CDKL5 p.Gln219Pro
c.656A>C · rs786204963 · VCV189549
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Likely Pathogenic for CDKL5 disorder. Applied ACMG criteria (verbatim):
PM2_Supporting PS4_Supporting PS3_Supporting PS2 PP3 PP4
Curation rationale (ClinGen, verbatim)
The p.Gln219Pro variant has been observed in at least 2 individuals with CDKL5 disorder (PMID 23151060, internal database - Ambry) (PS4_Supporting). The p.Gln219Pro variant in CDKL5 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with CDKL5 disorder (internal database - Ambry) (PS2). The p.Gln219Pro variant in CDKL5 is present in an individual with a clinical phenotype suggestive of CDKL5 disorder (internal database - Ambry) (PP4). The p.Gln219Pro variant in CDKL5 is absent from gnomAD v4.1 (PM2_Supporting). In vitro kinase assay has shown that this variant impacts protein function (PMID: 32034940) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Gln219Pro variant in CDKL5 is classified as likely pathogenic for CDKL5 disorder based on the ACMG/AMP criteria (PS4_Supporting, PS2, PP4, PM2_Supporting, PS3_Supporting, PP3). (CDKL5 Specifications v.5.0.0; curation approved on 8/27/2025)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9998 | likely pathogenic ✓ concordant with ClinVar · top 4% in CDKL5 |
|---|---|---|
| REVEL | 0.748 | pathogenic-leaning |
| SaProt | LLR -15.85 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 11 | GERP 2.5, phastCons 1 |
| Regional constraint | o/e 0.35 | constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic |
| Overall | ||
| CADD | 29.3 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- CDKL5
- Protein
- p.Gln219Pro
- Coding
- c.656A>C
- MANE Select
- NM_001323289
- dbSNP
- rs786204963
- Type
- single nucleotide variant
- Location
- chrX:18588055 (GRCh38)
- Structure
- AlphaFold pLDDT 53.76 · 3 PDB
- Residue 219
- the protein kinase domain; an α-helix
Similar variants
- CDKL5 p.Gln219Arg Likely pathogenic ★★★ same residue
- CDKL5 p.Gln219Lys Uncertain significance ★ ⚠ same residue
- RS1 p.Cys219Arg Likely pathogenic ★★★ same residue
- RS1 p.Cys219Gly Likely pathogenic ★★★ same residue
- RS1 p.Cys219Tyr Likely pathogenic ★★★ ⚠ same residue
- CDKL5 p.Gln219Ter Pathogenic ★ same residue
- RS1 p.Cys219Ser Likely pathogenic ★ ⚠ same residue
- CDKL5 c.146-1G>A 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-gln219pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown