# WFS1 Wolframin — P346L Variant Card

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

*Proline → Leucine at position 346 inside TM2. ClinVar Conflicting with broad clinical spectrum — Wolfram syndrome 1, Cataract 41, Wolfram-like syndrome. AlphaMissense 0.917, ΔΔG -0.62.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | P346L (p.Proline346Leucine) |
| **DNA change** | c.1037C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000229634 |
| **Amino acid change** | Proline (P) → Leucine (L) — rigid helix-breaking residue replaced by branched aliphatic hydrophobic. Removes backbone constraint. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 346** | **87.62** — well-folded |
| **Domain** | TM2 (340-360), helical transmembrane |
| **Position context** | TM2 (residues 340–360) · position 346 mid-helix (pLDDT 88). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 340-360 Helical

> Position 346 sits in TM2. Neighbors: ILE345 (2.5 Å), LEU347 (2.5 Å), ILE349 (4.4 Å — partner of F350I/I349 cluster), PHE344 (4.4 Å). The local environment is uniformly hydrophobic, characteristic of a bilayer-embedded helix interior.

The wild-type proline at 346 likely defines a controlled kink in TM2's middle. Replacing it with leucine removes the kink and lets the helix straighten. The |ΔΔG| of 0.62 reflects modest fold cost; AlphaMissense 0.917 + Wolfram 1 + Cataract 41 confirm severe multi-tissue consequence. The variant is in the broader F350I TM2 cluster.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9173** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.62 (Destabilising)** |
| Job ID | 177992456955 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992456955 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2024/10/26 00:00 |
| Inheritance | Wolfram syndrome 1, Wolfram-like syndrome, Cataract 41 documented. |
| WFS1 variant landscape | P346L is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1
- Cataract 41
- Wolfram-like syndrome

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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| = 0.62 — fold survives. AlphaMissense 0.917 + three documented phenotypes confirm severe consequence.<br/><br/>Mechanism: loss of TM2 helix kink. Therapeutic: TM2 site-directed (same broader region as F350I).

**Why this card matters.** P346L is the second TM2 variant in the Atlas (with F350I), establishing TM2 as a target region.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `P346L_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 346 with ball-and-stick + neighbors within 5Å)
- `P346L_variant_card.md` — this card (source of truth)
- `P346L_variant_card.html` — styled printable card
- `P346L_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)
- `P346L_wildtype_interactions.pse` / `P346L_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.*