# WFS1 Wolframin — L543R Variant Card

**Molecular Atlas Pilot Variant · RareResearch.AI · Windsor Symposium Demo**

Prepared: May 26, 2026 · Schema target: **Category 1 or 2 (TBD from DynaMut2)**

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## Identity

| Field | Value |
|---|---|
| **Variant** | L543R |
| **DNA change** | c.1628T>G |
| **Gene** | WFS1 |
| **Protein** | Wolframin (890 aa) |
| **UniProt ID** | O76024 |
| **ClinVar accession** | VCV002203523 |
| **Amino acid change** | L → R at position 543 |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 543** | **90.94** |
| **Domain** | TM7 (529-549), helical transmembrane |
| **UniProt features at this position** | |

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

Position 543 is in TM7 (residues 529–549), pLDDT 90.94 (very high confidence). Leucine → Arginine inserts a permanent positive charge into the hydrophobic lipid bilayer interior. This is one of the most thermodynamically costly substitutions a transmembrane helix can tolerate — equivalent to dragging a charged ion into a greasy environment.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| **am_pathogenicity** | **0.9686** |
| **am_class** | **LPath** |
| **Interpretation** | Likely pathogenic — strong signal |

### DynaMut2
| Field | Value |
|---|---|
| **Job ID** | 177985958201 |
| **ΔΔG (kcal/mol)** | **-1.75 kcal/mol (Destabilising)** |
| **Result URL** | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177985958201 |

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## Clinical Evidence

| Field | Value |
|---|---|
| **ClinVar classification** | **Pathogenic/Likely pathogenic** |
| **Review status** | criteria provided, multiple submitters, no conflicts |
| **Last evaluated** | 2024/02/16 00:00 |
| **Associated conditions** | not provided; Wolfram-like syndrome; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Cataract 41; Wolfram syndrome 1 |

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## Computational vs Clinical Tension

AlphaMissense 0.969 (LPath). ClinVar Pathogenic/Likely pathogenic, multi-submitter. Strong agreement.

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## Phenotype focus

Wolfram spectrum + autosomal dominant hearing loss + diabetes + cataract

## Carrier story

L543R sits in transmembrane helix 7 — the same helix that anchors R558. Two pathogenic variants, one helix, telling a 'structural neighborhood' story when you rotate the Mol* viewer.

## Mechanism hypothesis

Likely severely destabilizing in the TM context. Two possible mechanisms: (1) the protein never inserts properly into the membrane (translocon rejects the malformed helix), or (2) it inserts but the bilayer interfacial penalty distorts neighboring helices — including TM7's connection to R558's loop. Predicting Category 1 or upper Category 2.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `L543R_molstar_viewer.html` — interactive 3D viewer (auto-loads and highlights position 543)
- `L543R_variant_card.md` — this card
- `L543R_variant_card.html` — demo-ready styled version



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## Final Schema Categorization

**Category 2/3 — Most Druggable (chaperone candidate, upper boundary)**

L543R produced the largest magnitude of the pilot set (-1.75 kcal/mol) — consistent with inserting a charge into the transmembrane helix interior, but still below the Cat 2 boundary of |ΔΔG| ≥ 2. The fold accommodates the charged residue better than expected, possibly because nearby polar residues in TM7 provide partial compensation. Same druggable category as R558C, but a stronger destabilization signal — likely the higher-yield chaperone screening candidate.

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*Every assumption documented. Every score sourced. The Atlas standard.*