# WFS1 Wolframin — W678G Variant Card

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

*Tryptophan → Glycine at position 678. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance/Uncertain risk allele, AlphaMissense 0.964, DynaMut2 ΔΔG -3.13 kcal/mol (destabilising).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | W678G (p.Tryptophan678Glycine) |
| **DNA change** | c.2032T>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000666956 |
| **Amino acid change** | Tryptophan (W) → Glycine (G) |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 678** | **82.62** — well-folded |
| **Domain** | C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) |
| **Position context** | C-terminal lumenal domain · position 678 projects into the ER lumen |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  (none catalogued)

> Position 678 sits in the C-terminal lumenal domain (residues 653–869), wolframin's largest soluble region. This domain projects into the ER lumen and is implicated in calcium handling, ER stress sensing, and protein–protein interactions with ATF6 and Na+/K+ ATPase β1. The wild-type residue is bulky aromatic (tryptophan — indole ring); the mutant is small/flexible (glycine — backbone flexibility, no sidechain). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9636** |
| am_class | **likely pathogenic** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-3.13 (Destabilising)** |
| Job ID | 178092098041 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092098041 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Uncertain significance/Uncertain risk allele** |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2019/02/11 00:00 |
| Inheritance | Autosomal recessive Wolfram syndrome 1 phenotype documented. |
| WFS1 variant landscape | W678G 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 2 — Moderately Destabilizing**

<strong>Category 2 — Moderately Destabilizing</strong><br/><br/>|ΔΔG|=3.13 in the 2–4 range. Pharmacological chaperone candidate.



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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `W678G_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 678 with ball-and-stick + neighbors within 5Å)
- `W678G_variant_card.md` — this card (source of truth)
- `W678G_variant_card.html` — styled printable card
- `W678G_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)
- `W678G_wildtype_interactions.pse` / `W678G_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.*