# WFS1 Wolframin — S790W Variant Card

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

*Serine → Tryptophan at position 790. ClinVar Conflicting including Wolfram. AlphaMissense 0.15 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.81. pLDDT 42 — Category 5 IDR!*

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## Identity

| Field | Value |
|---|---|
| **Variant** | S790W (p.Serine790Tryptophan) |
| **DNA change** | c.2369C>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000166608 |
| **Amino acid change** | Serine (S) → Tryptophan (W) — small polar hydroxyl replaced by bulky aromatic indole. Massive volume increase. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 790** | **41.91** — **IDR (below 50 threshold)** |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 790 (pLDDT 42 — deep IDR). |
| **IDR flag** | YES — pLDDT below 50 (Cat 5) |

**UniProt features at this position:**

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

> Position 790 at pLDDT 42 — DEEP IDR. Sparse neighbors (GLY789, ARG791, ASP788). DynaMut2 untrustworthy.

S790W introduces massive aromatic volume into a disordered region. AM 0.15 under-call. Wolfram documented.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1451** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.81 (Destabilising)** |
| Job ID | 177992504586 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992504586 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/10/01 00:00 |
| Inheritance | Wolfram syndrome 1. |
| WFS1 variant landscape | S790W 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 5 — IDR Exclusion**

<strong>Category 5 — IDR Exclusion.</strong> pLDDT 42 deep IDR. AlphaMissense 0.15 below threshold. DynaMut2 prediction not trustworthy.<br/><br/>The Atlas routes Category 5 variants to wet-lab characterization.

**Why this card matters.** S790W is deep-IDR — Atlas flags for wet-lab work.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `S790W_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 790 with ball-and-stick + neighbors within 5Å)
- `S790W_variant_card.md` — this card (source of truth)
- `S790W_variant_card.html` — styled printable card
- `S790W_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)
- `S790W_wildtype_interactions.pse` / `S790W_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.*