# WFS1 Wolframin — Y508C Variant Card

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

*Tyrosine → Cysteine at position 508 inside TM6. ClinVar Conflicting including Wolfram. AlphaMissense 0.419 (below threshold), ΔΔG -1.22.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | Y508C (p.Tyrosine508Cysteine) |
| **DNA change** | c.1523A>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001027491 |
| **Amino acid change** | Tyrosine (Y) → Cysteine (C) — large aromatic phenol replaced by small thiol. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 508** | **84.75** — well-folded |
| **Domain** | TM6 (496-516), helical transmembrane |
| **Position context** | TM6 (residues 496–516) · position 508 (pLDDT 85). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 496-516 Helical
  - Natural variant: 508-512 in WFS1

> Position 508 in TM6. Neighbors: LEU507 (2.5 Å), VAL509 (2.5 Å), CYS505 (3.7 Å — C505Y region!), PRO504 (3.8 Å — P504L). The C505 contact at 3.7 Å is structurally significant.

Replacing Y508 with cysteine creates a potential new cysteine pair with the adjacent C505. The wild-type Y508 + C505 microregion now becomes a C505 + C508 cluster — two cysteines within 3.7 Å, geometrically capable of forming a new disulfide. This is potentially structurally disruptive.

|ΔΔG| 1.22 + AM 0.419 below threshold + Wolfram 1 confirm pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.4188** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.22 (Destabilising)** |
| Job ID | 177992472799 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992472799 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2024/01/17 00:00 |
| Inheritance | Wolfram syndrome 1. |
| WFS1 variant landscape | Y508C 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 4 — Stable Fold, Function Disrupted**

<strong>Category 3/4 — Most Druggable (AM under-call).</strong> |ΔΔG| 1.22 substantial. AlphaMissense 0.419 below threshold but Wolfram 1 + substantial ΔΔG confirm pathogenicity.<br/><br/>Mechanism: aberrant C505-C508 disulfide creation + lost Y508 aromatic packing. Therapeutic: TM6 P504-C505-Y508 microregion.

**Why this card matters.** Y508C joins the TM6 cluster (P504L, C505Y). Three Atlas variants at three consecutive positions in TM6.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `Y508C_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 508 with ball-and-stick + neighbors within 5Å)
- `Y508C_variant_card.md` — this card (source of truth)
- `Y508C_variant_card.html` — styled printable card
- `Y508C_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)
- `Y508C_wildtype_interactions.pse` / `Y508C_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.*