# WFS1 Wolframin — A575G Variant Card

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

*Alanine → Glycine at position 575 inside TM8. ClinVar Conflicting with broad spectrum — Wolfram-like, Cataract 41, Wolfram. AlphaMissense 0.14 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.41.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | A575G (p.Alanine575Glycine) |
| **DNA change** | c.1724C>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000440419 |
| **Amino acid change** | Alanine (A) → Glycine (G) — small methyl-bearing replaced by smallest amino acid. Side chain removed. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 575** | **80.88** — well-folded |
| **Domain** | TM8 (563-583), helical transmembrane |
| **Position context** | TM8 (residues 563–583) · position 575 (pLDDT 81). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 563-583 Helical

> Position 575 in TM8. Neighbors: VAL574 (2.5 Å), GLY576 (2.5 Å — G576S partner!), PRO571 (3.7 Å).

A575G removes side chain creating cavity. Adjacent to G576S (Atlas card). Three Atlas variants in TM8 (A569V, A575G, G576S). AM 0.14 under-call; multi-phenotype confirms.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1400** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.41 (Destabilising)** |
| Job ID | 177992505073 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992505073 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/11/05 00:00 |
| Inheritance | Multi-phenotype. |
| WFS1 variant landscape | A575G is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram-like syndrome
- Cataract 41
- 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 4 — Stable Fold, Function Disrupted**

<strong>Category 3/4 — Most Druggable (AM under-call).</strong> |ΔΔG| 0.41. AlphaMissense 0.14 below threshold but three phenotypes confirm.<br/><br/>Mechanism: cavity creation in TM8. Therapeutic: TM8 multi-variant cluster.

**Why this card matters.** A575G extends TM8 cluster — A569V + A575G + G576S now converge.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `A575G_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 575 with ball-and-stick + neighbors within 5Å)
- `A575G_variant_card.md` — this card (source of truth)
- `A575G_variant_card.html` — styled printable card
- `A575G_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)
- `A575G_wildtype_interactions.pse` / `A575G_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.*