P420S
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 | F417 | — | Lost |
| Polar contact | I416 | — | Lost |
| Polar contact | — | S418 | Gained |
| Van der Waals | — | A422 | Gained |
| Hydrophobic | A874 | — | Lost |
| Hydrophobic | F877 | — | 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
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
Full Variant Card
WFS1 Wolframin — P420S Variant Card
Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill
Proline → Serine at position 420. Transmembrane helix 4. ClinVar Uncertain significance, AlphaMissense 0.780, DynaMut2 ΔΔG -1.15 kcal/mol (destabilising).
Identity
| Field | Value |
|---|---|
| Variant | P420S (p.Proline420Serine) |
| DNA change | c.1258C>T |
| Gene · Protein | WFS1 · Wolframin (890 aa) |
| UniProt | O76024 · WFS1_HUMAN |
| ClinVar accession | VCV001707809 |
| Amino acid change | Proline (P) → Serine (S) |
Structural Context
| Field | Value |
|---|---|
| AlphaFold model | AF-O76024-F1, v6 |
| pLDDT at residue 420 | 87.56 — well-folded |
| Domain | Transmembrane helix 4 |
| Position context | Inside Transmembrane helix 4 · position 420 is bilayer-embedded |
| IDR flag | No — pLDDT above 50 threshold |
UniProt features at this position:
(none catalogued)
Position 420 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 small polar (serine — hydroxyl). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.
Computational Predictions
AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | 0.7804 |
| am_class | likely pathogenic |
| Interpretation | Likely pathogenic (threshold 0.564) |
DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | -1.15 (Destabilising) |
| Job ID | 178092150614 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092150614 |
Clinical Evidence
| Field | Value |
|---|---|
| Classification | Uncertain significance |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2022/07/05 00:00 |
| Inheritance | Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations. |
| WFS1 variant landscape | P420S 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|=1.15 < 2 kcal/mol (fold intact) + AlphaMissense 0.780 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|=1.15 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.780. 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 structureP420S_molstar_viewer.html— interactive 3D viewer (auto-highlights position 420 with ball-and-stick + neighbors within 5Å)P420S_variant_card.md— this card (source of truth)P420S_variant_card.html— styled printable cardP420S_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)P420S_wildtype_interactions.pse/P420S_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 P420S 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.