# WFS1 Wolframin — C850Y Variant Card

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

*Cysteine → Tyrosine at position 850 in wolframin's C-terminal lumenal domain. ClinVar Conflicting classifications including Wolfram syndrome 1. AlphaMissense 0.975, DynaMut2 ΔΔG -0.42 kcal/mol (destabilising). The C850 partner of C847Y in the inferred C847-C850 disulfide.*

---

## Identity

| Field | Value |
|---|---|
| **Variant** | C850Y (p.Cysteine850Tyrosine) |
| **DNA change** | c.2549G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000287170 |
| **Amino acid change** | Cysteine (C) → Tyrosine (Y) — thiol-bearing residue replaced by aromatic phenol. Loss of disulfide potential; aromatic introduction. |

---

## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 850** | **74.25** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 850 in the ER lumen (pLDDT 74 — borderline). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 850 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places C850 within 5 Å of MET851 (2.5 Å), ASN849 (2.5 Å), and CYS847 (3.6 Å — partner of C847Y Atlas card, possible disulfide). The C847-C850 distance of 3.6 Å is the strongest disulfide-distance signal in this batch.

Replacing C850 with tyrosine eliminates this potential disulfide and introduces aromatic volume. Combined with C847Y (Atlas card adjacent), both ends of the inferred C847-C850 disulfide are now known to be pathogenic when mutated.

The |ΔΔG| of 0.42 reflects fold accommodation. AlphaMissense's 0.975 confirms severe functional consequence. pLDDT 74 is borderline but above the IDR threshold.

---

## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9752** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.42 (Destabilising)** |
| Job ID | 177992299988 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992299988 |

---

## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2023/11/07 00:00 |
| Inheritance | Wolfram syndrome 1 documented. |
| WFS1 variant landscape | C850Y is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1

---

## 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| = 0.42 — fold survives. AlphaMissense 0.975 + Wolfram 1 confirm severe functional consequence.<br/><br/>Mechanism is loss of the inferred C847-C850 disulfide. Therapeutic strategy: same C847-C850 microregion as C847Y.

**Why this card matters.** C850Y + C847Y are the two pathogenic variants at opposite ends of the inferred C847-C850 disulfide. The Atlas now contains three identified disulfide-pair targets: C673-C690, C733-C765, C847-C850.

---

## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `C850Y_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 850 with ball-and-stick + neighbors within 5Å)
- `C850Y_variant_card.md` — this card (source of truth)
- `C850Y_variant_card.html` — styled printable card
- `C850Y_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)
- `C850Y_wildtype_interactions.pse` / `C850Y_mutant_interactions.pse` — PyMOL sessions

---

*Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas*
*Every assumption documented. Every score sourced.*