# WFS1 Wolframin — E462G Variant Card

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

*Glutamate → Glycine at position 462 in a connecting loop. ClinVar Likely pathogenic. AlphaMissense 0.805, DynaMut2 ΔΔG -1.10 kcal/mol (destabilising). Loss of charge plus loss of side chain entirely.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | E462G (p.Glutamate462Glycine) |
| **DNA change** | c.1385A>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000092252 |
| **Amino acid change** | Glutamate (E) → Glycine (G) — negatively-charged carboxylate replaced by smallest amino acid. Loss of charge and side-chain mass. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 462** | **84.75** — well-folded |
| **Domain** | Connecting loop |
| **Position context** | Connecting loop · position 462 in a loop region (pLDDT 85). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Natural variant: 461-463 in WFS1
  - Natural variant: 462-462 in CTRCT41; dbSNP:rs398123066

> Position 462 sits in a connecting loop. The AlphaFold model places E462 within 5 Å of VAL463 (2.5 Å), THR461 (2.5 Å), LEU459 (3.7 Å), ALA458 (3.8 Å), and THR464 (4.3 Å). The local environment is hydrophobic-leaning with two threonines providing H-bond options.

The wild-type glutamate's carboxylate likely engages T461 or T464 through H-bonding while extending the negative charge toward solvent. Replacing E462 with glycine eliminates both the charge and the side chain — substantial loss for a single substitution.

The |ΔΔG| of 1.10 reflects this. AlphaMissense's 0.805 confirms pathogenic functional consequence. Mechanism is loss of E462's H-bonding role in the loop's polar network plus introduction of backbone flexibility where the wild-type constrained.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.8046** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.1 (Destabilising)** |
| Job ID | 177992007254 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992007254 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2024/07/01 00:00 |
| Inheritance | Inheritance not specified. |
| WFS1 variant landscape | E462G 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| = 1.10 — fold survives. AlphaMissense 0.805 confirms severe functional consequence.<br/><br/>Mechanism is loss of E462 H-bonding plus backbone flexibility gain. Therapeutic strategy: site-directed at the loop polar network.

**Why this card matters.** E462G is one of several charge-loss-to-glycine variants in the Atlas — substantial structural and functional cost from a single substitution removing both charge and side chain.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `E462G_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 462 with ball-and-stick + neighbors within 5Å)
- `E462G_variant_card.md` — this card (source of truth)
- `E462G_variant_card.html` — styled printable card
- `E462G_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)
- `E462G_wildtype_interactions.pse` / `E462G_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.*