# WFS1 Wolframin — G695D Variant Card

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

*Glycine → Aspartate at position 695 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic. AlphaMissense 0.954, DynaMut2 ΔΔG -1.77 kcal/mol (destabilising) — second-largest |ΔΔG| in this batch. A glycine-removal variant with substantial structural cost.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | G695D (p.Glycine695Aspartate) |
| **DNA change** | c.2084G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV002798320 |
| **Amino acid change** | Glycine (G) → Aspartate (D) — smallest amino acid replaced by small negatively-charged carboxylate-bearing residue. Loss of backbone flexibility plus charge introduction. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 695** | **82.12** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 695 in the ER lumen (pLDDT 82). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 695-695 in WFS1; dbSNP:rs28937891

> Position 695 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places G695 within 5 Å of GLU694 (2.5 Å), HIS696 (2.5 Å — same H696 contacted by L829P at 3.9 Å), LEU829 (4.0 Å — partner of L829P!), ILE828 (4.0 Å), and LEU693 (4.5 Å).

The G695-L829 contact at 4.0 Å is structurally significant — G695 sits in spatial contact with the L829P-perturbed microregion (133 sequence positions away). The wild-type glycine at 695 enables the backbone geometry that brings these distant residues into contact.

Replacing glycine with aspartate at 695 introduces both backbone constraint and negative charge. The new D695 carboxylate competes with the existing E694 for local H-bonding. The L829 long-range contact is perturbed.

The |ΔΔG| of 1.77 — the second-largest in this batch and close to the Cat 2 threshold — reflects substantial structural cost. AlphaMissense's 0.954 confirms severe functional consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9536** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.77 (Destabilising)** |
| Job ID | 177991930572 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991930572 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2023/09/10 00:00 |
| Inheritance | Inheritance not specified. |
| WFS1 variant landscape | G695D is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued)

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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 (near Cat 2 boundary).</strong> |ΔΔG| = 1.77 — close to the Cat 2 threshold. AlphaMissense 0.954 confirms severe functional consequence.<br/><br/>Mechanism is glycine-removal at a position with long-range contact to L829 (133 sequence positions apart). Therapeutic strategy: stabilize the G695-L829 long-range geometry.

**Why this card matters.** G695D sits in long-range contact with L829P (Atlas card adjacent). Two Atlas variants 133 sequence positions apart converge on the same therapeutic target region through the folded geometry.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `G695D_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 695 with ball-and-stick + neighbors within 5Å)
- `G695D_variant_card.md` — this card (source of truth)
- `G695D_variant_card.html` — styled printable card
- `G695D_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)
- `G695D_wildtype_interactions.pse` / `G695D_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.*