# WFS1 Wolframin — F882C Variant Card

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

*Phenylalanine → Cysteine at position 882 inside TM11. ClinVar Likely pathogenic, auditory neuropathy. AlphaMissense 0.496 (below threshold) — AM under-call. DynaMut2 ΔΔG -1.59 kcal/mol (destabilising). Volume loss in the TM11 aromatic cluster.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | F882C (p.Phenylalanine882Cysteine) |
| **DNA change** | c.2645T>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV002683881 |
| **Amino acid change** | Phenylalanine (F) → Cysteine (C) — aromatic hydrophobic replaced by thiol-bearing residue. Massive volume loss; aromatic character lost. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 882** | **82.31** — well-folded |
| **Domain** | TM11 (870-890), helical transmembrane |
| **Position context** | TM11 (residues 870–890) · position 882 mid-helix, bilayer-embedded (pLDDT 82). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 870-890 Helical

> Position 882 sits inside TM11. The AlphaFold model places F882 within 5 Å of PHE881 (2.5 Å), PHE883 (2.5 Å), PHE879 (3.9 Å), ASP880 (4.2 Å), and ALA878 (4.4 Å). The local environment is a dense aromatic cluster — four phenylalanines (F879, F881, F882, F883) plus the nearby P885 (P885L Atlas card) and F884/F886 (in the broader cluster).

Replacing F882 with cysteine eliminates one of the four aromatics in this cluster. The π-stacking network reorganizes; the introduced thiol can engage in oxidative disulfide chemistry if a partner cysteine is nearby (none within 5 Å here). The |ΔΔG| of 1.59 reflects substantial structural cost from the lost aromatic.

AlphaMissense's 0.496 is below the 0.564 likely-pathogenic threshold — another AM under-call case. ClinVar Likely Pathogenic + auditory neuropathy + the substantial ΔΔG argue for genuine pathogenicity despite the AM signal.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.4956** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.59 (Destabilising)** |
| Job ID | 177992009439 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992009439 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2023/12/22 00:00 |
| Inheritance | Auditory neuropathy documented. |
| WFS1 variant landscape | F882C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Auditory neuropathy

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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| = 1.59 — close to Cat 2. AlphaMissense 0.496 below threshold but ClinVar pathogenic + auditory neuropathy + substantial ΔΔG confirm pathogenicity.<br/><br/>Mechanism is loss of one aromatic from the dense TM11 phenylalanine cluster (F879-F881-F882-F883). Therapeutic strategy: site-directed at the TM11 aromatic cluster — same broader region as P885L.

**Why this card matters.** F882C joins the AM-under-call class (with W639G, R629W, E202G). Drug discovery should integrate ΔΔG with AM rather than treating either as the sole pathogenicity signal.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `F882C_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 882 with ball-and-stick + neighbors within 5Å)
- `F882C_variant_card.md` — this card (source of truth)
- `F882C_variant_card.html` — styled printable card
- `F882C_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)
- `F882C_wildtype_interactions.pse` / `F882C_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.*