# WFS1 Wolframin — S790L Variant Card

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

*Ser→Leu p790 lumenal AM=0.09 ddg=-0.6 pLDDT=42. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | S790L (p.Serine790Leucine) |
| **DNA change** | c.2369C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000229641 |
| **Amino acid change** | polar→hydrophobic |

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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 IDR |
| **IDR flag** | YES — pLDDT below 50 (Cat 5) |

**UniProt features at this position:**

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

> Position analysis: GLY789 (2.4 Å), ARG791 (2.4 Å), ASP788 (3.9 Å). pLDDT 42 deep IDR. Same position as S790W. DynaMut2 untrustworthy. The Atlas's neighbor extraction surfaces this variant's contacts and connects them to the broader multi-variant target landscape.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.0949** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.6 (Destabilising)** |
| Job ID | 177992519178 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992519178 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/11/26 00:00 |
| Inheritance | Conflicting ClinVar classifications. |
| WFS1 variant landscape | S790L 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 5 — IDR Exclusion**

<strong>Cat 5 IDR — see structural prose.</strong> AlphaMissense below threshold (AM under-call class) but mechanism is structurally identified. Therapeutic strategy: site-directed at contacts identified above, or wet-lab validation if pLDDT borderline/below 50.

**Why this card matters.** Same position as S790W — deep IDR.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `S790L_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 790 with ball-and-stick + neighbors within 5Å)
- `S790L_variant_card.md` — this card (source of truth)
- `S790L_variant_card.html` — styled printable card
- `S790L_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)
- `S790L_wildtype_interactions.pse` / `S790L_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.*