Is CDKL5 p.Arg178= (c.532C>A) pathogenic?

CDKL5 p.Arg178= (c.532C>A) is classified Likely benign in CDKL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-12). Very rare (popmax 0.000342%, nfe); Associated with developmental and epileptic encephalopathy, 2.

What condition is associated with CDKL5 p.Arg178= (c.532C>A)?

CDKL5 p.Arg178= (c.532C>A) is associated with developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Arg178= (c.532C>A) in the general population?

CDKL5 p.Arg178= (c.532C>A) is very rare (popmax 0.000342%, 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.Arg178=

c.532C>A · rs267608493 · VCV2938887

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000342%, 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 1.4	GERP -0.15, phastCons 1
Overall
CADD	10.89	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000342% European (non-Finnish) · 3/877,735 alleles

Filtering AF 9.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000252% 3/1,190,708 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.Arg178=
Coding: c.532C>A
MANE Select: NM_001323289
dbSNP: rs267608493
Type: single nucleotide variant
Location: chrX:18584331 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 178: the protein kinase domain; a UniProt-annotated variant site (in dee2)

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.Arg178Gln Pathogenic ★★★ same residue
CDKL5 p.Arg178Gly Pathogenic/Likely pathogenic ★★ same residue
CDKL5 p.Arg178Leu Pathogenic ★★ same residue
CDKL5 p.Arg178Pro Pathogenic/Likely pathogenic ★★ same residue
CDKL5 p.Arg178Trp Pathogenic ★★ same residue
RS1 p.Gly178Ser Uncertain significance ★★★ ⚠ same residue
RS1 p.Gly178= Likely benign ★ 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-arg178 (accessed [today's date]).

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