# WFS1 Wolframin — K800E Variant Card

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

*Lysine → Glutamate at position 800 in lumenal domain. ClinVar Conflicting. AlphaMissense 0.778, ΔΔG -0.40. pLDDT 72 borderline. Same K800-D801 salt-bridge pair as D801G.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | K800E (p.Lysine800Glutamate) |
| **DNA change** | c.2398A>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000215400 |
| **Amino acid change** | Lysine (K) → Glutamate (E) — positively-charged amine replaced by negatively-charged carboxylate. Charge reversal. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 800** | **71.69** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 800 (pLDDT 72). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 800 sits adjacent to D801. Neighbors: ASP801 (2.5 Å — D801G Atlas card!), THR799 (2.5 Å), ASP797 (3.7 Å), VAL798 (4.3 Å).

The wild-type K800-D801 salt bridge (referenced in D801G Atlas card) breaks when K800 becomes E800: now TWO adjacent glutamates (E800, D801) with no positive charge to stabilize. The local electrostatic environment is transformed. ΔΔG 0.40 + AM 0.778 confirm severe consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.7777** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.4 (Destabilising)** |
| Job ID | 177992463771 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992463771 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/11/03 00:00 |
| Inheritance | Not specified. |
| WFS1 variant landscape | K800E 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 3/4 — Most Druggable.</strong> |ΔΔG| = 0.40. AlphaMissense 0.778 confirms severe consequence.<br/><br/>Mechanism: K800-D801 salt bridge broken by charge-flip at K800. Therapeutic: same K800-D801 microregion as D801G.

**Why this card matters.** K800E + D801G are sister variants at the salt-bridge pair. Two convergent variant targets at the same ionic contact.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `K800E_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 800 with ball-and-stick + neighbors within 5Å)
- `K800E_variant_card.md` — this card (source of truth)
- `K800E_variant_card.html` — styled printable card
- `K800E_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)
- `K800E_wildtype_interactions.pse` / `K800E_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.*