---
license: mit
tags:
  - stxbp1
  - rare-disease
  - base-editing
  - genome-editing
  - crispr
  - epileptic-encephalopathy
  - translational-genomics
pretty_name: "STXBP1 Base-Editing Parameter Sweep (Canonical 603-aa, v2)"
task_categories:
  - tabular-classification
size_categories:
  - 100M<n<1B
---

# STXBP1 Base-Editing Parameter Sweep — v2 (Canonical 603-aa frame)

## TL;DR

**170 pathogenic STXBP1 variants × 3,850,560 base-editing parameter combinations
per variant = 654.6 million rows.** Built on the **MANE Plus Clinical canonical
reference** `NM_003165.6 → NP_003156.1` (603 aa), the same frame
[ARIA](https://github.com/SkyWhal3) and ClinVar use.

This is the canonical successor to
[`SkyWhal3/STXBP1_Base_Editing_Parameter_Sweep`](https://huggingface.co/datasets/SkyWhal3/STXBP1_Base_Editing_Parameter_Sweep)
(v1), which was built on `NM_001032221.6` (594 aa MANE Select). For variants at
protein positions 1–575, v1 and v2 results are byte-identical because the two
transcripts encode identical residues in that region. v2 differs from v1 in two
places:

| Variant | v1 (594-aa frame) | v2 (603-aa canonical) |
|---|---|---|
| `Q576X` (`c.1726C>T`) | present but mislabeled — pos 576 is Q on 594-aa, T on canonical | **removed** (wrong-frame label; canonical[576]=T) |
| `E603D` (`c.1809G>T`) | errored (c.1809 past 594-aa CDS end at nt 1782) | **present and correct** |

## Reference frame

| Field | Value |
|---|---|
| Transcript | `NM_003165.6` |
| Protein | `NP_003156.1` |
| UniProt | `P61764-2` (MANE Plus Clinical) |
| Length | 603 aa |
| CDS | 1812 nt (including stop codon) |
| First 10 aa | `MAPIGLKAVV` |
| Last 4 aa | `PTME` |
| SHA-256 (protein) | `f09d3d8cab1a46153031896bab6713a241b2eabd497cb2d354285d3a87756e6c` |

The canonical protein is pinned in
[`stxbp1_canonical.py`](https://github.com/SkyWhal3/...) with a module-load
SHA-256 assertion that fails loud if any byte of the sequence is modified.

## Why two frames?

STXBP1 has two MANE-designated transcripts:

- **MANE Select:** `NM_001032221.6` → `P61764-1` (594 aa). Default in many
  older databases including UniProt's landing page.
- **MANE Plus Clinical:** `NM_003165.6` → `NP_003156.1` / `P61764-2` (603 aa).
  What ClinVar reports variants against. What the clinical community uses.
  What ARIA and its Foundation partners use.

The two are byte-identical for residues 1–575 (which covers all common
pathogenic variants like K196X, R292H, R406H) but diverge at the C-terminus.
v2 exists because audiences evaluating ARIA and related tools expect
variant-position data to be on the same frame as clinical reports.

## What's in this dataset

### Files

| File | Size | Description |
|---|---|---|
| `stxbp1_ULTIMATE_v2_canonical_best.json` | ~200 KB | Top-scoring parameter set per variant. Start here if you want one guide per variant. |
| `stxbp1_ULTIMATE_v2_canonical_sweep.csv.gz` | ~5 GB | All 654.6 M param combos, gzipped. Full search space for your own re-ranking. |
| `stxbp1_snv_variants_170_canonical.txt` | 8 KB | The 170-variant input list with provenance comments. |

### Schema (CSV)

| Column | Type | Description |
|---|---|---|
| `label` | str | Short variant label (e.g. `K196X`) |
| `cdna` | str | c.DNA change (e.g. `c.586A>T`) — on `NM_003165.6` |
| `edit_type` | str | `ABE` (A>G, T>C), `CBE` (C>T, G>A), or `PRIME` |
| `scan` | int | Guide search radius in nt (10–200) |
| `ctx` | int | Context identity window in nt (5–100) |
| `win` | str | Edit-window range (e.g. `4-8`) |
| `identity` | float | Human/mouse sequence identity in the context window (0–1) |
| `candidates` | int | Number of PAM-containing guides found in scan window |
| `best_mm` | int | Mismatches between best human guide and mouse at same site |
| `in_window` | bool | Whether the edit site falls inside the edit window |
| `compat` | bool | Pass/fail composite: identity ≥ 0.90 AND mm ≤ 3 AND in_window |
| `score` | float | 0–100 composite score (identity × 40 + guide quality) |

The CSV header includes three comment rows (`#`-prefixed) with the reference
frame, build date, and variant list filename.

## Quick-start

```python
import pandas as pd
best = pd.read_json("stxbp1_ULTIMATE_v2_canonical_best.json", orient="index")
best.loc[best.index.str.startswith("K196X")]
```

```python
# Or stream the full sweep for one variant
import pandas as pd
iter = pd.read_csv("stxbp1_ULTIMATE_v2_canonical_sweep.csv.gz", chunksize=1_000_000)
for chunk in iter:
    k196x = chunk[chunk["label"] == "K196X"]
    if not k196x.empty:
        print(k196x.sort_values("score", ascending=False).head())
```

## Reproducibility

Pipeline source: [`run_canonical_parameter_sweep.py`](https://github.com/SkyWhal3/...)
with the canonical-input file committed alongside. The build script:
1. Fetches `NM_003165.6` + `NM_011502` CDS live from NCBI (cached on first run).
2. Reads the 170-variant canonical input file.
3. Runs one variant at a time through a CPU multiprocessing pool over the
   191 × 96 × 210 = 3,850,560 parameter grid.
4. Writes the CSV with a banner header declaring the reference frame.

The canonical assertion test
([`assert_canonical_state.py`](https://github.com/SkyWhal3/...)) should be run
before each rebuild to confirm the reference is still pinned at the
SHA-256 above.

## Provenance and prior work

- **v1** (`SkyWhal3/STXBP1_Base_Editing_Parameter_Sweep`, Jan 2026): built on
  `NM_001032221.6` (594 aa). Archived-not-deprecated — valid for variants
  1–575. This v2 supersedes it for demo-facing and publication-facing use.
- **Session 96** (2026-04-24): a wider canonical rebuild corrected a
  years-old contamination in an adjacent ARIA dataset that had been folded
  against a 586-aa non-Munc18-1 protein. The 603-aa frame lock-in described
  here is the downstream of that fix.

## Citation

If you use this dataset, please cite both the v1 build (which produced the
original 170-variant input list and scoring methodology) and this v2 rebuild
for the canonical frame correction.

## License

MIT (matches v1).

## Contact

Adam Freygang — STXBP1 parent, ARIA developer.