W540C

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Tryptophan → Cysteine at position 540 · Transmembrane helix 8 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type W540 — hydrogen bond to V536

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DynaMut2 mutant · W540C

Mutant C540 — hydrogen bond to T440 lost (14 contacts lost)

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Bond changes · DynaMut2 interaction analysis

14 lost2 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	T440	—	Lost
Hydrogen bond	V536	V536	Preserved
Hydrogen bond	C537	C537	Preserved
Hydrogen bond	S544	S544	Preserved
Polar contact	T440	T440	Preserved
Polar contact	V536	V536	Preserved
Polar contact	C537	C537	Preserved
Polar contact	F538	F538	Preserved
Polar contact	S544	S544	Preserved
Aromatic / π	F354	—	Lost
Aromatic / π	F408	—	Lost
Aromatic / π	F439	—	Lost
Van der Waals	M357	—	Lost
Van der Waals	—	T440	Gained
Van der Waals	—	V536	Gained
Van der Waals	F538	F538	Preserved
Van der Waals	S544	—	Lost
Hydrophobic	F354	—	Lost
Hydrophobic	M357	—	Lost
Hydrophobic	V358	—	Lost
Hydrophobic	T361	—	Lost
Hydrophobic	F408	—	Lost
Hydrophobic	T436	—	Lost
Hydrophobic	F439	—	Lost
Hydrophobic	L543	—	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

-1.06kcal/mol

Destabilising — moderate

AlphaMissense

0.996

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditionsWolfram-like syndrome; Wolfram syndrome 1

Population frequency (gnomAD v4)Ultra-rare · AF 0.00012%

cDNA changec.1620G>T

ClinVar accessionVCV001803909

Last evaluated2020/11/02 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — W540C Variant Card

Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill

Tryptophan → Cysteine at position 540. Transmembrane helix 8. ClinVar Uncertain significance, AlphaMissense 0.996, DynaMut2 ΔΔG -1.06 kcal/mol (destabilising).

Identity

Field	Value
Variant	W540C (p.Tryptophan540Cysteine)
DNA change	c.1620G>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001803909
Amino acid change	Tryptophan (W) → Cysteine (C)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 540	93.38 — well-folded
Domain	Transmembrane helix 8
Position context	Inside Transmembrane helix 8 · position 540 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 540 sits in a transmembrane helix (Transmembrane helix 8). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. The wild-type residue is bulky aromatic (tryptophan — indole ring); the mutant is thiol (cysteine — disulfide-capable, free -SH). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.9960
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.06 (Destabilising)
Job ID	178092086312
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092086312

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2020/11/02 00:00
Inheritance	Autosomal recessive Wolfram syndrome 1 phenotype documented.
WFS1 variant landscape	W540C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Wolfram-like syndrome
Wolfram syndrome 1

Research Path Decision Tree

ΔΔG < 2  + binding site affected   →  CATEGORY 3 — docking experiments
ΔΔG 2–4                            →  CATEGORY 2 — pharmacological chaperones
ΔΔG > 4                            →  CATEGORY 1 — gene therapy
pLDDT < 50                         →  CATEGORY 5 — IDR, experimental only
Stable fold + functional site hit  →  CATEGORY 4 — site-specific docking

Final Schema Categorization

Category 3/4 — Most Druggable

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=1.06 < 2 kcal/mol (fold intact) + AlphaMissense 0.996 confirms functional impact. Specific local contacts disrupted — priority for docking and pharmacological chaperone screening.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.06 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.996. Protein still folds, but a specific local site is broken. Pharmacological chaperones and small-molecule binders are the rational therapeutic vector.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
W540C_molstar_viewer.html — interactive 3D viewer (auto-highlights position 540 with ball-and-stick + neighbors within 5Å)
W540C_variant_card.md — this card (source of truth)
W540C_variant_card.html — styled printable card
W540C_dynamut2_summary.html — clean offline DynaMut2 result card
dynamut2_result.json — structured result data
dynamut2_result_page.html — local snapshot of the Biosig result page (asset URLs absolutized)
W540C_wildtype_interactions.pse / W540C_mutant_interactions.pse — PyMOL sessions

Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas Every assumption documented. Every score sourced.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the W540C 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 W540C PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.