# WFS1 Wolframin — R756G Variant Card

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

*Arginine → Glycine at position 756 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.317 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.71 kcal/mol (destabilising). Charge loss + side-chain loss entirely.*

---

## Identity

| Field | Value |
|---|---|
| **Variant** | R756G (p.Arginine756Glycine) |
| **DNA change** | c.2266C>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV003338037 |
| **Amino acid change** | Arginine (R) → Glycine (G) — large positively-charged guanidinium replaced by smallest amino acid. Complete loss of charge and side chain. |

---

## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 756** | **83.44** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 756 in the ER lumen (pLDDT 83). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal

> Position 756 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places R756 within 5 Å of LEU757 (2.5 Å), CYS755 (2.5 Å — potential disulfide site), GLU753 (3.7 Å — likely salt-bridge partner), GLU752 (4.0 Å — second nearby glutamate), and LYS758 (4.4 Å).

The wild-type arginine sits in a charge-rich environment — likely forming a salt bridge with E753 or E752, contributing positive charge to the local electrostatic surface. Replacing R756 with glycine eliminates both the charge and the side chain, leaving a cavity and disrupting the E752/E753 salt-bridge network.

The |ΔΔG| of 0.71 reflects substantial fold cost. AlphaMissense's 0.317 is below threshold — AM under-call. ClinVar Pathogenic + Wolfram 1 confirms clinical pathogenicity.

---

## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.3173** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.71 (Destabilising)** |
| Job ID | 177992010625 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992010625 |

---

## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2024/08/20 00:00 |
| Inheritance | Wolfram syndrome 1 (AR) documented. |
| WFS1 variant landscape | R756G is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1

---

## 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| = 0.71 — fold survives. AlphaMissense 0.317 below threshold but ClinVar + Wolfram 1 confirm pathogenicity.<br/><br/>Mechanism is loss of R756-E752/E753 salt-bridge network. Therapeutic strategy: site-directed at the E752-E753 microregion.

**Why this card matters.** R756G is another AM-under-call variant with substantial ΔΔG signal. The class continues to grow — variants where structure-based analysis catches what AM training does not.

---

## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R756G_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 756 with ball-and-stick + neighbors within 5Å)
- `R756G_variant_card.md` — this card (source of truth)
- `R756G_variant_card.html` — styled printable card
- `R756G_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)
- `R756G_wildtype_interactions.pse` / `R756G_mutant_interactions.pse` — PyMOL sessions

---

*Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas*
*Every assumption documented. Every score sourced.*