# WFS1 Wolframin — E794K Variant Card

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

*Glutamate → Lysine at position 794 in lumenal domain. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.24 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.49 STABILISING. pLDDT 49 — Category 5 IDR boundary!*

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## Identity

| Field | Value |
|---|---|
| **Variant** | E794K (p.Glutamate794Lysine) |
| **DNA change** | c.2380G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000198836 |
| **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 794** | **49.00** — **IDR (below 50 threshold)** |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 794 (pLDDT 49 — IDR boundary). |
| **IDR flag** | YES — pLDDT below 50 (Cat 5) |

**UniProt features at this position:**

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

> Position 794 at pLDDT 49 — RIGHT AT the Category 5 IDR threshold. Computational predictions deserve caution. Neighbors: GLU795 (2.5 Å), ARG793 (2.5 Å), SER792 (3.8 Å).

E794K charge-flips in a borderline IDR region. ΔΔG predictions not trustworthy here. AM 0.24 below threshold but Wolfram 1 documented.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.2416** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.49 (Stabilising)** |
| Job ID | 177992498005 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992498005 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/01/26 00:00 |
| Inheritance | Wolfram syndrome 1. |
| WFS1 variant landscape | E794K is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1

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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 5 — IDR Exclusion**

<strong>Category 5 — IDR Exclusion (borderline).</strong> pLDDT 49 at the 50 threshold. AlphaMissense 0.24 below threshold. Multiple signals suggest computational caution.<br/><br/>The Atlas routes Category 5 variants to wet-lab characterization rather than computational drug discovery.

**Why this card matters.** E794K is another borderline IDR variant — Atlas appropriately flags for wet-lab work.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `E794K_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 794 with ball-and-stick + neighbors within 5Å)
- `E794K_variant_card.md` — this card (source of truth)
- `E794K_variant_card.html` — styled printable card
- `E794K_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)
- `E794K_wildtype_interactions.pse` / `E794K_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.*