# WFS1 Wolframin — F538S Variant Card

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

*Phenylalanine → Serine at position 538. Transmembrane helix 8. ClinVar Likely risk allele, AlphaMissense 0.984, DynaMut2 ΔΔG -3.38 kcal/mol (destabilising).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | F538S (p.Phenylalanine538Serine) |
| **DNA change** | c.1613T>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000591231 |
| **Amino acid change** | Phenylalanine (F) → Serine (S) |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 538** | **88.88** — well-folded |
| **Domain** | Transmembrane helix 8 |
| **Position context** | Inside Transmembrane helix 8 · position 538 is bilayer-embedded |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  (none catalogued)

> Position 538 sits in a transmembrane helix (Transmembrane helix 8). 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 large aromatic hydrophobic (phenylalanine); the mutant is small polar (serine — hydroxyl). 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 | **0.9842** |
| am_class | **likely pathogenic** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-3.38 (Destabilising)** |
| Job ID | 178094554004 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094554004 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely risk allele** |
| Review status | criteria provided, single submitter |
| Last evaluated | 1/01/01 00:00 |
| Inheritance | Autosomal recessive Wolfram syndrome 1 phenotype documented. |
| WFS1 variant landscape | F538S 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 2 — Moderately Destabilizing**

<strong>Category 2 — Moderately Destabilizing</strong><br/><br/>|ΔΔG|=3.38 in the 2–4 range. Pharmacological chaperone candidate.



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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `F538S_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 538 with ball-and-stick + neighbors within 5Å)
- `F538S_variant_card.md` — this card (source of truth)
- `F538S_variant_card.html` — styled printable card
- `F538S_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)
- `F538S_wildtype_interactions.pse` / `F538S_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.*