# WFS1 Wolframin — L672P Variant Card

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

*Leucine → Proline at position 672 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic. AlphaMissense 0.947, DynaMut2 ΔΔG -0.28 kcal/mol (destabilising). A proline-introduction variant adjacent to C673 (the cysteine partner in the C690R disulfide discussion).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | L672P (p.Leucine672Proline) |
| **DNA change** | c.2015T>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000918069 |
| **Amino acid change** | Leucine (L) → Proline (P) — flexible branched hydrophobic replaced by rigid helix-breaking residue. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 672** | **87.69** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 672 in the ER lumen (pLDDT 88). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 672 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places L672 within 5 Å of CYS673 (2.4 Å — same C673 discussed in C690R/C690Y Atlas cards for the inferred disulfide), ALA671 (2.5 Å), TYR669 (3.8 Å — partner of Y669C/Y669H), GLN668 (4.1 Å), and ALA677 (4.5 Å).

The wild-type leucine at 672 contributes hydrophobic packing in a region densely populated by structurally important residues: C673 (potential disulfide), Y669 (aromatic packing partner), Q668. Replacing it with proline introduces a backbone kink that perturbs the geometry of this multi-residue contact cluster.

The |ΔΔG| of 0.28 reflects fold accommodation. AlphaMissense's 0.947 confirms severe functional consequence. The mechanism is geometric — backbone kink propagates through the C673-Y669-Q668 microregion.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9470** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.28 (Destabilising)** |
| Job ID | 177991930402 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991930402 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2025/07/24 00:00 |
| Inheritance | Inheritance not specified. |
| WFS1 variant landscape | L672P 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| = 0.28 — fold survives. AlphaMissense 0.947 confirms severe functional consequence.<br/><br/>Mechanism is proline-induced backbone kink near the C673-Y669 microregion (shared with Y669C, Y669H, C690R, C690Y atlas cards). Therapeutic strategy: site-directed at this dense contact cluster.

**Why this card matters.** L672P sits adjacent to the C673-Y669-C690 cluster — one of the densest variant-target hubs in the Atlas. Multiple variants converge here, all with site-directed rescue opportunities.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `L672P_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 672 with ball-and-stick + neighbors within 5Å)
- `L672P_variant_card.md` — this card (source of truth)
- `L672P_variant_card.html` — styled printable card
- `L672P_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)
- `L672P_wildtype_interactions.pse` / `L672P_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.*