — hydrogen bond to N335

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DynaMut2 mutant · F331I

Mutant I331 — hydrogen bond to S334 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost1 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L327	L327	Preserved
Hydrogen bond	I328	—	Lost
Hydrogen bond	S334	S334	Preserved
Hydrogen bond	N335	N335	Preserved
Polar contact	L327	L327	Preserved
Polar contact	I328	I328	Preserved
Polar contact	F329	F329	Preserved
Polar contact	S334	S334	Preserved
Polar contact	N335	N335	Preserved
Van der Waals	—	L327	Gained
Van der Waals	F329	—	Lost
Van der Waals	S334	—	Lost
Van der Waals	N335	—	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

DynaMut2 ΔΔG

0.56kcal/mol

Stabilising — mild

AlphaMissense

0.458

Amb

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditionsInborn genetic diseases; Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

InheritanceDFNA6.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0049%

cDNA changec.991T>A

ClinVar accessionVCV000229648

Last evaluated2025/04/08 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 331 near end of TM1. Neighbors: ILE332 (2.5 Å), PHE330 (2.5 Å — adjacent existing phenylalanine), SER334 (3.5 Å), LEU327 (3.6 Å). Aromatic cluster F330-F331.

Replacing F331 with isoleucine eliminates aromatic packing with F330 + lost adjacency. ΔΔG +0.56 stabilising; AM 0.458 under-call; DFNA6 + WFS1 spectrum confirm pathogenicity.

Amino-acid chemistry

Phenylalanine (F) → Isoleucine (I) — aromatic replaced by branched aliphatic.

Position in the protein

TM1 (residues 314–334) · position 331 near TM1 end (pLDDT 75).

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted (AM under-call, stabilising). ΔΔG +0.56. AlphaMissense 0.458 below threshold but DFNA6 confirm pathogenicity.

Mechanism: lost F330-F331 aromatic packing in TM1. Therapeutic: TM1 microregion.

Why this matters

F331I extends the TM1 cluster (now 7+ variants in or near TM1).

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the F331I 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 F331I PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane314–334 · Helical