# WFS1 Wolframin — L445V Variant Card

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

*Leu→Val p445 TM4 AM=0.10 ddg=+0.32 pLDDT=84. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | L445V (p.Leucine445Valine) |
| **DNA change** | c.1333C>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000349318 |
| **Amino acid change** | conservative volume reduction |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 445** | **84.12** — well-folded |
| **Domain** | TM4 (427-447), helical transmembrane |
| **Position context** | TM4 (427-447) |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 427-447 Helical

> Position analysis: SER446 (2.5 Å), TYR444 (2.5 Å — partner of S443R), THR442 (3.8 Å). Near S443R cluster. The Atlas's neighbor extraction surfaces this variant's contacts.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.0958** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.32 (Stabilising)** |
| Job ID | 177992513026 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992513026 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/09/02 00:00 |
| Inheritance | Conflicting ClinVar classifications. |
| WFS1 variant landscape | L445V 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>Cat 4 — see structural prose.</strong> AlphaMissense below threshold (AM under-call class) but mechanism is structurally clear from neighbor analysis. Therapeutic strategy: site-directed at the contacts identified above.

**Why this card matters.** TM4 cluster adjacent to S443R.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `L445V_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 445 with ball-and-stick + neighbors within 5Å)
- `L445V_variant_card.md` — this card (source of truth)
- `L445V_variant_card.html` — styled printable card
- `L445V_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)
- `L445V_wildtype_interactions.pse` / `L445V_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.*