C529W
Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource cardInteractive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | E394 | Gained |
| Hydrogen bond | K525 | K525 | Preserved |
| Hydrogen bond | P533 | P533 | Preserved |
| Polar contact | K525 | K525 | Preserved |
| Polar contact | — | P533 | Gained |
| Aromatic / π | — | W371 | Gained |
| Van der Waals | — | G398 | Gained |
| Hydrophobic | — | W371 | Gained |
| Hydrophobic | — | F397 | 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
Clinical Evidence
Observed at very low frequency in gnomAD.
Full Variant Card
WFS1 Wolframin — C529W Variant Card
Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill
Cysteine → Tryptophan at position 529. Cytoplasmic loop 4. ClinVar Uncertain significance, AlphaMissense 0.661, DynaMut2 ΔΔG -0.80 kcal/mol (destabilising).
Identity
| Field | Value |
|---|---|
| Variant | C529W (p.Cysteine529Tryptophan) |
| DNA change | c.1587C>G |
| Gene · Protein | WFS1 · Wolframin (890 aa) |
| UniProt | O76024 · WFS1_HUMAN |
| ClinVar accession | VCV002830264 |
| Amino acid change | Cysteine (C) → Tryptophan (W) |
Structural Context
| Field | Value |
|---|---|
| AlphaFold model | AF-O76024-F1, v6 |
| pLDDT at residue 529 | 73.00 — well-folded |
| Domain | Cytoplasmic loop 4 |
| Position context | Loop region · position 529 sits between transmembrane segments, solvent-accessible |
| IDR flag | No — pLDDT above 50 threshold |
UniProt features at this position:
(none catalogued)
Position 529 sits in a connecting loop between transmembrane helices. Loop residues are typically solvent-exposed and often contribute to interhelical contacts or serve as recognition sites for binding partners. The wild-type residue is thiol (cysteine — disulfide-capable, free -SH); the mutant is bulky aromatic (tryptophan — indole ring). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.
Computational Predictions
AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | 0.6615 |
| am_class | likely pathogenic |
| Interpretation | Likely pathogenic (threshold 0.564) |
DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | -0.8 (Destabilising) |
| Job ID | 178092128004 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092128004 |
Clinical Evidence
| Field | Value |
|---|---|
| Classification | Uncertain significance |
| Review status | criteria provided, single submitter |
| Last evaluated | 2023/01/19 00:00 |
| Inheritance | Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations. |
| WFS1 variant landscape | C529W is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |
(no conditions catalogued)
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|=0.80 < 2 kcal/mol (fold intact) + AlphaMissense 0.661 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|=0.80 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.661. 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 structureC529W_molstar_viewer.html— interactive 3D viewer (auto-highlights position 529 with ball-and-stick + neighbors within 5Å)C529W_variant_card.md— this card (source of truth)C529W_variant_card.html— styled printable cardC529W_dynamut2_summary.html— clean offline DynaMut2 result carddynamut2_result.json— structured result datadynamut2_result_page.html— local snapshot of the Biosig result page (asset URLs absolutized)C529W_wildtype_interactions.pse/C529W_mutant_interactions.pse— PyMOL sessions
Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas Every assumption documented. Every score sourced.
Feed this card to Wolfram Intelligence
Download the C529W 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.