# WFS1 Wolframin — E301K Variant Card

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

*Glutamate → Lysine at position 301 in N-terminal cytoplasmic domain. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.757, ΔΔG -0.63. Charge-flip variant.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | E301K (p.Glutamate301Lysine) |
| **DNA change** | c.901G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000591065 |
| **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 301** | **73.44** — well-folded |
| **Domain** | N-terminal cytoplasmic domain (87-313) |
| **Position context** | N-terminal cytoplasmic domain · position 301 (pLDDT 73). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Region: 1-321 Interaction with ATP6V1A

> Position 301 in cytoplasmic domain. Neighbors: TYR302 (2.5 Å), LYS300 (2.5 Å — adjacent existing lysine!), GLU298 (3.6 Å), MET297 (3.8 Å).

E301K creates two adjacent positives (K300-K301) where wild-type had K300-E301 alternating. The E298 partner of wild-type E301 loses one of its like-charged neighbors. ΔΔG 0.63 + AM 0.757 + Wolfram 1 confirm severe consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.7573** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.63 (Destabilising)** |
| Job ID | 177992465376 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992465376 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/09/20 00:00 |
| Inheritance | Wolfram syndrome 1. |
| WFS1 variant landscape | E301K 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 3/4 — Most Druggable**

<strong>Category 3/4 — Most Druggable.</strong> |ΔΔG| = 0.63. AlphaMissense 0.757 + Wolfram 1 confirm severe consequence.<br/><br/>Mechanism: charge-flip creating adjacent two-lysine cluster. Therapeutic: site-directed at the 298-302 microregion.

**Why this card matters.** E301K joins the charge-flip class. The 298-302 region has a deliberate alternating positive-negative pattern that the variant disrupts.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `E301K_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 301 with ball-and-stick + neighbors within 5Å)
- `E301K_variant_card.md` — this card (source of truth)
- `E301K_variant_card.html` — styled printable card
- `E301K_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)
- `E301K_wildtype_interactions.pse` / `E301K_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.*