Is CDKL5 p.Pro740Ala (c.2218C>G) pathogenic?

CDKL5 p.Pro740Ala (c.2218C>G) is classified Likely benign in CDKL5 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-07-27). AlphaMissense: likely benign (0.0718); Very rare (popmax 0.00218%, amr); Associated with developmental and epileptic encephalopathy, 2.

What condition is associated with CDKL5 p.Pro740Ala (c.2218C>G)?

CDKL5 p.Pro740Ala (c.2218C>G) is associated with developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Pro740Ala (c.2218C>G) in the general population?

CDKL5 p.Pro740Ala (c.2218C>G) is very rare (popmax 0.00218%, amr) (gnomAD).

How is CDKL5-deficiency disorder inherited?

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

What do computational predictors say about CDKL5 p.Pro740Ala (c.2218C>G)?

AlphaMissense predicts likely benign (score 0.0718) — an in-silico prediction, not a clinical call.

CDKL5 p.Pro740Ala

c.2218C>G · VCV3762768

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0718 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00218%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 2

Computational evidence

Protein change
AlphaMissense	0.0718	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -6.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 30 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00218% Admixed American · 1/45,786 alleles

Overall 9.21e-05% 1/1,085,892 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.Pro740Ala
Coding: c.2218C>G
MANE Select: NM_001323289
Type: single nucleotide variant
Location: chrX:18613217 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB
Residue 740: the 'disordered' region; 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.Pro740Leu Uncertain significance ★ ⚠ same residue
CDKL5 p.Pro740= Likely benign ★ 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.Ala40Val 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-pro740ala (accessed [today's date]).

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