# WFS1 Wolframin — C847Y Variant Card

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

*Cysteine → Tyrosine at position 847 in wolframin's C-terminal lumenal domain. ClinVar Conflicting classifications including Wolfram syndrome 1 and autistic behavior. AlphaMissense 0.994 (near-maximum), DynaMut2 ΔΔG -0.92 kcal/mol (destabilising). Cysteine-removal with potential disulfide loss to C850.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | C847Y (p.Cysteine847Tyrosine) |
| **DNA change** | c.2540G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000437421 |
| **Amino acid change** | Cysteine (C) → Tyrosine (Y) — thiol-bearing residue replaced by aromatic phenol. Loss of disulfide potential; aromatic introduction. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 847** | **86.19** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 847 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 847 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places C847 within 5 Å of SER846 (2.4 Å), LEU848 (2.5 Å), LEU822 (3.8 Å — long-range), ILE823 (4.3 Å), and CYS850 (4.4 Å — another cysteine!). The C847-C850 distance of 4.4 Å is consistent with a possible structural disulfide bond.

Replacing C847 with tyrosine eliminates this potential disulfide and introduces aromatic volume. The C850 partner residue (partner of C850Y Atlas card) loses its disulfide partner if one existed. The |ΔΔG| of 0.92 reflects substantial fold cost.

AlphaMissense 0.994 confirms severe functional consequence. The C847-C850 microregion has variants at both cysteines (C847Y and C850Y), suggesting both cysteines are structurally important and disulfide-related.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9943** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.92 (Destabilising)** |
| Job ID | 177992012957 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992012957 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2024/07/05 00:00 |
| Inheritance | Conflicting classifications including Wolfram syndrome 1. |
| WFS1 variant landscape | C847Y is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1
- Autistic behavior

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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 3/4 — Most Druggable.</strong> |ΔΔG| = 0.92 — fold survives. AlphaMissense 0.994 confirms severe functional consequence.<br/><br/>Mechanism is potential C847-C850 disulfide loss plus aromatic volume introduction. Therapeutic strategy: site-directed at the C847-C850 microregion.

**Why this card matters.** C847Y + C850Y are sister variants at adjacent cysteines, possibly a structural disulfide pair. The Atlas now identifies THREE possible disulfide pairs in the lumenal domain: C673-C690, C733-C765, C847-C850. The lumenal fold appears to rely on multiple disulfides for structural integrity.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `C847Y_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 847 with ball-and-stick + neighbors within 5Å)
- `C847Y_variant_card.md` — this card (source of truth)
- `C847Y_variant_card.html` — styled printable card
- `C847Y_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)
- `C847Y_wildtype_interactions.pse` / `C847Y_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.*