# WFS1 Wolframin — D367Y Variant Card

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

*Aspartate → Tyrosine at position 367 in a connecting loop. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.685, ΔΔG +0.53 STABILISING.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | D367Y (p.Aspartate367Tyrosine) |
| **DNA change** | c.1099G>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001810357 |
| **Amino acid change** | Aspartate (D) → Tyrosine (Y) — small negatively-charged carboxylate replaced by large aromatic phenol. Charge loss + aromatic introduction. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 367** | **79.50** — well-folded |
| **Domain** | Connecting loop |
| **Position context** | Connecting loop · position 367 (pLDDT 80). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin

> Position 367 in connecting loop. Neighbors: GLN366 (2.5 Å), SER368 (2.5 Å), VAL364 (3.7 Å — near K363T), LYS363 (3.8 Å — partner of K363T!). The K363 contact is structurally significant: D367 wild-type likely salt-bridges with K363.

Replacing D367 with tyrosine eliminates the salt-bridge potential. The variant fold stabilises (+0.53) because the aromatic ring packs into the local environment. AM 0.685 + Wolfram 1 confirm severe consequence. Mechanism is loss of D367-K363 salt bridge.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.6853** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.53 (Stabilising)** |
| Job ID | 177992465215 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992465215 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2023/02/13 00:00 |
| Inheritance | Wolfram syndrome 1. |
| WFS1 variant landscape | D367Y 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 = +0.53 stabilising. AlphaMissense 0.685 + Wolfram 1 confirm severe consequence.<br/><br/>Mechanism: loss of D367-K363 salt bridge. Therapeutic: same K363 microregion as K363T.

**Why this card matters.** D367Y + K363T are sister variants at the K363-D367 salt-bridge pair.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `D367Y_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 367 with ball-and-stick + neighbors within 5Å)
- `D367Y_variant_card.md` — this card (source of truth)
- `D367Y_variant_card.html` — styled printable card
- `D367Y_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)
- `D367Y_wildtype_interactions.pse` / `D367Y_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.*