L543F

Category 4 — Stable Fold, Function DisruptedLikely pathogenicTransmembrane · predictedEditorial

Leucine → Phenylalanine at position 543 · TM7 (529-549), helical transmembrane · WFS1 (Wolframin)

Leucine → Phenylalanine at position 543 inside TM7. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.303 (below threshold) — AM under-call. DynaMut2 ΔΔG -1.34 kcal/mol (destabilising). Same position as L543P (Atlas card adjacent) but with aromatic introduction.

Interactive 3D Structure

Wild-type reference

Wild-type L543 — hydrogen bond to M539

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DynaMut2 mutant · L543F

Mutant F543 — polar contact to I547 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost5 gained11 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	M539	M539	Preserved
Hydrogen bond	V546	V546	Preserved
Hydrogen bond	I547	I547	Preserved
Polar contact	M539	M539	Preserved
Polar contact	C541	C541	Preserved
Polar contact	—	V545	Gained
Polar contact	V546	V546	Preserved
Polar contact	I547	I547	Preserved
Aromatic / π	—	F881	Gained
Van der Waals	—	V545	Gained
Van der Waals	I547	—	Lost
Hydrophobic	F354	—	Lost
Hydrophobic	M357	M357	Preserved
Hydrophobic	—	V412	Gained
Hydrophobic	V415	V415	Preserved
Hydrophobic	—	I416	Gained
Hydrophobic	T436	T436	Preserved
Hydrophobic	W540	—	Lost
Hydrophobic	I547	—	Lost
Hydrophobic	F881	F881	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

-1.34kcal/mol

Destabilising — moderate

AlphaMissense

0.303

LBen

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationLikely pathogenic

Review statuscriteria provided, single submitter

Associated conditionsWolfram syndrome 1

InheritanceWolfram syndrome 1 (AR) documented.

Population frequency (gnomAD v4)Ultra-rare · AF 0.000068%

cDNA changec.1627C>T

ClinVar accessionVCV002499486

Last evaluated2023/03/01 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 543 sits in TM7. Same neighbor environment as L543P: GLU542 (2.5 Å), SER544 (2.5 Å), MET539 (3.7 Å), TRP540 (3.9 Å), PHE881 (4.1 Å — TM7-TM11 cross-helix).

Replacing L543 with phenylalanine adds aromatic volume to the TM7 mid-helix. Unlike L543P which introduces a backbone kink, L543F preserves α-helical structure but creates a tandem aromatic motif with W540 nearby. The TM7-TM11 cross-helix contact to F881 now involves two phenylalanines in TM7 (F543, with W540 aromatic neighbor) interacting with F881 across the interface.

The |ΔΔG| of 1.34 reflects meaningful fold cost. AlphaMissense's 0.303 below threshold is AM under-call; ClinVar Pathogenic + Wolfram 1 establishes pathogenicity.

Amino-acid chemistry

Leucine (L) → Phenylalanine (F) — branched aliphatic hydrophobic replaced by aromatic hydrophobic.

Position in the protein

TM7 (residues 529–549) · position 543 mid-helix, bilayer-embedded (pLDDT 91).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| = 1.34 — fold survives at meaningful cost. AlphaMissense 0.303 below threshold but ClinVar Pathogenic + Wolfram 1.

Mechanism is aromatic volume mismatch in TM7 plus rearrangement of TM7-TM11 cross-helix contact. Therapeutic strategy: same TM7-TM11 interface as L543P.

Why this matters

L543F + L543P at the same position, different chemistries, both pathogenic — position 543 is a multi-substitution hotspot in TM7.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the L543F 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 L543F PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane529–549 · Helical