Is CDKL5 p.Ala509= (c.1527G>A) pathogenic?

CDKL5 p.Ala509= (c.1527G>A) is classified Benign/Likely benign in CDKL5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-08). Ultra-rare (popmax 0.0123%, afr); Associated with developmental and epileptic encephalopathy, 2.

What condition is associated with CDKL5 p.Ala509= (c.1527G>A)?

CDKL5 p.Ala509= (c.1527G>A) is associated with developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Ala509= (c.1527G>A) in the general population?

CDKL5 p.Ala509= (c.1527G>A) is ultra-rare (popmax 0.0123%, afr) (gnomAD).

How is CDKL5-deficiency disorder inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

CDKL5 p.Ala509=

c.1527G>A · rs369561849 · VCV509971

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, afr)

Conditions

developmental and epileptic encephalopathy, 2

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 -0.077	GERP -2.7, phastCons 0.004
Overall
CADD	0.547	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0123% African / African-American · 7/57,129 alleles

Filtering AF 0.00568% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00406%

Overall 0.00529% 64/1,209,724 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0123%	8,161
Remaining individualsnot grpmax-eligible	0.0084%	11,904
Admixed American	0.00655%	15,258
South Asian	0.00528%	18,939
European (non-Finnish)	0.00525%	19,042

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.Ala509=
Coding: c.1527G>A
MANE Select: NM_001323289
dbSNP: rs369561849
Type: single nucleotide variant
Location: chrX:18604451 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 509: the 'disordered' region

Full CDKL5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CDKL5-deficiency disorder (Orphanet):

Inheritance: X-linked dominant
Onset: Infancy, Neonatal

Similar variants

CDKL5 p.Ala509Val Benign/Likely 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
CDKL5 p.Arg948Ter 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-ala509 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown