# WFS1 Wolframin — L592V Variant Card

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

*Leucine → Valine at position 592 inside TM9. ClinVar Conflicting. AlphaMissense 0.13 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.52. pLDDT 63 borderline.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | L592V (p.Leucine592Valine) |
| **DNA change** | c.1774C>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001320760 |
| **Amino acid change** | Leucine (L) → Valine (V) — branched aliphatic to smaller branched aliphatic. Conservative volume reduction. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 592** | **62.62** — confident |
| **Domain** | TM9 (589-609), helical transmembrane |
| **Position context** | TM9 (residues 589–609) · position 592 (pLDDT 63 borderline). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 589-609 Helical

> Position 592 in TM9. Neighbors: GLU593 (2.4 Å), SER591 (2.5 Å), PHE589 (4.0 Å — TM9 start).

L592V conservative volume reduction in TM9. AM 0.13 under-call; Conflicting clinical evidence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1280** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.52 (Destabilising)** |
| Job ID | 177992508277 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992508277 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/06/24 00:00 |
| Inheritance | Not specified. |
| WFS1 variant landscape | L592V is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific 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 4 — Stable Fold, Function Disrupted**

<strong>Category 4 — Stable Fold, Function Disrupted (AM under-call, pLDDT borderline).</strong> |ΔΔG| 0.52. AlphaMissense 0.13 below threshold.<br/><br/>Mechanism: conservative TM9 volume reduction. Therapeutic: TM9 site-directed.

**Why this card matters.** L592V is TM9 — same helix as P607L/P607R. TM9 cluster grows.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `L592V_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 592 with ball-and-stick + neighbors within 5Å)
- `L592V_variant_card.md` — this card (source of truth)
- `L592V_variant_card.html` — styled printable card
- `L592V_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)
- `L592V_wildtype_interactions.pse` / `L592V_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.*