# WFS1 Wolframin — G656C Variant Card

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

*Glycine → Cysteine at position 656. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.946, DynaMut2 ΔΔG -0.47 kcal/mol (destabilising).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | G656C (p.Glycine656Cysteine) |
| **DNA change** | c.1966G>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV004802688 |
| **Amino acid change** | Glycine (G) → Cysteine (C) |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 656** | **48.88** — **IDR (below 50 threshold)** |
| **Domain** | C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) |
| **Position context** | C-terminal lumenal domain · position 656 projects into the ER lumen |
| **IDR flag** | YES — pLDDT below 50 (Cat 5) |

**UniProt features at this position:**

  (none catalogued)

> Position 656 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 small/flexible (glycine — backbone flexibility, no sidechain); the mutant is thiol (cysteine — disulfide-capable, free -SH). 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 | **0.9461** |
| am_class | **likely pathogenic** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.47 (Destabilising)** |
| Job ID | 178092141279 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092141279 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Uncertain significance** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2025/05/24 00:00 |
| Inheritance | Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations. |
| WFS1 variant landscape | G656C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

(no 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>Category 5 — IDR Exclusion</strong><br/><br/>pLDDT 48.88 is below 50; DynaMut2 result not trustworthy. Route to wet-lab.

**Why this card matters.** Position sits in a low-confidence region. Computational stability estimates here are unreliable; this variant needs experimental characterization before any therapeutic strategy is set.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `G656C_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 656 with ball-and-stick + neighbors within 5Å)
- `G656C_variant_card.md` — this card (source of truth)
- `G656C_variant_card.html` — styled printable card
- `G656C_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)
- `G656C_wildtype_interactions.pse` / `G656C_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.*