S334R
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 | F330 | F330 | Preserved |
| Hydrogen bond | F331 | — | Lost |
| Polar contact | F330 | F330 | Preserved |
| Polar contact | F331 | — | Lost |
| Polar contact | I332 | I332 | Preserved |
| Polar contact | — | L336 | Gained |
| Van der Waals | F331 | — | Lost |
| Van der Waals | I332 | I332 | 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
Clinical Evidence
Observed at very low frequency in gnomAD.
Full Variant Card
WFS1 Wolframin — S334R Variant Card
Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill
Serine → Arginine at position 334. Cytoplasmic loop 1. ClinVar Uncertain significance, AlphaMissense 0.986, DynaMut2 ΔΔG -0.19 kcal/mol (destabilising).
Identity
| Field | Value |
|---|---|
| Variant | S334R (p.Serine334Arginine) |
| DNA change | c.1002C>G |
| Gene · Protein | WFS1 · Wolframin (890 aa) |
| UniProt | O76024 · WFS1_HUMAN |
| ClinVar accession | VCV001331236 |
| Amino acid change | Serine (S) → Arginine (R) |
Structural Context
| Field | Value |
|---|---|
| AlphaFold model | AF-O76024-F1, v6 |
| pLDDT at residue 334 | 68.25 — confident |
| Domain | Cytoplasmic loop 1 |
| Position context | Loop region · position 334 sits between transmembrane segments, solvent-accessible |
| IDR flag | No — pLDDT above 50 threshold |
UniProt features at this position:
(none catalogued)
Position 334 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 small polar (serine — hydroxyl); the mutant is positively charged (arginine — guanidinium, strong H-bond donor). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.
Computational Predictions
AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | 0.9856 |
| am_class | likely pathogenic |
| Interpretation | Likely pathogenic (threshold 0.564) |
DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | -0.19 (Destabilising) |
| Job ID | 178092089777 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092089777 |
Clinical Evidence
| Field | Value |
|---|---|
| Classification | Uncertain significance |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2025/05/19 00:00 |
| Inheritance | Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations. |
| WFS1 variant landscape | S334R is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |
- Inborn genetic diseases
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|=0.19 < 2 kcal/mol (fold intact) + AlphaMissense 0.986 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|=0.19 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.986. 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 structureS334R_molstar_viewer.html— interactive 3D viewer (auto-highlights position 334 with ball-and-stick + neighbors within 5Å)S334R_variant_card.md— this card (source of truth)S334R_variant_card.html— styled printable cardS334R_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)S334R_wildtype_interactions.pse/S334R_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 S334R 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.