# WFS1 Wolframin — D866N Variant Card

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

*Aspartate → Asparagine at position 866. ClinVar Conflicting including monogenic diabetes + Wolfram. AlphaMissense 0.18 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.59.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | D866N (p.Aspartate866Asparagine) |
| **DNA change** | c.2596G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000178655 |
| **Amino acid change** | Aspartate (D) → Asparagine (N) — charge loss; H-bonding preserved. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 866** | **63.50** — confident |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 866 (pLDDT 64 borderline). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 866 in C-terminal cluster. Neighbors: TRP867 (2.5 Å), HIS865 (2.5 Å — partner of E864K via H865), ARG868 (4.3 Å — R868H!). The 864-868 cluster has E864K, H865 (E864K's neighbor), D866N (this card), R868H — four variants/positions in five residues.

D866N charge loss in dense multi-variant cluster. AM 0.18 under-call; multi-phenotype confirms.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1765** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.59 (Destabilising)** |
| Job ID | 177992500249 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992500249 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/01/28 00:00 |
| Inheritance | Monogenic diabetes + Wolfram. |
| WFS1 variant landscape | D866N is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Monogenic diabetes
- 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| 0.59. AlphaMissense 0.18 below threshold but multi-phenotype confirms.<br/><br/>Mechanism: charge loss in dense 864-868 cluster. Therapeutic: same C-terminal cluster.

**Why this card matters.** D866N extends the 864-868 multi-variant cluster — 5+ Atlas variants now in this 5-residue stretch.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `D866N_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 866 with ball-and-stick + neighbors within 5Å)
- `D866N_variant_card.md` — this card (source of truth)
- `D866N_variant_card.html` — styled printable card
- `D866N_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)
- `D866N_wildtype_interactions.pse` / `D866N_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.*