Is CDKL5 p.Phe154= (c.462T>C) pathogenic?

CDKL5 p.Phe154= (c.462T>C) is classified Likely benign in CDKL5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-23). Ultra-rare (popmax 0.0237%, mid); Associated with developmental and epileptic encephalopathy, 2.

What condition is associated with CDKL5 p.Phe154= (c.462T>C)?

CDKL5 p.Phe154= (c.462T>C) is associated with developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Phe154= (c.462T>C) in the general population?

CDKL5 p.Phe154= (c.462T>C) is ultra-rare (popmax 0.0237%, mid) (gnomAD).

How is CDKL5-deficiency disorder inherited?

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

CDKL5 p.Phe154=

c.462T>C · rs898874642 · VCV373584

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0237%, mid)

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 0.028	GERP 2.5, phastCons 0.96
Overall
CADD	14.81	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0237% Middle Eastern · 1/4,216 alleles

Filtering AF 0.000723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00027%

Overall 0.000656% 7/1,066,986 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0237%	4,216
Admixed American	0.00436%	22,933
Remaining individualsnot grpmax-eligible	0.00215%	46,578
European (non-Finnish)	0.000346%	289,246

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.Phe154=
Coding: c.462T>C
MANE Select: NM_001323289
dbSNP: rs898874642
Type: single nucleotide variant
Location: chrX:18581949 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 154: the protein kinase domain

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.Phe154Leu Uncertain significance ★ ⚠ same residue
CDKL5 p.Phe154fs Pathogenic ★ same residue
RS1 p.Gln154Arg Pathogenic/Likely pathogenic ★★ same residue
RS1 p.Gln154Ter Pathogenic/Likely pathogenic ★★ same residue
RS1 p.Gln154His Likely pathogenic ★ same residue
RS1 p.Gln154Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
RS1 p.Gln154= 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-phe154 (accessed [today's date]).

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