# WFS1 Wolframin — G576S Variant Card

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

*Glycine → Serine at position 576 inside TM8. ClinVar Conflicting including monogenic diabetes + WFS1 spectrum. AlphaMissense 0.15 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.46.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | G576S (p.Glycine576Serine) |
| **DNA change** | c.1726G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000045439 |
| **Amino acid change** | Glycine (G) → Serine (S) — smallest replaced by polar hydroxyl. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 576** | **83.75** — well-folded |
| **Domain** | TM8 (563-583), helical transmembrane |
| **Position context** | TM8 (residues 563–583) · position 576 (pLDDT 84). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 563-583 Helical
  - Natural variant: 576-576 in dbSNP:rs1805069

> Position 576 in TM8. Neighbors: LEU577 (2.5 Å), ALA575 (2.5 Å — A575G partner!), ILE572 (3.5 Å). The 575-576 region — A575G + G576S adjacent.

G576S removes glycine flexibility + adds polarity to TM8 bilayer environment. AM 0.15 under-call; multi-phenotype confirms.

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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) | **-0.46 (Destabilising)** |
| Job ID | 177992503415 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992503415 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/02/02 00:00 |
| Inheritance | Multi-phenotype. |
| WFS1 variant landscape | G576S is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Monogenic diabetes
- WFS1-Related Spectrum Disorders

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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| 0.46. AlphaMissense 0.15 below threshold but multi-phenotype confirms.<br/><br/>Mechanism: glycine removal + polarity in TM8. Therapeutic: same 575-576 region as A575G.

**Why this card matters.** G576S + A575G — adjacent TM8 variants both pathogenic.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `G576S_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 576 with ball-and-stick + neighbors within 5Å)
- `G576S_variant_card.md` — this card (source of truth)
- `G576S_variant_card.html` — styled printable card
- `G576S_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)
- `G576S_wildtype_interactions.pse` / `G576S_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.*