C541W

Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorial

Cysteine → Tryptophan at position 541 · TM7 (529-549), helical transmembrane · WFS1 (Wolframin)

Cysteine → Tryptophan at position 541 inside TM7. ClinVar Conflicting including Wolfram. AlphaMissense 0.657, ΔΔG -1.54.

Interactive 3D Structure

Wild-type reference

Wild-type C541 — hydrogen bond to C537

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DynaMut2 mutant · C541W

Mutant W541 — hydrogen bond to F538 lost (2 contacts lost)

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Bond changes · DynaMut2 interaction analysis

2 lost6 gained12 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	E462	E462	Preserved
Hydrogen bond	C537	C537	Preserved
Hydrogen bond	F538	F538	Preserved
Hydrogen bond	S544	S544	Preserved
Hydrogen bond	V545	V545	Preserved
Polar contact	T440	T440	Preserved
Polar contact	E462	E462	Preserved
Polar contact	C537	C537	Preserved
Polar contact	F538	F538	Preserved
Polar contact	L543	—	Lost
Polar contact	S544	S544	Preserved
Polar contact	V545	V545	Preserved
Van der Waals	—	E462	Gained
Van der Waals	—	V463	Gained
Van der Waals	S544	—	Lost
Van der Waals	—	V545	Gained
Hydrophobic	T440	T440	Preserved
Hydrophobic	—	E462	Gained
Hydrophobic	—	V463	Gained
Hydrophobic	—	V545	Gained

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

-1.54kcal/mol

Destabilising — moderate

AlphaMissense

0.657

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 conditionsWolfram syndrome 1; Inborn genetic diseases

InheritanceWolfram syndrome 1.

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1623T>G

ClinVar accessionVCV001046024

Last evaluated2023/05/23 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Structural Context

Position 541 in TM7 (same broader region as L543P, L543F). Neighbors: TRP540 (2.5 Å — adjacent existing tryptophan!), GLU542 (2.5 Å), THR440 (3.4 Å — TM4-TM7 cross-helix!), PHE538 (3.5 Å).

The wild-type C541 is a small thiol in a bilayer-embedded position with aromatic neighbor (W540) and TM4 cross-contact (T440). Replacing it with tryptophan adds massive aromatic volume — creating W540-W541 tandem tryptophan motif. |ΔΔG| 1.54 substantial. AM 0.657 + Wolfram confirm severe consequence.

Amino-acid chemistry

Cysteine (C) → Tryptophan (W) — small thiol replaced by bulky aromatic indole. Massive volume increase + loss of disulfide potential.

Position in the protein

TM7 (residues 529–549) · position 541 (pLDDT 90).

Druggability Assessment

Category 3/4 — Most Druggable. |ΔΔG| = 1.54. AlphaMissense 0.657 + Wolfram confirm severe consequence.

Mechanism: tandem tryptophan motif creation + TM4-TM7 cross-helix disruption at T440. Therapeutic: TM4-TM7 interface site-directed.

Why this matters

C541W identifies a TM4-TM7 cross-helix contact at T440 — adding to the F408 (TM3-TM7) and S444/S551 (TM4-TM7) cross-helix targets.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the C541W 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 C541W PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Transmembrane529–549 · Helical