Is CDKL5 p.Pro719= (c.2157A>G) pathogenic?

CDKL5 p.Pro719= (c.2157A>G) is classified Conflicting classifications of pathogenicity in CDKL5 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-11-10). Very rare (popmax 0.00224%, amr); Associated with developmental and epileptic encephalopathy, 2.

What condition is associated with CDKL5 p.Pro719= (c.2157A>G)?

CDKL5 p.Pro719= (c.2157A>G) is associated with developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Pro719= (c.2157A>G) in the general population?

CDKL5 p.Pro719= (c.2157A>G) is very rare (popmax 0.00224%, amr) (gnomAD).

How is CDKL5-deficiency disorder inherited?

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

CDKL5 p.Pro719=

c.2157A>G · rs200333632 · VCV2439887

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00224%, amr)

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 1.1	GERP -1.7, phastCons 0.99
Overall
CADD	7.788	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00224% Admixed American · 1/44,703 alleles

Filtering AF 0.00128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00106%

Overall 0.00169% 20/1,181,452 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00224%	44,703
European (non-Finnish)	0.00205%	48,705
African / African-American	0.00179%	55,798

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.Pro719=
Coding: c.2157A>G
MANE Select: NM_001323289
dbSNP: rs200333632
Type: single nucleotide variant
Location: chrX:18613156 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 719: 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 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-pro719 (accessed [today's date]).

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