# WFS1 Wolframin — E809K Variant Card

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

*Glutamate → Lysine at position 809 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic, associated with Wolfram-like syndrome. AlphaMissense 0.718 (moderately pathogenic), DynaMut2 ΔΔG +0.41 kcal/mol — STABILISING. A clean charge-flip variant with structural stabilization.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | E809K (p.Glutamate809Lysine) |
| **DNA change** | c.2425G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000215413 |
| **Amino acid change** | Glutamate (E) → Lysine (K) — negatively-charged carboxylate replaced by positively-charged primary amine. Same charge-flip mechanism as E169K but in a different domain. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 809** | **83.44** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 809 in the ER lumen (pLDDT 83). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 809 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places E809 within 5 Å of SER808 (2.5 Å), PHE810 (2.5 Å), SER807 (4.3 Å), LYS811 (4.3 Å), and ILE863 (4.8 Å, long-range). The local environment contains a nearby existing lysine (K811) — the wild-type E809 may have formed an intramolecular salt bridge with K811.

Replacing glutamate with lysine reverses the charge sign at position 809. The E809-K811 salt bridge breaks; the local environment now has two adjacent positive charges (K809 and K811) instead of one positive and one negative. The DynaMut2 ΔΔG of +0.41 (stabilising) reflects that the new local geometry is more energetically favorable than the wild-type — likely because both lysines can extend their flexible side chains toward solvent.

Yet AlphaMissense places this at 0.718 (moderately pathogenic, above the 0.564 likely-pathogenic threshold) and ClinVar classifies it as Pathogenic. The mechanism is functional: the lost E809 negative charge was part of the lumenal interaction surface; the introduced K809 creates a new positive patch that disrupts whatever partner recognition the wild-type surface enabled.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.7181** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.41 (Stabilising)** |
| Job ID | 177990267533 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990267533 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2025/10/09 00:00 |
| Inheritance | Documented in association with Wolfram-like syndrome. AD-leaning presentation. |
| WFS1 variant landscape | E809K is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram-like syndrome

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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.</strong> ΔΔG = +0.41 kcal/mol — fold is more stable than wild-type. AlphaMissense 0.718 plus clinical evidence confirm pathogenic mechanism is functional rather than structural.<br/><br/>The mechanism is charge-flip at a lumenal interaction surface — broken E809-K811 salt bridge plus a new positive patch where the wild-type contributed negative charge. Therapeutic strategy: site-directed at the recognition surface, restoring or compensating for the lost negatively-charged contribution.

**Why this card matters.** E809K joins T361I, L402P, R685P, and others as Atlas variants where ΔΔG is positive (stabilising) but pathogenicity is real. The class is consistent: charge-flip or chemistry-flip variants where the new residue accommodates structurally but disrupts functional recognition. Drug discovery for this class requires AlphaMissense + clinical evidence — ΔΔG alone would miss them.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `E809K_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 809 with ball-and-stick + neighbors within 5Å)
- `E809K_variant_card.md` — this card (source of truth)
- `E809K_variant_card.html` — styled printable card
- `E809K_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)
- `E809K_wildtype_interactions.pse` / `E809K_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.*