# WFS1 Wolframin — A684G Variant Card

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

*Alanine → Glycine at position 684 in lumenal domain. ClinVar Conflicting including type 2 diabetes. AlphaMissense 0.808, ΔΔG -0.38. THIRD substitution at position 684 (with A684T, A684V).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | A684G (p.Alanine684Glycine) |
| **DNA change** | c.2051C>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000930623 |
| **Amino acid change** | Alanine (A) → Glycine (G) — small methyl-bearing residue replaced by smallest amino acid. Loss of side chain entirely. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 684** | **87.94** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 684 (pLDDT 88). Same as A684T, A684V. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 684-684 in WFSL; greatly reduces protein expression compared to wild-type; dbSNP:rs387906930

> Position 684 same neighbors as A684T/V: MET683 (2.5 Å), ARG685 (2.5 Å — R685P), GLN687 (4.0 Å — Q687H), ASN682 (4.0 Å), THR686 (4.4 Å).

A684G is the third substitution at position 684 — eliminating side chain entirely, introducing glycine backbone flexibility. The variant fold may shift more substantially than A684T's hydroxyl-introduction or A684V's volume-increase because of the backbone freedom.

ΔΔG 0.38 + AM 0.808 + T2D confirm severe consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.8083** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.38 (Destabilising)** |
| Job ID | 177992461961 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992461961 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2023/12/18 00:00 |
| Inheritance | Type 2 diabetes documented. |
| WFS1 variant landscape | A684G is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Type 2 diabetes mellitus

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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| = 0.38. AlphaMissense 0.808 + T2D confirm severe consequence.<br/><br/>Mechanism: backbone-flexibility introduction in the R685 microregion. Therapeutic: same A684 cluster.

**Why this card matters.** A684G is the FOURTH variant at position 684 (with A684T, A684V, and adjacent R685P, Q687H, I688F). The 684-688 cluster is one of the densest Atlas hubs.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `A684G_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 684 with ball-and-stick + neighbors within 5Å)
- `A684G_variant_card.md` — this card (source of truth)
- `A684G_variant_card.html` — styled printable card
- `A684G_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)
- `A684G_wildtype_interactions.pse` / `A684G_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.*