# WFS1 Wolframin — P607L Variant Card

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

*Proline → Leucine at position 607 inside TM9. ClinVar Conflicting including monogenic diabetes, T2D, DFNA6. AlphaMissense 0.416 (below threshold), ΔΔG -0.27. Same position as P607R — proline-removal pair.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | P607L (p.Proline607Leucine) |
| **DNA change** | c.1820C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000045441 |
| **Amino acid change** | Proline (P) → Leucine (L) — rigid helix-breaking replaced by branched aliphatic. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 607** | **65.88** — confident |
| **Domain** | TM9 (589-609), helical transmembrane |
| **Position context** | TM9 (residues 589–609) · position 607 (pLDDT 66 borderline). Same as P607R. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 589-609 Helical

> Position 607 same neighbors as P607R: LEU608 (2.5 Å), VAL606 (2.5 Å), LEU610 (4.1 Å), SER605 (4.5 Å).

P607L is the second pathogenic substitution at 607 (with P607R). Both remove the wild-type proline kink at TM9's end. P607L is the conservative hydrophobic substitution; P607R adds charge.

AM 0.416 below threshold but multi-phenotype confirms pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.4163** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.27 (Destabilising)** |
| Job ID | 177992473138 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992473138 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/12/29 00:00 |
| Inheritance | Multi-phenotype AD. |
| WFS1 variant landscape | P607L is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Monogenic diabetes
- Type 2 diabetes mellitus
- Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

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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 4 — Stable Fold, Function Disrupted**

<strong>Category 3/4 — Most Druggable (AM under-call).</strong> |ΔΔG| 0.27. AlphaMissense 0.416 below threshold but multi-phenotype confirms pathogenicity.<br/><br/>Mechanism: same TM9 kink-removal as P607R. Therapeutic: TM9 site-directed.

**Why this card matters.** P607L + P607R confirm position 607 as TM9 multi-substitution hotspot.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `P607L_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 607 with ball-and-stick + neighbors within 5Å)
- `P607L_variant_card.md` — this card (source of truth)
- `P607L_variant_card.html` — styled printable card
- `P607L_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)
- `P607L_wildtype_interactions.pse` / `P607L_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.*