# WFS1 Wolframin — D801G Variant Card

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

*Aspartate → Glycine at position 801 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic. AlphaMissense 0.985, DynaMut2 ΔΔG -0.26 kcal/mol (destabilising). The inverse mechanism of glycine-removal variants: here glycine is INTRODUCED into a position that previously carried a charge.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | D801G (p.Aspartate801Glycine) |
| **DNA change** | c.2402A>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV003637018 |
| **Amino acid change** | Aspartate (D) → Glycine (G) — a small negatively-charged carboxylate-bearing residue replaced by the smallest amino acid (backbone-only). Loss of charge and side chain entirely. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 801** | **83.50** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 801 in the ER lumen (pLDDT 84). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 801 sits in wolframin's C-terminal lumenal domain near the C-terminus. The AlphaFold model places D801 within 5 Å of ILE802 (2.4 Å), LYS800 (2.5 Å), VAL779 (3.5 Å, longer-range), VAL798 (3.9 Å), and GLY780 (4.8 Å). Critically, LYS800 sits 2.5 Å from D801 — a salt-bridge distance. The wild-type D801 carboxylate and K800 amine form a likely intramolecular salt bridge stabilizing the local fold.

Replacing aspartate with glycine eliminates the negative charge and removes the side chain entirely. The K800-D801 salt bridge breaks. The local geometry that depends on that ionic contact rearranges, and the introduced glycine permits backbone conformations that the wild-type aspartate constrained.

The |ΔΔG| of 0.26 is modest — the fold absorbs the loss of a single salt bridge. But the functional consequence is severe: AlphaMissense 0.985 captures it. The lost salt bridge likely contributed to a specific lumenal geometry required for partner interactions or for the wolframin C-terminus to engage its target proteins.

Notably, VAL779 (3.5 Å) is the partner residue in the V779G atlas card (a Category 2 outlier). D801 and V779 are spatially close. Drug discovery aimed at the V779 region may also engage the D801 microenvironment.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9846** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.26 (Destabilising)** |
| Job ID | 177990263828 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990263828 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2025/03/18 00:00 |
| Inheritance | Inheritance not specified. ClinVar Pathogenic classification. |
| WFS1 variant landscape | D801G is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued for D801G — 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| = 0.26 kcal/mol — fold survives. AlphaMissense 0.985 confirms severe functional consequence.<br/><br/>The mechanism is loss of the K800-D801 intramolecular salt bridge plus introduction of glycine backbone flexibility into a previously constrained position. Therapeutic strategy: site-directed small molecules that restore the K800-region electrostatic geometry the wild-type D801 carboxylate provided.<br/><br/>Spatial proximity to V779 (3.5 Å, see V779G atlas card) suggests this region of the C-terminus harbors multiple pathogenic variants. A drug aimed at the V779-D801 region could rescue multiple Atlas variants simultaneously.

**Why this card matters.** D801G is one of the Atlas's clearest salt-bridge-loss variants. The K800-D801 ionic contact is visible in the AlphaFold model at exact salt-bridge geometry, and the substitution to glycine removes the contact completely. The Atlas's neighbor analysis surfaces the contact partner (K800 at 2.5 Å) and the spatially-adjacent Cat 2 outlier (V779). Drug discovery in this region has multiple convergent targets.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `D801G_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 801 with ball-and-stick + neighbors within 5Å)
- `D801G_variant_card.md` — this card (source of truth)
- `D801G_variant_card.html` — styled printable card
- `D801G_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)
- `D801G_wildtype_interactions.pse` / `D801G_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.*