# WFS1 Wolframin — D339N Variant Card

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

*Aspartate → Asparagine at position 339 in connecting loop. ClinVar Conflicting including Wolfram. AlphaMissense 0.14 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.04 (neutral).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | D339N (p.Aspartate339Asparagine) |
| **DNA change** | c.1015G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000215354 |
| **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 339** | **66.81** — confident |
| **Domain** | Connecting loop |
| **Position context** | Connecting loop · position 339 (pLDDT 67). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin

> Position 339 in connecting loop. Neighbors: ILE338 (2.5 Å), PHE340 (2.5 Å — TM2 start), ALA342 (3.8 Å — A342T position).

D339N at boundary with TM2. The T337I-I338-D339-F340 region — adjacent to T337I Atlas card. AM 0.14 under-call; Wolfram confirms.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1393** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.04 (Destabilising)** |
| Job ID | 177992505559 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992505559 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/05/14 00:00 |
| Inheritance | Wolfram syndrome 1. |
| WFS1 variant landscape | D339N 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 4 — Stable Fold, Function Disrupted (AM under-call).</strong> ΔΔG ≈ 0. AlphaMissense 0.14 below threshold but Wolfram 1 confirms.<br/><br/>Mechanism: charge loss in 337-339 loop microregion. Therapeutic: same loop as T337I.

**Why this card matters.** D339N + T337I in same loop region — A342T just downstream — multi-variant cluster.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `D339N_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 339 with ball-and-stick + neighbors within 5Å)
- `D339N_variant_card.md` — this card (source of truth)
- `D339N_variant_card.html` — styled printable card
- `D339N_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)
- `D339N_wildtype_interactions.pse` / `D339N_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.*