# WFS1 Wolframin — L382P Variant Card

**Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill**

*Leucine → Proline at position 382 in a connecting loop. ClinVar Conflicting including Wolfram-like syndrome. AlphaMissense 0.922, ΔΔG -0.40 (mild destabilising). Proline-introduction in a loop region.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | L382P (p.Leucine382Proline) |
| **DNA change** | c.1145T>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001699545 |
| **Amino acid change** | Leucine (L) → Proline (P) — branched aliphatic hydrophobic replaced by rigid helix-breaking residue. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 382** | **85.31** — well-folded |
| **Domain** | Connecting loop |
| **Position context** | Connecting loop · position 382 (pLDDT 85). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin

> Position 382 sits in a connecting loop. Neighbors: ARG383 (2.5 Å — partner of R383H — not yet in Atlas), LEU381 (2.5 Å), GLU385 (3.6 Å — partner of E385K), THR378 (3.8 Å).

Replacing L382 with proline introduces a backbone kink in the loop. The R383 partner residue (with E385 forming a likely salt-bridge or H-bond network) experiences perturbed geometry. The |ΔΔG| of 0.40 reflects modest fold cost; AlphaMissense 0.922 + Wolfram-like confirm severe consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9216** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.4 (Destabilising)** |
| Job ID | 177992457478 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992457478 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2024/10/17 00:00 |
| Inheritance | Wolfram-like syndrome documented. |
| WFS1 variant landscape | L382P is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram-like syndrome

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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 3/4 — Most Druggable**

<strong>Category 3/4 — Most Druggable.</strong> |ΔΔG| = 0.40 — fold survives. AlphaMissense 0.922 confirms severe consequence.<br/><br/>Mechanism: proline-induced backbone kink in the R383-E385 microregion. Therapeutic: same loop region (E385K adjacent).

**Why this card matters.** L382P + E385K at adjacent positions — multi-variant target cluster in the 382-385 loop.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `L382P_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 382 with ball-and-stick + neighbors within 5Å)
- `L382P_variant_card.md` — this card (source of truth)
- `L382P_variant_card.html` — styled printable card
- `L382P_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)
- `L382P_wildtype_interactions.pse` / `L382P_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.*