# WFS1 Wolframin — G674R Variant Card

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

*Glycine → Arginine at position 674 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic. AlphaMissense 0.994, DynaMut2 ΔΔG -0.83 kcal/mol (destabilising). The most charge-heavy substitution at position 674 (compare G674E, G674W).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | G674R (p.Glycine674Arginine) |
| **DNA change** | c.2020G>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV004806428 |
| **Amino acid change** | Glycine (G) → Arginine (R) — the smallest amino acid replaced by a large, positively-charged guanidinium-bearing residue. Maximum chemistry contrast: from no side chain to one of the largest, from no charge to positive charge. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 674** | **84.12** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 674 sits in the ER lumen (pLDDT 84). Same structural microenvironment as G674E and G674W. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 674-674 in dbSNP:rs200672755

> Position 674 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places G674 within 5 Å of CYS673 (2.5 Å), PRO675 (2.5 Å), GLY670 (3.1 Å), TRP678 (4.0 Å), and ARG676 (4.5 Å) — the same neighbors as G674E and G674W. Notably, ARG676 is already at this position; introducing another arginine at 674 creates an unusual two-arginine cluster in a tight loop.

Replacing glycine with arginine here has the same backbone-flexibility loss as G674E (no glycine, no left-handed helix conformation), but the chemistry of the new side chain is opposite. Where G674E introduces negative charge, G674R introduces positive charge. The local environment with ARG676 already in place plus a new R674 produces a positively-charged loop region where the wild-type had a flexible, neutral one.

The |ΔΔG| of 0.83 kcal/mol is larger than G674E's 0.34, reflecting the additional cost of accommodating two adjacent positive charges. The fold still survives — both arginines can extend toward solvent in the lumenal environment — but the local geometry is materially perturbed.

AlphaMissense's 0.994 score is comparable to G674E's, confirming that the mechanism is dominated by loss of glycine flexibility rather than by the specific charge of the introduced residue.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9943** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.83 (Destabilising)** |
| Job ID | 177990253578 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990253578 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2025/04/11 00:00 |
| Inheritance | Inheritance not specified in this ClinVar entry. ClinVar Pathogenic classification with multiple submitters establishes clinical relevance. |
| WFS1 variant landscape | G674R is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued for G674R — 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| = 0.83 kcal/mol — fold survives. AlphaMissense 0.994 confirms severe functional consequence.<br/><br/>Same mechanism as G674E (loss of glycine flexibility), with charge sign opposite. Therapeutic strategy: same as G674E — stabilize the wild-type C673-G674-P675 backbone geometry. A drug designed for one of these three variants at position 674 likely rescues all three.<br/><br/>The two-arginine cluster (R674 + R676 in the variant) is a structurally unusual feature that might also offer a specific small-molecule docking handle — a compound that engages both positive charges simultaneously could selectively bind the variant.

**Why this card matters.** G674R is part of a three-variant set at position 674 (with G674E and G674W) that together demonstrate glycine's structural irreplaceability. The atlas surfaces this position as a high-value drug target because three known pathogenic substitutions converge on a single therapeutic geometry.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `G674R_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 674 with ball-and-stick + neighbors within 5Å)
- `G674R_variant_card.md` — this card (source of truth)
- `G674R_variant_card.html` — styled printable card
- `G674R_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)
- `G674R_wildtype_interactions.pse` / `G674R_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.*