# WFS1 Wolframin — D797N Variant Card

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

*Aspartate → Asparagine at position 797. ClinVar Conflicting including monogenic hearing loss + DFNA6. AlphaMissense 0.556 (borderline), ΔΔG -0.02 (neutral). Same position as D797V — second substitution at 797.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | D797N (p.Aspartate797Asparagine) |
| **DNA change** | c.2389G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000517360 |
| **Amino acid change** | Aspartate (D) → Asparagine (N) — carboxylate replaced by amide. Loss of charge; H-bonding preserved. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 797** | **64.88** — confident |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 797 (pLDDT 65 borderline). Same as D797V. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 797-797 in WFSL

> Position 797 same neighbors as D797V: VAL798 (2.4 Å), ASP796 (2.4 Å), GLU794 (4.2 Å), THR799 (4.3 Å).

D797N conserves the local geometry but eliminates the charge. The D796-D797-E794 charged cluster loses one negative member. AM 0.556 borderline + dual deafness phenotype confirm severe consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.5562** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.02 (Destabilising)** |
| Job ID | 177992469266 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992469266 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/12/05 00:00 |
| Inheritance | Monogenic hearing loss + DFNA6. |
| WFS1 variant landscape | D797N is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Monogenic hearing loss
- Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

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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.</strong> ΔΔG ≈ 0. AlphaMissense 0.556 borderline + DFNA6 confirm severe consequence.<br/><br/>Mechanism: charge loss from D796-D797-E794 cluster. Therapeutic: same target as D797V.

**Why this card matters.** D797N + D797V at same position. Two charge-loss variants at the D796-D797-E794 cluster.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `D797N_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 797 with ball-and-stick + neighbors within 5Å)
- `D797N_variant_card.md` — this card (source of truth)
- `D797N_variant_card.html` — styled printable card
- `D797N_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)
- `D797N_wildtype_interactions.pse` / `D797N_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.*