Is CDKL5 p.Ala40= (c.120G>C) pathogenic?

CDKL5 p.Ala40= (c.120G>C) is classified Likely benign in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-15). Very rare (popmax 0.000244%, nfe); Associated with developmental and epileptic encephalopathy, 2.

What condition is associated with CDKL5 p.Ala40= (c.120G>C)?

CDKL5 p.Ala40= (c.120G>C) is associated with developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Ala40= (c.120G>C) in the general population?

CDKL5 p.Ala40= (c.120G>C) is very rare (popmax 0.000244%, nfe) (gnomAD).

How is CDKL5-deficiency disorder inherited?

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

CDKL5 p.Ala40=

c.120G>C · rs1924900032 · VCV2022860

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000244%, nfe)

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 0.3	GERP -4.9, phastCons 0.51
Overall
CADD	4.903	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000244% European (non-Finnish) · 2/821,040 alleles

Filtering AF 4.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.5e-05%

Overall 0.000198% 2/1,011,040 alleles · very rare

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.Ala40=
Coding: c.120G>C
MANE Select: NM_001323289
dbSNP: rs1924900032
Type: single nucleotide variant
Location: chrX:18564497 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 40: the protein kinase domain; a UniProt-annotated variant site (in dee2; causes mislocalization of the protein in the cytoplasm); a β-strand

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.Ala40Val Pathogenic ★★★ same residue
CDKL5 p.Ala40Glu Likely pathogenic ★ same residue
CDKL5 p.Ala40Thr 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.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-ala40 (accessed [today's date]).

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