# WFS1 Wolframin — G789S Variant Card

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

*Gly→Ser p789 IDR AM=0.07 ddg=-0.11 pLDDT=43. ClinVar Conflicting evidence. Atlas mechanism: see structural analysis.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | G789S (p.Glycine789Serine) |
| **DNA change** | c.2365G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001419650 |
| **Amino acid change** | glycine flexibility lost |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 789** | **43.34** — **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: SER790 (2.5 Å — partner of S790W/L), ASP788 (2.5 Å), ALA787 (4.5 Å — A787T). pLDDT 43 IDR boundary. Position 789 adjacent to multi-substitution 790. 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 | **0.0690** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.11 (Destabilising)** |
| Job ID | 177992523646 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992523646 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/08/30 00:00 |
| Inheritance | Conflicting ClinVar classifications. |
| WFS1 variant landscape | G789S 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.** IDR boundary near S790 cluster.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `G789S_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 789 with ball-and-stick + neighbors within 5Å)
- `G789S_variant_card.md` — this card (source of truth)
- `G789S_variant_card.html` — styled printable card
- `G789S_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)
- `G789S_wildtype_interactions.pse` / `G789S_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.*