# WFS1 Wolframin — I802M Variant Card

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

*Isoleucine → Methionine at position 802 in lumenal domain. ClinVar Conflicting for DFNA6. AlphaMissense 0.35 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.44 kcal/mol (destabilising). Same position as I802T (Cat 2 boundary).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | I802M (p.Isoleucine802Methionine) |
| **DNA change** | c.2406C>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000229642 |
| **Amino acid change** | Isoleucine (I) → Methionine (M) — branched aliphatic replaced by flexible sulfur-containing hydrophobic. Conservative 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). Same position as I802T. |
| **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 same neighbors as I802T: VAL803 (2.4 Å), ASP801 (2.5 Å — partner of D801G), VAL779 (3.9 Å — V779G Cat 2 outlier region!). I802M is the second pathogenic substitution at position 802.

Where I802T introduced polarity (Cat 2 boundary ΔΔG of -1.99), I802M is conservative — flexible sulfur-containing hydrophobic replaces branched aliphatic hydrophobic. The fold absorbs the substitution more easily (|ΔΔG| 0.44).

AlphaMissense's 0.35 is below threshold (AM under-call). DFNA6 clinical evidence confirms pathogenicity. Both I802T and I802M perturb the V779-D801-I802 microregion that connects the V779G Cat 2 outlier to the D801G salt-bridge position.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.3457** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.44 (Destabilising)** |
| Job ID | 177992493707 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992493707 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/12/18 00:00 |
| Inheritance | DFNA6 hearing loss. |
| WFS1 variant landscape | I802M 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 4 — Stable Fold, Function Disrupted**

<strong>Category 3/4 — Most Druggable (AM under-call).</strong> |ΔΔG| = 0.44. AlphaMissense 0.35 below threshold but DFNA6 confirms pathogenicity.<br/><br/>Mechanism: conservative chemistry shift in the V779-D801-I802 microregion. Therapeutic strategy: same target as I802T, V779G, V779M, D801G, K800E.

**Why this card matters.** I802M is the 5th variant in the V779-D801-I802 microregion. The cluster's structural importance is now extensively documented across multiple variants.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `I802M_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 802 with ball-and-stick + neighbors within 5Å)
- `I802M_variant_card.md` — this card (source of truth)
- `I802M_variant_card.html` — styled printable card
- `I802M_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)
- `I802M_wildtype_interactions.pse` / `I802M_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.*