# WFS1 Wolframin — Y650D Variant Card

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

*Tyrosine → Aspartate at position 650 inside TM10. ClinVar Likely pathogenic. AlphaMissense 0.829, DynaMut2 ΔΔG +0.38 STABILISING. pLDDT 69 borderline. Same position as Y650H (Atlas card adjacent) but with charge introduction.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | Y650D (p.Tyrosine650Aspartate) |
| **DNA change** | c.1948T>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV002783903 |
| **Amino acid change** | Tyrosine (Y) → Aspartate (D) — large aromatic phenol replaced by small negatively-charged carboxylate. Volume decrease plus charge introduction. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 650** | **68.69** — confident |
| **Domain** | TM10 (632-652), helical transmembrane |
| **Position context** | TM10 (residues 632–652) · position 650 near the C-terminus of TM10 (pLDDT 69 borderline). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 632-652 Helical

> Position 650 sits at the end of TM10, in the same aromatic-rich pocket discussed in the Y650H Atlas card: PHE649 (2.5 Å), VAL651 (2.5 Å), CYS647 (3.7 Å), PHE646 (3.7 Å), TRP648 (4.4 Å).

Replacing tyrosine with aspartate is more disruptive than Y650H. Y650H preserved aromatic character (histidine imidazole). Y650D eliminates the aromatic ring entirely and introduces a small carboxylate where the wild-type phenol provided bulky aromatic packing. The aromatic cluster (F646, F649, W648) loses its tyrosine partner; the new carboxylate is also unfavorable in the bilayer-embedded environment.

The DynaMut2 ΔΔG of +0.38 (stabilising) is surprising — possibly because the aspartate can extend toward the lumenal face of TM10 where its charge is more compatible. AlphaMissense's 0.829 + ClinVar Pathogenic confirm severe functional consequence despite the stabilization.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.8288** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.38 (Stabilising)** |
| Job ID | 177992006596 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992006596 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2024/01/04 00:00 |
| Inheritance | Inheritance not specified. |
| WFS1 variant landscape | Y650D is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued)

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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 = +0.38 stabilising. AlphaMissense 0.829 confirms severe functional consequence.<br/><br/>Mechanism is loss of Y650 aromatic packing with the TM10 C-terminal aromatic cluster (F646, F649, W648). Therapeutic strategy: same microregion as Y650H.

**Why this card matters.** Y650D + Y650H together establish position 650 as a critical aromatic-anchor position. Two variants at the same position with different chemistries — both pathogenic, same therapeutic target.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `Y650D_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 650 with ball-and-stick + neighbors within 5Å)
- `Y650D_variant_card.md` — this card (source of truth)
- `Y650D_variant_card.html` — styled printable card
- `Y650D_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)
- `Y650D_wildtype_interactions.pse` / `Y650D_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.*