W588C

Category 4 — Stable Fold, Function DisruptedUncertain significanceTransmembrane · predictedSource card

Tryptophan → Cysteine at position 588 · Transmembrane helix 9 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type W588 — hydrogen bond to Q584

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DynaMut2 mutant · W588C

Mutant C588 — hydrogen bond to F585 lost (8 contacts lost)

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Bond changes · DynaMut2 interaction analysis

8 lost0 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	Q584	Q584	Preserved
Hydrogen bond	F585	—	Lost
Hydrogen bond	S591	S591	Preserved
Hydrogen bond	L592	L592	Preserved
Polar contact	Q584	Q584	Preserved
Polar contact	F585	F585	Preserved
Polar contact	A586	A586	Preserved
Polar contact	T590	—	Lost
Polar contact	S591	S591	Preserved
Polar contact	L592	L592	Preserved
Aromatic / π	F585	—	Lost
Van der Waals	L592	—	Lost
Van der Waals	T600	—	Lost
Hydrophobic	F585	—	Lost
Hydrophobic	L592	—	Lost
Hydrophobic	T600	—	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

-0.36kcal/mol

Destabilising — mild

AlphaMissense

0.527

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsCataract 41; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome; Wolfram syndrome 1

Population frequency (gnomAD v4)Ultra-rare · AF 0.00027%

cDNA changec.1764G>T

ClinVar accessionVCV001407986

Last evaluated2025/05/03 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — W588C Variant Card

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

Tryptophan → Cysteine at position 588. Transmembrane helix 9. ClinVar Uncertain significance, AlphaMissense 0.527, DynaMut2 ΔΔG -0.36 kcal/mol (destabilising).

Identity

Field	Value
Variant	W588C (p.Tryptophan588Cysteine)
DNA change	c.1764G>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001407986
Amino acid change	Tryptophan (W) → Cysteine (C)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 588	72.88 — well-folded
Domain	Transmembrane helix 9
Position context	Inside Transmembrane helix 9 · position 588 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 588 sits in a transmembrane helix (Transmembrane helix 9). 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	0.5273
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.36 (Destabilising)
Job ID	178094730681
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094730681

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/05/03 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	W588C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Cataract 41
Autosomal dominant nonsyndromic hearing loss 6
Type 2 diabetes mellitus
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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.36 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.36 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.527. 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
W588C_molstar_viewer.html — interactive 3D viewer (auto-highlights position 588 with ball-and-stick + neighbors within 5Å)
W588C_variant_card.md — this card (source of truth)
W588C_variant_card.html — styled printable card
W588C_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)
W588C_wildtype_interactions.pse / W588C_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 W588C 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 W588C PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.