F329I

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Phenylalanine → Isoleucine at position 329 · TM1 (314-334), helical transmembrane · WFS1 (Wolframin)

Phenylalanine → Isoleucine at position 329 inside TM1. ClinVar Conflicting including WFS1 spectrum + Wolfram. AlphaMissense 0.15 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.22.

Interactive 3D Structure

Wild-type reference

Wild-type F329 — hydrogen bond to V333

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DynaMut2 mutant · F329I

Mutant I329 — polar contact contact to F331 lost

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Bond changes · DynaMut2 interaction analysis

1 lost0 gained12 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	N325	N325	Preserved
Hydrogen bond	A326	A326	Preserved
Hydrogen bond	I332	I332	Preserved
Hydrogen bond	V333	V333	Preserved
Polar contact	N325	N325	Preserved
Polar contact	A326	A326	Preserved
Polar contact	F331	—	Lost
Polar contact	I332	I332	Preserved
Polar contact	V333	V333	Preserved
Van der Waals	L327	L327	Preserved
Van der Waals	F331	F331	Preserved
Van der Waals	V333	V333	Preserved
Hydrophobic	V333	V333	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

-0.22kcal/mol

Destabilising — mild

AlphaMissense

0.154

LBen

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 conditionsWFS1-Related Spectrum Disorders; Wolfram syndrome 1

InheritanceWFS1 spectrum + Wolfram.

Population frequency (gnomAD v4)Low frequency · AF 0.016%

cDNA changec.985T>A

ClinVar accessionVCV000504708

Last evaluated2026/02/03 00:00

Observed in the general population.

Structural Context

Position 329 in TM1. Neighbors: ILE328 (2.5 Å), PHE330 (2.5 Å — F330-F331 cluster region; F331I!), ASN325 (3.6 Å — A325 in A326 region).

F329I loses aromatic. Adjacent to F331I (Atlas card). Both perturb the F329-F330-F331 aromatic cluster. AM 0.15 under-call; multi-phenotype confirms.

Amino-acid chemistry

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

Position in the protein

TM1 (residues 314–334) · position 329 near TM1 end (pLDDT 77).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| 0.22. AlphaMissense 0.15 below threshold but multi-phenotype confirms.

Mechanism: aromatic loss in F329-F330-F331 TM1 cluster. Therapeutic: TM1 multi-variant target.

Why this matters

F329I + F331I — adjacent TM1 aromatic-loss variants in same F329-F330-F331 cluster.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the F329I 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 F329I PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane314–334 · Helical