# WFS1 Wolframin — V288G Variant Card

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

*Valine → Glycine at position 288 in wolframin's N-terminal cytoplasmic domain. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.480 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.23 kcal/mol. pLDDT 58 borderline.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | V288G (p.Valine288Glycine) |
| **DNA change** | c.863T>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV003767181 |
| **Amino acid change** | Valine (V) → Glycine (G) — branched aliphatic hydrophobic replaced by smallest amino acid. Loss of side chain entirely. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 288** | **58.47** — confident |
| **Domain** | N-terminal cytoplasmic domain (87-313) |
| **Position context** | N-terminal cytoplasmic domain · position 288 in a borderline-confidence region (pLDDT 58). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Region: 1-321 Interaction with ATP6V1A

> Position 288 sits in wolframin's N-terminal cytoplasmic domain. The AlphaFold model places V288 within 5 Å of VAL289 (2.5 Å), LYS287 (2.5 Å), LEU284 (4.0 Å), ALA295 (4.5 Å), and LEU286 (4.5 Å). Mostly hydrophobic environment.

Replacing V288 with glycine removes the branched aliphatic side chain entirely, creating a cavity. The fold absorbs the substitution (|ΔΔG| 0.23 small) — the glycine permits backbone conformations the wild-type valine constrained, possibly compensating somewhat for the lost packing volume.

AlphaMissense's 0.480 is below the threshold — AM under-call. ClinVar Likely Pathogenic + Wolfram 1 establishes clinical pathogenicity. pLDDT 58 is borderline; structural details deserve wet-lab confirmation.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.4796** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.23 (Destabilising)** |
| Job ID | 177992009249 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992009249 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2024/02/27 00:00 |
| Inheritance | Wolfram syndrome 1 (AR) documented. |
| WFS1 variant landscape | V288G 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 4 — Stable Fold, Function Disrupted**

<strong>Category 3/4 — Most Druggable (AM + pLDDT caveats).</strong> |ΔΔG| = 0.23 — fold survives. AlphaMissense 0.480 below threshold but ClinVar Pathogenic + Wolfram 1.<br/><br/>Mechanism is hydrophobic cavity creation. Therapeutic strategy: wet-lab validation before committing to design.

**Why this card matters.** V288G joins the AM-under-call class. The borderline pLDDT and AM signal together make this a wet-lab-priority variant.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `V288G_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 288 with ball-and-stick + neighbors within 5Å)
- `V288G_variant_card.md` — this card (source of truth)
- `V288G_variant_card.html` — styled printable card
- `V288G_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)
- `V288G_wildtype_interactions.pse` / `V288G_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.*