Is CDKL5 p.Phe998= (c.2994C>T) pathogenic?

CDKL5 p.Phe998= (c.2994C>T) is classified Benign/Likely benign in CDKL5 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-03). Rare (popmax 0.749%, afr); Associated with History of neurodevelopmental disorder.

What condition is associated with CDKL5 p.Phe998= (c.2994C>T)?

CDKL5 p.Phe998= (c.2994C>T) is associated with History of neurodevelopmental disorder, developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Phe998= (c.2994C>T) in the general population?

CDKL5 p.Phe998= (c.2994C>T) is rare (popmax 0.749%, afr) (gnomAD).

CDKL5 p.Phe998=

c.2994C>T · rs150900695 · VCV136716

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.749%, afr)

Conditions

History of neurodevelopmental disorder

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 -0.82	GERP -2.4
Overall
CADD	1.007	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.749% African / African-American · 428/57,131 alleles

Filtering AF 0.691% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.667%

Overall 0.043% 520/1,209,395 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.749%	133
Remaining individualsnot grpmax-eligible	0.0799%	1,252
Middle Eastern	0.0705%	1,418
Admixed American	0.0635%	1,575
South Asian	0.0106%	9,455
European (non-Finnish)	0.00179%	55,946

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.Phe998=
Coding: c.2994C>T
MANE Select: NM_001323289 · reported on NM_003159
dbSNP: rs150900695
Type: single nucleotide variant
Location: chrX:18653445 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB

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

Disease context

History of neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy, 2

Similar variants

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
CDKL5 p.Asp193Gly 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-phe998 (accessed [today's date]).

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