# WFS1 Wolframin — R805W Variant Card

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

*Arginine → Tryptophan at position 805 in lumenal domain. ClinVar Conflicting. AlphaMissense 0.487 (borderline), ΔΔG +0.26 STABILISING. R→W class — aromatic replaces charge.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | R805W (p.Arginine805Tryptophan) |
| **DNA change** | c.2413C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001675945 |
| **Amino acid change** | Arginine (R) → Tryptophan (W) — long positively-charged guanidinium replaced by bulky aromatic indole. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 805** | **91.44** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 805 (pLDDT 91). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 805 in lumenal domain. Neighbors: ALA806 (2.4 Å — A806P), LEU804 (2.5 Å — L804P!), PHE775 (3.4 Å — F775V!), PHE840 (3.7 Å).

R805 sits in the dense 804-806 cluster (with L804P, A806P) and contacts F775 (F775V). Replacing R805 with tryptophan eliminates the positive charge and creates a tryptophan-phenylalanine aromatic cluster with F775 + F840. The variant fold packs efficiently (+0.26).

AM 0.487 borderline; ClinVar Conflicting. The mechanism is loss of R805 charge from the F775-R805 ionic/cation-π contact discussed in F775V Atlas card.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.4867** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.26 (Stabilising)** |
| Job ID | 177992470439 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992470439 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2024/10/28 00:00 |
| Inheritance | Not specified. |
| WFS1 variant landscape | R805W 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 4 — Stable Fold, Function Disrupted**

<strong>Category 4 — Stable Fold, Function Disrupted.</strong> ΔΔG = +0.26 stabilising. AlphaMissense 0.487 borderline.<br/><br/>Mechanism: loss of R805 cation-π contribution to F775 contact. Therapeutic: same 775-806 microregion (with L804P, A806P, F775V).

**Why this card matters.** R805W is the fifth variant in the dense 775-806 microregion.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R805W_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 805 with ball-and-stick + neighbors within 5Å)
- `R805W_variant_card.md` — this card (source of truth)
- `R805W_variant_card.html` — styled printable card
- `R805W_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)
- `R805W_wildtype_interactions.pse` / `R805W_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.*