# WFS1 Wolframin — L829P Variant Card

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

*Leucine → Proline at position 829 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic/Likely pathogenic with the full clinical spectrum — DFNA6 hearing loss, type 2 diabetes, inborn genetic diseases. AlphaMissense 0.997 (near-maximum), DynaMut2 ΔΔG -1.02 kcal/mol (destabilising). Another proline-introduction variant with substantial structural cost.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | L829P (p.Leucine829Proline) |
| **DNA change** | c.2486T>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000004521 |
| **Amino acid change** | Leucine (L) → Proline (P) — flexible branched hydrophobic replaced by rigid helix-breaking residue. Same proline-introduction mechanism as L402P, L543P, L723P, L804P. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 829** | **85.56** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 829 near the C-terminus of the soluble domain (pLDDT 86). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 829-829 in DFNA6; dbSNP:rs104893883

> Position 829 sits in wolframin's C-terminal lumenal domain near the C-terminus. The AlphaFold model places L829 within 5 Å of GLU830 (2.4 Å), ILE828 (2.5 Å), HIS696 (3.9 Å — long-range across the fold), LEU833 (4.2 Å), and PHE840 (4.4 Å). The HIS696 contact at 3.9 Å is particularly notable: a residue 133 sequence positions away brought into structural contact through the folded geometry of the lumenal domain.

The wild-type leucine at 829 contributes branched hydrophobic packing into this multi-residue contact environment. Replacing it with proline introduces backbone constraint where flexibility was needed, breaks any α-helical character of the local region, and likely perturbs the long-range L829-H696 contact.

The |ΔΔG| of 1.02 is larger than the other proline-introduction variants in the Atlas (L723P 0.19, L402P +0.16, L543P 0.34) — reflecting that this position is more structurally constrained, and the proline kink has farther to propagate. AlphaMissense's 0.997 (near-maximum) confirms severe functional consequence.

The broad clinical spectrum (DFNA6 hearing loss, type 2 diabetes, inborn genetic diseases) reflects the multi-tissue impact of disrupting this fold-locking position.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9970** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-1.02 (Destabilising)** |
| Job ID | 177990267194 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990267194 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic/Likely pathogenic** |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2025/07/30 00:00 |
| Inheritance | Autosomal dominant pattern indicated by DFNA6 association. |
| WFS1 variant landscape | L829P is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Inborn genetic diseases
- Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)
- Type 2 diabetes mellitus

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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| = 1.02 kcal/mol — fold survives but with meaningful cost. AlphaMissense 0.997 + three documented phenotypes confirm severe functional consequence.<br/><br/>The mechanism is proline-induced backbone disruption at a position with long-range structural contact (HIS696 at 3.9 Å, 133 residues away in sequence). Therapeutic strategy: stabilize the L829-H696 long-range contact via small molecules engaging both sides of the contact.<br/><br/>The clinical breadth makes this a high-value docking target across multiple tissue contexts.

**Why this card matters.** L829P's long-range H696 contact (133 sequence positions away) is exactly the kind of structural relationship invisible to sequence-based analysis. The Atlas surfaces it through the PDB neighbor extraction. Drug discovery aimed at the L829-H696 contact is a target that pre-atlas analysis could not have identified.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `L829P_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 829 with ball-and-stick + neighbors within 5Å)
- `L829P_variant_card.md` — this card (source of truth)
- `L829P_variant_card.html` — styled printable card
- `L829P_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)
- `L829P_wildtype_interactions.pse` / `L829P_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.*