# WFS1 Wolframin — D797V Variant Card

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

*Aspartate → Valine at position 797 in lumenal domain. ClinVar Conflicting. AlphaMissense 0.876, ΔΔG +0.04 (neutral). pLDDT 65 borderline.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | D797V (p.Aspartate797Valine) |
| **DNA change** | c.2390A>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV002203531 |
| **Amino acid change** | Aspartate (D) → Valine (V) — negatively-charged carboxylate replaced by branched aliphatic hydrophobic. |

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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). |
| **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 sits in the lumenal C-terminal region. Neighbors: VAL798 (2.4 Å), ASP796 (2.4 Å — adjacent aspartate), GLU794 (4.2 Å), THR799 (4.3 Å).

Replacing D797 with valine eliminates the negative charge in a local charged cluster (D796, E794 nearby). Fold accommodates (ΔΔG essentially zero). AlphaMissense 0.876 confirms severe consequence. Same position as D797N — both pathogenic.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.8764** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.04 (Stabilising)** |
| Job ID | 177992461163 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992461163 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/03/31 00:00 |
| Inheritance | Not specified. |
| WFS1 variant landscape | D797V 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 (pLDDT caveat).</strong> ΔΔG ≈ 0. AlphaMissense 0.876 confirms severe consequence. pLDDT 65 borderline.<br/><br/>Mechanism: charge loss from local D796-D797-E794 cluster. Therapeutic: site-directed at this charge cluster.

**Why this card matters.** D797V + D797N at same position. Charge cluster D796-D797-E794 is a recognition surface; multiple variants disrupt it.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `D797V_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 797 with ball-and-stick + neighbors within 5Å)
- `D797V_variant_card.md` — this card (source of truth)
- `D797V_variant_card.html` — styled printable card
- `D797V_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)
- `D797V_wildtype_interactions.pse` / `D797V_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.*