# WFS1 Wolframin — E824K Variant Card

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

*Glutamate → Lysine at position 824 in lumenal domain. ClinVar Conflicting including DFNA6. AlphaMissense 0.566 (borderline), ΔΔG -0.13.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | E824K (p.Glutamate824Lysine) |
| **DNA change** | c.2470G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000166612 |
| **Amino acid change** | Glutamate (E) → Lysine (K) — charge reversal. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 824** | **89.81** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 824 (pLDDT 90). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 824 in lumenal domain. Neighbors: PHE825 (2.4 Å — W700-F825 π-stacking partner!), ILE823 (2.5 Å), TRP700 (3.5 Å — direct contact with W700 Cat 2 region!), SER846 (3.7 Å).

E824 sits in direct contact with W700 and F825 — the same aromatic cluster identified in W700C and T699P Atlas cards. The wild-type E824 negative charge contributes to this microregion. Charge-flipping to K824 disrupts the local environment supporting W700-F825 π-stacking.

Mild ΔΔG; AM 0.566 borderline + DFNA6 confirm severe consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.5661** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.13 (Destabilising)** |
| Job ID | 177992469795 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992469795 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2024/03/21 00:00 |
| Inheritance | DFNA6. |
| WFS1 variant landscape | E824K is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- 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 3/4 — Most Druggable**

<strong>Category 3/4 — Most Druggable.</strong> |ΔΔG| = 0.13. AlphaMissense 0.566 borderline + DFNA6 confirm severe consequence.<br/><br/>Mechanism: charge-flip in the W700-F825 aromatic cluster. Therapeutic: same W700-F825 microregion (with W700S/C, T699P/M).

**Why this card matters.** E824K is the FIFTH variant converging on the W700-F825 π-stacking microregion. Drug discovery here has unusually dense convergence.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `E824K_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 824 with ball-and-stick + neighbors within 5Å)
- `E824K_variant_card.md` — this card (source of truth)
- `E824K_variant_card.html` — styled printable card
- `E824K_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)
- `E824K_wildtype_interactions.pse` / `E824K_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.*