# WFS1 Wolframin — F810L Variant Card

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

*Phenylalanine → Leucine at position 810 in wolframin's C-terminal lumenal domain. ClinVar Conflicting classifications including Wolfram syndrome 1. AlphaMissense 0.994 (near-maximum), DynaMut2 ΔΔG +0.08 kcal/mol — essentially neutral. Conservative-looking aromatic-to-aliphatic swap with strong pathogenic signal.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | F810L (p.Phenylalanine810Leucine) |
| **DNA change** | c.2430C>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000517479 |
| **Amino acid change** | Phenylalanine (F) → Leucine (L) — aromatic hydrophobic replaced by branched aliphatic hydrophobic. Aromatic character lost; volume modestly reduced. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 810** | **86.50** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 810 in the ER lumen (pLDDT 86). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal

> Position 810 sits in wolframin's C-terminal lumenal domain near the E809K region (Atlas card adjacent). The AlphaFold model places F810 within 5 Å of GLU809 (2.5 Å — partner of E809K), LYS811 (2.5 Å), SER807 (3.9 Å), SER808 (4.3 Å), and LEU814 (4.5 Å).

Replacing F810 with leucine eliminates the aromatic ring and replaces it with branched aliphatic. The local environment — with E809 and K811 as charged neighbors and multiple serines — was sized around the wild-type aromatic ring. The variant fold accommodates the substitution easily (essentially neutral ΔΔG).

AlphaMissense's 0.994 (near-maximum) confirms severe functional consequence despite the conservative chemistry. The mechanism is loss of the F810 aromatic packing that the wild-type fold depended on for the E809-K811 salt bridge geometry — F810's aromatic ring likely positions E809 and K811 in the productive salt-bridge orientation.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9942** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.08 (Stabilising)** |
| Job ID | 177992013681 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992013681 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2017/07/13 00:00 |
| Inheritance | Conflicting classifications including Wolfram syndrome 1. |
| WFS1 variant landscape | F810L 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 3/4 — Most Druggable**

<strong>Category 4 — Stable Fold, Function Disrupted.</strong> ΔΔG = +0.08 — fold essentially unchanged. AlphaMissense 0.994 (near-maximum) confirms severe functional consequence.<br/><br/>Mechanism is loss of F810 aromatic packing that supported E809-K811 salt-bridge geometry. Therapeutic strategy: same microregion as E809K.

**Why this card matters.** F810L + E809K are sister variants at adjacent positions, both pathogenic, both perturbing the local salt-bridge geometry from different angles.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `F810L_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 810 with ball-and-stick + neighbors within 5Å)
- `F810L_variant_card.md` — this card (source of truth)
- `F810L_variant_card.html` — styled printable card
- `F810L_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)
- `F810L_wildtype_interactions.pse` / `F810L_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.*