# WFS1 Wolframin — L543F Variant Card

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

*Leucine → Phenylalanine at position 543 inside TM7. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.303 (below threshold) — AM under-call. DynaMut2 ΔΔG -1.34 kcal/mol (destabilising). Same position as L543P (Atlas card adjacent) but with aromatic introduction.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | L543F (p.Leucine543Phenylalanine) |
| **DNA change** | c.1627C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV002499486 |
| **Amino acid change** | Leucine (L) → Phenylalanine (F) — branched aliphatic hydrophobic replaced by aromatic hydrophobic. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 543** | **90.94** — well-folded |
| **Domain** | TM7 (529-549), helical transmembrane |
| **Position context** | TM7 (residues 529–549) · position 543 mid-helix, bilayer-embedded (pLDDT 91). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 529-549 Helical

> Position 543 sits in TM7. Same neighbor environment as L543P: GLU542 (2.5 Å), SER544 (2.5 Å), MET539 (3.7 Å), TRP540 (3.9 Å), PHE881 (4.1 Å — TM7-TM11 cross-helix).

Replacing L543 with phenylalanine adds aromatic volume to the TM7 mid-helix. Unlike L543P which introduces a backbone kink, L543F preserves α-helical structure but creates a tandem aromatic motif with W540 nearby. The TM7-TM11 cross-helix contact to F881 now involves two phenylalanines in TM7 (F543, with W540 aromatic neighbor) interacting with F881 across the interface.

The |ΔΔG| of 1.34 reflects meaningful fold cost. AlphaMissense's 0.303 below threshold is AM under-call; ClinVar Pathogenic + Wolfram 1 establishes pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.3029** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.34 (Destabilising)** |
| Job ID | 177992012776 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992012776 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2023/03/01 00:00 |
| Inheritance | Wolfram syndrome 1 (AR) documented. |
| WFS1 variant landscape | L543F is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- 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 4 — Stable Fold, Function Disrupted**

<strong>Category 3/4 — Most Druggable (AM under-call).</strong> |ΔΔG| = 1.34 — fold survives at meaningful cost. AlphaMissense 0.303 below threshold but ClinVar Pathogenic + Wolfram 1.<br/><br/>Mechanism is aromatic volume mismatch in TM7 plus rearrangement of TM7-TM11 cross-helix contact. Therapeutic strategy: same TM7-TM11 interface as L543P.

**Why this card matters.** L543F + L543P at the same position, different chemistries, both pathogenic — position 543 is a multi-substitution hotspot in TM7.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `L543F_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 543 with ball-and-stick + neighbors within 5Å)
- `L543F_variant_card.md` — this card (source of truth)
- `L543F_variant_card.html` — styled printable card
- `L543F_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)
- `L543F_wildtype_interactions.pse` / `L543F_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.*