# WFS1 Wolframin — P607R Variant Card

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

*Proline → Arginine at position 607 inside TM9. ClinVar Conflicting. AlphaMissense 0.922, ΔΔG +0.03 (neutral). pLDDT 66 borderline. Proline-removal in TM9 with charge introduction.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | P607R (p.Proline607Arginine) |
| **DNA change** | c.1820C>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001297726 |
| **Amino acid change** | Proline (P) → Arginine (R) — rigid helix-breaking replaced by large positively-charged amine. Removes constraint, introduces charge into bilayer. |

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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 near the end of TM9 (pLDDT 66 borderline). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 607 sits near the end of TM9. Neighbors: LEU608 (2.5 Å), VAL606 (2.5 Å), LEU610 (4.1 Å), SER605 (4.5 Å).

The wild-type proline likely defines a helix-end geometry. Replacing it with arginine removes the kink and introduces charge near the membrane-water interface. The near-zero ΔΔG reflects fold accommodation through the arginine extending toward solvent.

AlphaMissense 0.922 confirms severe consequence. P607L (Atlas card next) is the same position with leucine — both pathogenic.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9219** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.03 (Stabilising)** |
| Job ID | 177992458317 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992458317 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2023/05/03 00:00 |
| Inheritance | Not specified. |
| WFS1 variant landscape | P607R 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 4 — Stable Fold, Function Disrupted.</strong> ΔΔG ≈ 0 — fold unchanged. AlphaMissense 0.922 confirms severe consequence.<br/><br/>Mechanism: loss of TM9 helix-end kink plus charge introduction. Therapeutic: site-directed at the TM9 C-terminal region.

**Why this card matters.** P607R + P607L (next card) are both at position 607 — multi-substitution hotspot in TM9. First Atlas TM9 variants.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `P607R_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 607 with ball-and-stick + neighbors within 5Å)
- `P607R_variant_card.md` — this card (source of truth)
- `P607R_variant_card.html` — styled printable card
- `P607R_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)
- `P607R_wildtype_interactions.pse` / `P607R_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.*