# WFS1 Wolframin — L514F Variant Card

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

*Leucine → Phenylalanine at position 514. Transmembrane helix 7. ClinVar Uncertain significance, AlphaMissense 0.597, DynaMut2 ΔΔG -1.32 kcal/mol (destabilising).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | L514F (p.Leucine514Phenylalanine) |
| **DNA change** | c.1540C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001208897 |
| **Amino acid change** | Leucine (L) → Phenylalanine (F) |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 514** | **88.12** — well-folded |
| **Domain** | Transmembrane helix 7 |
| **Position context** | Inside Transmembrane helix 7 · position 514 is bilayer-embedded |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  (none catalogued)

> Position 514 sits in a transmembrane helix (Transmembrane helix 7). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. The wild-type residue is medium hydrophobic (leucine — branched); the mutant is large aromatic hydrophobic (phenylalanine). 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 | **0.5971** |
| am_class | **likely pathogenic** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.32 (Destabilising)** |
| Job ID | 178092155662 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092155662 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Uncertain significance** |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2022/01/01 00:00 |
| Inheritance | Autosomal recessive Wolfram syndrome 1 phenotype documented. |
| WFS1 variant landscape | L514F is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Optic atrophy
- Wolfram syndrome 1

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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><br/><br/>|ΔΔG|=1.32 < 2 kcal/mol (fold intact) + AlphaMissense 0.597 confirms functional impact. Specific local contacts disrupted — priority for docking and pharmacological chaperone screening.

**Why this card matters.** Wolframin's fold survives this substitution (|ΔΔG|=1.32 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.597. Protein still folds, but a specific local site is broken. Pharmacological chaperones and small-molecule binders are the rational therapeutic vector.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `L514F_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 514 with ball-and-stick + neighbors within 5Å)
- `L514F_variant_card.md` — this card (source of truth)
- `L514F_variant_card.html` — styled printable card
- `L514F_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)
- `L514F_wildtype_interactions.pse` / `L514F_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.*