# WFS1 Wolframin — P216R Variant Card

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

*Proline → Arginine at position 216 in N-terminal cytoplasmic domain. ClinVar Conflicting including monogenic diabetes, Cataract 41, Wolfram. AlphaMissense 0.11 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.20. pLDDT 41 — Category 5 IDR!*

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## Identity

| Field | Value |
|---|---|
| **Variant** | P216R (p.Proline216Arginine) |
| **DNA change** | c.647C>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000393386 |
| **Amino acid change** | Proline (P) → Arginine (R) — rigid helix-breaking replaced by long positively-charged amine. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 216** | **41.28** — **IDR (below 50 threshold)** |
| **Domain** | N-terminal cytoplasmic domain (87-313) |
| **Position context** | N-terminal cytoplasmic domain · position 216 IDR (pLDDT 41 — deep IDR). |
| **IDR flag** | YES — pLDDT below 50 (Cat 5) |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Region: 1-321 Interaction with ATP6V1A

> Position 216 at pLDDT 41 — DEEP IDR. Sparse neighbors (GLY217, GLN215, ALA214). DynaMut2 untrustworthy.

P216R introduces charge + removes backbone constraint in disordered region. AM 0.11 under-call; multi-phenotype confirms clinical pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1051** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.2 (Stabilising)** |
| Job ID | 177992511205 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992511205 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/12/20 00:00 |
| Inheritance | Multi-phenotype. |
| WFS1 variant landscape | P216R is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Monogenic diabetes
- Cataract 41
- Wolfram syndrome 1

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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 5 — IDR Exclusion**

<strong>Category 5 — IDR Exclusion.</strong> pLDDT 41 deep IDR. AlphaMissense 0.11 below threshold. DynaMut2 prediction not trustworthy.<br/><br/>The Atlas routes Category 5 variants to wet-lab characterization. Multi-phenotype confirms clinical pathogenicity.

**Why this card matters.** P216R is another deep-IDR variant in this batch — Atlas appropriately flags for wet-lab.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `P216R_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 216 with ball-and-stick + neighbors within 5Å)
- `P216R_variant_card.md` — this card (source of truth)
- `P216R_variant_card.html` — styled printable card
- `P216R_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)
- `P216R_wildtype_interactions.pse` / `P216R_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.*