CDKL5 p.Pro574=
c.1722G>A · rs371603866 · VCV210643
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Benign for CDKL5 disorder. Applied ACMG criteria (verbatim):
BP7 BA1
Curation rationale (ClinGen, verbatim)
The allele frequency of the p.Pro574= variant in CDKL5 in South Asian sub population in gnomAD, which is high enough to be classified as benign based on the thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The silent p.Pro574 variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP7). In summary, the p.Pro574= variant in CDKL5 is classified as Benign based on the ACMG/AMP criteria (BA1, BP7).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -8.4 | GERP -4.9 |
| Overall | ||
| CADD | 0.137 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0493% | 2,030 |
| Remaining individualsnot grpmax-eligible | 0.021% | 4,760 |
| Admixed American | 0.00436% | 22,933 |
| European (non-Finnish) | 0.000335% | 298,399 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- CDKL5
- Protein
- p.Pro574=
- Coding
- c.1722G>A
- MANE Select
- NM_001323289
- dbSNP
- rs371603866
- Type
- single nucleotide variant
- Location
- chrX:18604646 (GRCh38)
- Structure
- AlphaFold pLDDT 53.76 · 3 PDB
- Residue 574
- a UniProt-annotated variant site (in an ovarian serous carcinoma sample; somatic mutation)
Similar variants
- CDKL5 p.Pro574Gln Likely benign ★★★ ⚠ same residue
- CDKL5 p.Pro574Leu Benign ★★★ same residue
- CDKL5 c.146-1G>A Pathogenic ★★★ same condition
- CDKL5 p.Ala157Pro Likely pathogenic ★★★ same condition
- CDKL5 p.Ala157Val Likely pathogenic ★★★ same condition
- CDKL5 p.Ala40Val Pathogenic ★★★ same condition
- CDKL5 p.Arg178Gln Pathogenic ★★★ same condition
- CDKL5 p.Arg717= Likely pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cdkl5-p-pro574 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown