# WFS1 Wolframin — I802T Variant Card

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

*Isoleucine → Threonine at position 802 in lumenal domain. ClinVar Conflicting including Wolfram + Wolfram-like. AlphaMissense 0.851, ΔΔG -1.99 — RIGHT AT Cat 2 boundary.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | I802T (p.Isoleucine802Threonine) |
| **DNA change** | c.2405T>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000976364 |
| **Amino acid change** | Isoleucine (I) → Threonine (T) — branched aliphatic hydrophobic replaced by small polar hydroxyl. Major chemistry shift. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 802** | **87.19** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 802 (pLDDT 87). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 802-802 in dbSNP:rs746922325

> Position 802 sits in the lumenal domain. Neighbors: VAL803 (2.4 Å), ASP801 (2.5 Å — partner of D801G), VAL779 (3.9 Å — V779G outlier region!), PRO838 (4.1 Å).

Replacing I802 with threonine introduces polarity into a hydrophobic environment near both D801G's salt-bridge region and V779G's Cat 2 outlier site. The |ΔΔG| of 1.99 is the largest in this batch — RIGHT AT the Category 2 threshold. The variant nearly bridges the fold-intact / moderately-destabilizing boundary.

AlphaMissense 0.851 + Wolfram + Wolfram-like confirm severe consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.8505** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.99 (Destabilising)** |
| Job ID | 177992461623 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992461623 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2018/07/02 00:00 |
| Inheritance | AD and AR documented. |
| WFS1 variant landscape | I802T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1
- 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 3/4 — Most Druggable (AT Cat 2 boundary).</strong> |ΔΔG| = 1.99 — at the Category 2 boundary. AlphaMissense 0.851 + dual-syndrome confirm severe consequence.<br/><br/>Mechanism: polarity in hydrophobic environment + perturbation of V779 outlier region. Therapeutic: site-directed at the V779-D801-I802 microregion — chaperone screening may also be warranted given near-Cat-2 stability.

**Why this card matters.** I802T sits at the Cat 2 threshold — Atlas's edge case for category assignment. The proximity to V779G (Cat 2 outlier) suggests this region is structurally fragile.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `I802T_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 802 with ball-and-stick + neighbors within 5Å)
- `I802T_variant_card.md` — this card (source of truth)
- `I802T_variant_card.html` — styled printable card
- `I802T_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)
- `I802T_wildtype_interactions.pse` / `I802T_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.*