# WFS1 Wolframin — G736R Variant Card

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

*Glycine → Arginine at position 736 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic. AlphaMissense 0.984, DynaMut2 ΔΔG -0.92 kcal/mol (destabilising). Another glycine-removal variant — paralleling the G674 cluster mechanism.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | G736R (p.Glycine736Arginine) |
| **DNA change** | c.2206G>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV002734647 |
| **Amino acid change** | Glycine (G) → Arginine (R) — smallest amino acid replaced by a large, positively-charged guanidinium-bearing residue. Same chemistry shift as G674R but at a different position. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 736** | **88.12** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 736 sits in the ER lumen (pLDDT 88). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 736-736 in WFS1; dbSNP:rs71532864

> Position 736 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places G736 within 5 Å of GLU737 (2.4 Å), TYR735 (2.5 Å), ARG732 (3.1 Å — a four-residue-back contact), HIS766 (3.3 Å — long-range), and ILE767 (4.1 Å). The local environment combines polar (E737, Y735), basic (R732), and titratable (H766) residues with a hydrophobic contact (I767).

The wild-type glycine at 736 plays the same backbone-flexibility role described for the G674 cluster. The neighbor analysis shows particularly tight packing — multiple residues within 4 Å — suggesting the local fold is geometrically constrained, and glycine's lack of side chain is what enables that geometry. Notably, ARG732 sits 3.1 Å away; the wild-type G736 plus R732 form a tight cluster where a single basic residue dominates the local electrostatic character.

Replacing glycine with arginine adds a second positive charge at 3.1 Å from the existing R732. This produces a two-arginine cluster similar to the G674R case — local electrostatic repulsion between adjacent positive charges plus the loss of glycine's backbone flexibility.

The |ΔΔG| of 0.92 reflects this combined cost. AlphaMissense's 0.984 score captures the severe functional consequence — likely disruption of a specific lumenal interaction surface where R732 alone served as the recognized positive charge.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9842** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.92 (Destabilising)** |
| Job ID | 177990255019 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990255019 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2022/10/26 00:00 |
| Inheritance | Inheritance not specified. ClinVar Pathogenic classification with multiple submitters. |
| WFS1 variant landscape | G736R is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued for G736R — ClinVar Pathogenic by review evidence)

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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 3/4 — Most Druggable**

<strong>Category 3/4 — Most Druggable.</strong> |ΔΔG| = 0.92 kcal/mol — fold survives. AlphaMissense 0.984 confirms severe functional consequence.<br/><br/>The mechanism is loss of glycine flexibility plus introduction of a second positive charge adjacent to R732 — disrupting a likely partner-recognition surface where R732 alone was the wild-type signature.<br/><br/>Therapeutic strategy: site-directed small molecules at the R732-G736-Y735 microregion. Pharmacological chaperones biasing the local backbone toward the wild-type glycine-enabled geometry.

**Why this card matters.** G736R parallels the G674R mechanism — glycine removal in a tightly-packed loop adjacent to an existing arginine. The Atlas's per-variant analysis shows that this 'glycine-adjacent-to-arginine' pattern repeats multiple times across the WFS1 lumenal domain, and substitutions at the glycine positions are consistently pathogenic. The class is a coherent therapeutic target — drug discovery against the geometric niche of these glycines.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `G736R_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 736 with ball-and-stick + neighbors within 5Å)
- `G736R_variant_card.md` — this card (source of truth)
- `G736R_variant_card.html` — styled printable card
- `G736R_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)
- `G736R_wildtype_interactions.pse` / `G736R_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.*