# WFS1 Wolframin — A844V Variant Card

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

*Alanine → Valine at position 844 in lumenal C-terminal region. ClinVar Conflicting including spastic ataxia. AlphaMissense 0.782, ΔΔG +0.09 (near-neutral).*

---

## Identity

| Field | Value |
|---|---|
| **Variant** | A844V (p.Alanine844Valine) |
| **DNA change** | c.2531C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000666957 |
| **Amino acid change** | Alanine (A) → Valine (V) — small replaced by branched aliphatic. Modest volume increase. |

---

## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 844** | **87.62** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 844 (pLDDT 88). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 844 sits in the lumenal C-terminus. Neighbors: ILE845 (2.4 Å), LYS843 (2.4 Å — partner of K843 cluster from L842F), VAL861 (3.2 Å — long-range; near K862N), SER826 (3.7 Å).

The wild-type alanine provides minimal volume. Replacing it with valine introduces branched aliphatic into a pocket sized for alanine. The K843-A844-V861 microregion is perturbed. AM 0.782 + spastic ataxia confirm severe consequence.

---

## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.7822** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.09 (Stabilising)** |
| Job ID | 177992462121 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992462121 |

---

## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/01/17 00:00 |
| Inheritance | Spastic ataxia documented. |
| WFS1 variant landscape | A844V is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Spastic ataxia
- Inborn genetic diseases

---

## 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 4 — Stable Fold, Function Disrupted.</strong> ΔΔG near-neutral. AlphaMissense 0.782 + spastic ataxia confirm severe consequence.<br/><br/>Mechanism: volume mismatch in the K843-V861 long-range microregion. Therapeutic: site-directed at the C-terminal cluster (with L842F, K862N targets).

**Why this card matters.** A844V joins L842F and K862N as variants in the K843-V861 long-range cluster.

---

## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `A844V_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 844 with ball-and-stick + neighbors within 5Å)
- `A844V_variant_card.md` — this card (source of truth)
- `A844V_variant_card.html` — styled printable card
- `A844V_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)
- `A844V_wildtype_interactions.pse` / `A844V_mutant_interactions.pse` — PyMOL sessions

---

*Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas*
*Every assumption documented. Every score sourced.*