P283L
Category 5 — IDR ExclusionUncertain significanceCytoplasmic · predictedSource cardInteractive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | L286 | L286 | Preserved |
| Hydrogen bond | K287 | K287 | Preserved |
| Polar contact | R285 | R285 | Preserved |
| Polar contact | L286 | L286 | Preserved |
| Polar contact | K287 | K287 | Preserved |
| Van der Waals | R285 | — | 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
Observed at very low frequency in gnomAD.
Full Variant Card
WFS1 Wolframin — P283L Variant Card
Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill
Proline → Leucine at position 283. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.561, DynaMut2 ΔΔG -0.08 kcal/mol (destabilising).
Identity
| Field | Value |
|---|---|
| Variant | P283L (p.Proline283Leucine) |
| DNA change | c.848C>T |
| Gene · Protein | WFS1 · Wolframin (890 aa) |
| UniProt | O76024 · WFS1_HUMAN |
| ClinVar accession | VCV001698178 |
| Amino acid change | Proline (P) → Leucine (L) |
Structural Context
| Field | Value |
|---|---|
| AlphaFold model | AF-O76024-F1, v6 |
| pLDDT at residue 283 | 49.81 — IDR (below 50 threshold) |
| Domain | N-terminal cytoplasmic (intrinsically disordered) |
| Position context | N-terminal cytoplasmic (intrinsically disordered) |
| IDR flag | YES — pLDDT below 50 (Cat 5) |
UniProt features at this position:
(none catalogued)
Position 283 sits in N-terminal cytoplasmic (intrinsically disordered). The wild-type residue is rigid/helix-breaking (proline — kinks backbone); the mutant is medium hydrophobic (leucine — branched). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.
Computational Predictions
AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | 0.5612 |
| am_class | ambiguous |
| Interpretation | Likely benign (threshold 0.564) |
DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | -0.08 (Destabilising) |
| Job ID | 178094717889 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094717889 |
Clinical Evidence
| Field | Value |
|---|---|
| Classification | Uncertain significance |
| Review status | criteria provided, single submitter |
| Last evaluated | 2022/01/18 00:00 |
| Inheritance | Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations. |
| WFS1 variant landscape | P283L 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 5 — IDR Exclusion
<strong>Category 5 — IDR Exclusion</strong><br/><br/>pLDDT 49.81 is below 50; DynaMut2 result not trustworthy. Route to wet-lab.
Why this card matters. Position sits in a low-confidence region. Computational stability estimates here are unreliable; this variant needs experimental characterization before any therapeutic strategy is set.
Files in this folder
AF-O76024-F1-model_v6.pdb— AlphaFold structureP283L_molstar_viewer.html— interactive 3D viewer (auto-highlights position 283 with ball-and-stick + neighbors within 5Å)P283L_variant_card.md— this card (source of truth)P283L_variant_card.html— styled printable cardP283L_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)P283L_wildtype_interactions.pse/P283L_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 P283L 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.