# WFS1 Wolframin — R146C Variant Card

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

*Arginine → Cysteine at position 146 in N-terminal cytoplasmic domain. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.19 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.38. R→C class.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | R146C (p.Arginine146Cysteine) |
| **DNA change** | c.436C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000517251 |
| **Amino acid change** | Arginine (R) → Cysteine (C) — charge loss + thiol introduction. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 146** | **92.31** — well-folded |
| **Domain** | N-terminal cytoplasmic domain (87-313) |
| **Position context** | N-terminal cytoplasmic domain · position 146 (pLDDT 92). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 146 in cytoplasmic domain. Neighbors: ARG147 (2.4 Å — adjacent existing arginine), LEU145 (2.5 Å), LYS143 (3.8 Å). R146-R147 adjacent positives + K143 nearby — positively-charged surface patch.

R146C eliminates one of the cluster's positives + introduces thiol. AM 0.19 under-call; Wolfram 1 confirms.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1949** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.38 (Destabilising)** |
| Job ID | 177992498999 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992498999 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2017/02/16 00:00 |
| Inheritance | Wolfram syndrome 1. |
| WFS1 variant landscape | R146C is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- 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 4 — Stable Fold, Function Disrupted**

<strong>Category 3/4 — Most Druggable (AM under-call).</strong> |ΔΔG| 0.38. AlphaMissense 0.19 below threshold but Wolfram 1 confirms.<br/><br/>Mechanism: charge loss from R146-R147-K143 cluster. Therapeutic: site-directed at cytoplasmic recognition surface.

**Why this card matters.** R146C continues R→C class (now 9+ variants).

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `R146C_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 146 with ball-and-stick + neighbors within 5Å)
- `R146C_variant_card.md` — this card (source of truth)
- `R146C_variant_card.html` — styled printable card
- `R146C_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)
- `R146C_wildtype_interactions.pse` / `R146C_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.*