# WFS1 Wolframin — R756C Variant Card

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

*Arginine → Cysteine at position 756. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.385, DynaMut2 ΔΔG +0.32 kcal/mol (stabilising).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | R756C (p.Arginine756Cysteine) |
| **DNA change** | c.2266C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001695517 |
| **Amino acid change** | Arginine (R) → Cysteine (C) |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 756** | **83.44** — well-folded |
| **Domain** | C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) |
| **Position context** | C-terminal lumenal domain · position 756 projects into the ER lumen |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  (none catalogued)

> Position 756 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 positively charged (arginine — guanidinium, strong H-bond donor); 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 | **0.3854** |
| am_class | **ambiguous** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.32 (Stabilising)** |
| Job ID | 178094703908 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094703908 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Uncertain significance** |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2026/01/21 00:00 |
| Inheritance | Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6). |
| WFS1 variant landscape | R756C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram-like syndrome
- Wolfram syndrome 1
- Autosomal dominant nonsyndromic hearing loss 6
- Type 2 diabetes mellitus
- Cataract 41

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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 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.32 negligible. Likely site-specific functional disruption — docking strategy.

**Why this card matters.** Wolframin's fold survives this substitution (|ΔΔG|=0.32 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.385. Protein still folds, but a specific local site is broken. Pharmacological chaperones and small-molecule binders are the rational therapeutic vector.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R756C_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 756 with ball-and-stick + neighbors within 5Å)
- `R756C_variant_card.md` — this card (source of truth)
- `R756C_variant_card.html` — styled printable card
- `R756C_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)
- `R756C_wildtype_interactions.pse` / `R756C_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.*