# 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).*

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## 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) |

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## 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.

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## 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 |

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## 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)

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## 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.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `P283L_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 card
- `P283L_dynamut2_summary.html` — clean offline DynaMut2 result card
- `dynamut2_result.json` — structured result data
- `dynamut2_result_page.html` — local snapshot of the Biosig result page (asset URLs absolutized)
- `P283L_wildtype_interactions.pse` / `P283L_mutant_interactions.pse` — PyMOL sessions

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*Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas*
*Every assumption documented. Every score sourced.*