# WFS1 Wolframin — L723P Variant Card

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

*Leucine → Proline at position 723 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic. AlphaMissense 0.959, DynaMut2 ΔΔG -0.19 kcal/mol (destabilising). Another proline-introduction variant in the lumenal fold.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | L723P (p.Leucine723Proline) |
| **DNA change** | c.2168T>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV002203530 |
| **Amino acid change** | Leucine (L) → Proline (P) — flexible branched hydrophobic replaced by rigid helix-breaking residue. Same proline-introduction mechanism class as L543P, L402P, L804P. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 723** | **82.69** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 723 in the ER lumen (pLDDT 83). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 723 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places L723 within 5 Å of MET722 (2.5 Å), PRO724 (2.5 Å), ILE720 (3.6 Å), ASN721 (4.6 Å), and ALA719 (4.8 Å). The local environment is hydrophobic-rich (M722, I720, A719) with a single polar residue (N721). Notably, PRO724 sits at 2.5 Å — the immediate downstream neighbor is already a proline.

Replacing L723 with proline introduces a second proline immediately adjacent to the existing P724 — a Pro-Pro motif is unusual and structurally distinctive. Two adjacent prolines create a particularly rigid backbone segment with restricted conformational options. The wild-type Leu-Pro motif at 723-724 transitions from flexible to constrained backbone; the variant Pro-Pro motif is constrained on both sides.

The |ΔΔG| of 0.19 is modest — the fold absorbs the new proline because the local environment was already constrained. But the geometry shifts: the Pro-Pro motif likely adopts a different local conformation than the wild-type Leu-Pro, and surrounding residues (M722, I720) rearrange to accommodate.

AlphaMissense's 0.959 score captures the functional severity — the shifted local geometry disrupts whatever interaction the wild-type Leu-Pro motif enabled.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9592** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.19 (Destabilising)** |
| Job ID | 177990271493 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990271493 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2024/12/16 00:00 |
| Inheritance | Inheritance not specified. ClinVar Pathogenic. |
| WFS1 variant landscape | L723P is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued for L723P — 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| = 0.19 kcal/mol — fold essentially unperturbed. AlphaMissense 0.959 confirms pathogenic mechanism is functional rather than structural.<br/><br/>The mechanism is creation of an unusual Pro-Pro motif at positions 723-724, shifting the local backbone geometry from a Leu-Pro transition to a rigid Pro-Pro segment. Therapeutic strategy: site-directed small molecules at the position 720-724 region, ideally compensating for the geometric shift.<br/><br/>This is one of several proline-introduction variants in the Atlas (L402P, L543P, L723P, L804P). The therapeutic vocabulary across this class is consistent: stabilize local backbone geometry against the introduced proline kink.

**Why this card matters.** L723P creates a Pro-Pro motif rare in folded proteins. The Atlas's neighbor analysis surfaces this directly — PRO724 at 2.5 Å is the next-residue neighbor. The unusual geometry of two adjacent prolines is what distinguishes L723P's mechanism from other proline-introduction variants in the Atlas.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `L723P_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 723 with ball-and-stick + neighbors within 5Å)
- `L723P_variant_card.md` — this card (source of truth)
- `L723P_variant_card.html` — styled printable card
- `L723P_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)
- `L723P_wildtype_interactions.pse` / `L723P_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.*