CDKL5 p.Arg59Gln
c.176G>A · rs1555949009 · VCV496681
ClinGen expert panel — Rett and Angelman-like Disorders VCEP
Uncertain Significance for CDKL5 disorder. Applied ACMG criteria (verbatim):
PM6 BS2_Supporting
Curation rationale (ClinGen, verbatim)
The highest population minor allele frequency of the p.Arg59Gln variant in CDKL5 in gnomAD v4.1 is 0.00000112 in Non-Finnish European population (not sufficient to meet BS1 criteria). The p.Arg59Gln variant is observed in at least 1 unaffected individual (internal database - GeneDx) (BS2-supporting). Computational prediction analysis tools are inconclusive for this variant. The p.Arg59Gln variant in CDKL5 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with epileptic encephalopathy (internal database - Équipe Génétique des Anomalies du Développement (GAD)) (PM6). In summary, the p.Arg59Gln variant in CDKL5 is classified as uncertain significance based on the ACMG/AMP criteria (BS2_Supporting, PM6). (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 | 0.9939 | likely pathogenic |
|---|---|---|
| REVEL | 0.622 | indeterminate |
| SaProt | LLR -12.79 | damaging |
| ⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 2.4, phastCons 1 |
| Regional constraint | o/e 0.35 | constrained · MANE · 91 kb · p 1.2e-21 · regional, not allelic |
| Overall | ||
| CADD | 32.0 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
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.Arg59Gln
- Coding
- c.176G>A
- MANE Select
- NM_001323289
- dbSNP
- rs1555949009
- Type
- single nucleotide variant
- Location
- chrX:18575384 (GRCh38)
- Structure
- AlphaFold pLDDT 53.76 · 3 PDB
- Residue 59
- the protein kinase domain; an α-helix
Similar variants
- CDKL5 p.Arg59Pro Likely pathogenic ★★ same residue
- CDKL5 p.Arg59Ter Pathogenic ★★ 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-arg59gln (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown