# WFS1 Wolframin — D771Y Variant Card

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

*Aspartate → Tyrosine at position 771. ClinVar Conflicting. AlphaMissense 0.855, ΔΔG +0.18. Third variant at position 771 — same as D771H plus the N714 network position.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | D771Y (p.Aspartate771Tyrosine) |
| **DNA change** | c.2311G>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV002430988 |
| **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 771** | **88.06** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 771 (pLDDT 88). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 771 same neighbors as D771H: ARG772 (2.4 Å — salt-bridge partner), PHE770 (2.5 Å), LYS768 (3.8 Å), ASP713 (3.8 Å — same D713 in the N714 polar network).

D771Y is the second pathogenic substitution at position 771 (with D771H). Where D771H reversed charge and added aromatic, D771Y eliminates charge entirely and adds aromatic volume. The R772 salt-bridge is broken; the F770 aromatic now has a tyrosine neighbor creating a tandem aromatic.

ΔΔG essentially neutral; AM 0.855 confirms severe consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.8547** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.18 (Stabilising)** |
| Job ID | 177992461786 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992461786 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2023/09/11 00:00 |
| Inheritance | Not specified. |
| WFS1 variant landscape | D771Y 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 = +0.18. AlphaMissense 0.855 confirms severe consequence.<br/><br/>Mechanism: loss of D771-R772 salt bridge + tandem aromatic formation. Therapeutic: same D771 microregion as D771H, N714T/S/K.

**Why this card matters.** D771Y + D771H = second multi-substitution position in the D713-N714-D771-K768 polar network. Five+ variants converge here.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `D771Y_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 771 with ball-and-stick + neighbors within 5Å)
- `D771Y_variant_card.md` — this card (source of truth)
- `D771Y_variant_card.html` — styled printable card
- `D771Y_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)
- `D771Y_wildtype_interactions.pse` / `D771Y_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.*