# WFS1 Wolframin — P724L Variant Card

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

*Proline → Leucine at position 724 in lumenal domain. ClinVar Conflicting. AlphaMissense 0.906, ΔΔG -0.24. Same position as P724S (Atlas card adjacent) — proline-removal pair.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | P724L (p.Proline724Leucine) |
| **DNA change** | c.2171C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000004509 |
| **Amino acid change** | Proline (P) → Leucine (L) — rigid helix-breaking replaced by branched aliphatic. Removes backbone constraint. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 724** | **89.25** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 724 (pLDDT 89). Same as P724S. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 724-724 in WFS1; dbSNP:rs28937890

> Position 724 same neighbors as P724S: LEU723 (2.5 Å — partner of L723P), PHE725 (2.5 Å), PHE726 (4.6 Å), ILE727 (5.0 Å).

P724L is the second substitution at 724 (with P724S). Where P724S added polarity into hydrophobic environment, P724L is conservative hydrophobic-to-hydrophobic. Both lose the backbone kink. Combined with L723P, three Atlas variants converge on the 723-724 Leu-Pro motif.

|ΔΔG| 0.24 + AlphaMissense 0.906 confirm severe consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9065** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.24 (Destabilising)** |
| Job ID | 177992458146 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992458146 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2024/11/05 00:00 |
| Inheritance | Not specified. |
| WFS1 variant landscape | P724L 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.</strong> |ΔΔG| = 0.24 — fold survives. AlphaMissense 0.906 confirms severe consequence.<br/><br/>Mechanism: loss of wild-type Leu-Pro backbone geometry. Therapeutic: same target as L723P, P724S.

**Why this card matters.** P724L + P724S + L723P all converge on the 723-724 backbone microregion — three convergent variant targets.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `P724L_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 724 with ball-and-stick + neighbors within 5Å)
- `P724L_variant_card.md` — this card (source of truth)
- `P724L_variant_card.html` — styled printable card
- `P724L_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)
- `P724L_wildtype_interactions.pse` / `P724L_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.*