CDKL4

Summary

CDKL4 (cyclin dependent kinase like 4, HGNC:19287) is a protein-coding gene on chromosome 2p22.1, encoding Cyclin-dependent kinase-like 4 (Q5MAI5).

Predicted to enable protein serine/threonine kinase activity. Predicted to be involved in regulation of cell cycle. Predicted to be located in cytoplasm. Predicted to be active in nucleus.

Source: NCBI Gene 344387 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 52 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001397900

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19287
Approved symbol	CDKL4
Name	cyclin dependent kinase like 4
Location	2p22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000205111
Ensembl biotype	protein_coding
Entrez	344387

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 nonsense_mediated_decay

ENST00000378803, ENST00000395035, ENST00000419111, ENST00000451199, ENST00000699627, ENST00000699628, ENST00000862327

RefSeq mRNA: 3 — MANE Select: NM_001397900 NM_001009565, NM_001346911, NM_001397900

CCDS: CCDS33184, CCDS86834, CCDS92740

Canonical transcript exons

ENST00000451199 — 10 exons

Exon	Start	End
ENSE00001478815	39225839	39225960
ENSE00001802741	39229365	39229588
ENSE00003468524	39213400	39213472
ENSE00003504790	39204527	39204617
ENSE00003977154	39243871	39243970
ENSE00003977155	39175646	39176096
ENSE00003977156	39184591	39184647
ENSE00003977157	39179187	39179321
ENSE00003977160	39190305	39190502
ENSE00003977162	39187627	39187709

Expression profiles

Bgee: expression breadth ubiquitous, 119 present calls, max score 86.14.

Top tissues by expression

130 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.14	gold quality
adrenal tissue	UBERON:0018303	66.42	gold quality
testis	UBERON:0000473	65.00	gold quality
right testis	UBERON:0004534	64.72	gold quality
left testis	UBERON:0004533	64.61	gold quality
stromal cell of endometrium	CL:0002255	62.42	gold quality
calcaneal tendon	UBERON:0003701	61.63	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	61.27	gold quality
right uterine tube	UBERON:0001302	60.23	gold quality
placenta	UBERON:0001987	59.28	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	58.94	gold quality
adrenal gland	UBERON:0002369	56.92	gold quality
left adrenal gland	UBERON:0001234	56.47	gold quality
right adrenal gland	UBERON:0001233	55.39	gold quality
left adrenal gland cortex	UBERON:0035825	54.88	gold quality
pituitary gland	UBERON:0000007	54.87	gold quality
endometrium	UBERON:0001295	54.00	gold quality
right adrenal gland cortex	UBERON:0035827	53.48	gold quality
adenohypophysis	UBERON:0002196	52.46	gold quality
corpus callosum	UBERON:0002336	52.09	silver quality
superior frontal gyrus	UBERON:0002661	50.92	gold quality
islet of Langerhans	UBERON:0000006	50.24	gold quality
hypothalamus	UBERON:0001898	50.13	gold quality
tonsil	UBERON:0002372	49.78	silver quality
Brodmann (1909) area 9	UBERON:0013540	49.16	gold quality
apex of heart	UBERON:0002098	48.99	gold quality
right lung	UBERON:0002167	48.33	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	47.99	gold quality
kidney	UBERON:0002113	46.30	gold quality
lung	UBERON:0002048	46.05	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.25

Regulation

Is transcription factor: no

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cdkl4	ENSMUSG00000033966
rattus_norvegicus	Cdkl4	ENSRNOG00000040266

Paralogs (26): CDKL3 (ENSG00000006837), CDKL5 (ENSG00000008086), CDK11A (ENSG00000008128), CDK14 (ENSG00000058091), CDK17 (ENSG00000059758), CDK13 (ENSG00000065883), CDKL1 (ENSG00000100490), CDK16 (ENSG00000102225), CDK6 (ENSG00000105810), PRP4K (ENSG00000112739), CDK18 (ENSG00000117266), CDK2 (ENSG00000123374), CDK8 (ENSG00000132964), CDK7 (ENSG00000134058), CDK4 (ENSG00000135446), CDK9 (ENSG00000136807), CDK15 (ENSG00000138395), CDKL2 (ENSG00000138769), CDK19 (ENSG00000155111), CDK20 (ENSG00000156345), CDK5 (ENSG00000164885), CDK12 (ENSG00000167258), CDK1 (ENSG00000170312), CDK10 (ENSG00000185324), CDK11B (ENSG00000248333), CDK3 (ENSG00000250506)

Protein

Protein identifiers

Cyclin-dependent kinase-like 4 — Q5MAI5 (reviewed: Q5MAI5)

All UniProt accessions (4): A0A8V8TNQ4, Q5MAI5, F8WC88, H7BZI6

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Cytoplasm.

Domain organisation. The [NKR]KIAxRE motif seems to be a cyclin-binding region.

Similarity. Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5MAI5-1	1	yes
Q5MAI5-2	2

RefSeq proteins (3): NP_001009565, NP_001333840, NP_001384829* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR050108	CDK	Family

Pfam: PF00069

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (13 total): sequence variant 6, binding site 2, chain 1, domain 1, short sequence motif 1, active site 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5MAI5-F1	79.67	0.57

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 126 (proton acceptor)

Ligand- & substrate-binding residues (2): 10–18; 33

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 47 (showing top): GOBP_REGULATION_OF_CELL_CYCLE, GOMF_PROTEIN_KINASE_ACTIVITY, GOMF_KINASE_ACTIVITY, GOMF_CYCLIN_DEPENDENT_PROTEIN_KINASE_ACTIVITY, GOMF_PROTEIN_SERINE_THREONINE_KINASE_ACTIVITY, GOMF_ADENYL_NUCLEOTIDE_BINDING, GOMF_TRANSFERASE_ACTIVITY_TRANSFERRING_PHOSPHORUS_CONTAINING_GROUPS, chr2p22, HES2_TARGET_GENES, TERT_TARGET_GENES, ZNF7_TARGET_GENES, MIR4310, MIR4766_5P, MIR3145_3P, MIR7157_5P

GO Biological Process (2): protein phosphorylation (GO:0006468), regulation of cell cycle (GO:0051726)

GO Molecular Function (8): protein serine/threonine kinase activity (GO:0004674), cyclin-dependent protein serine/threonine kinase activity (GO:0004693), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	2
phosphorylation	1
protein modification process	1
cell cycle	1
regulation of cellular process	1
protein serine/threonine kinase activity	1
cyclin-dependent protein kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

338 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDKL4	C2orf78	A6NCI8	445
CDKL4	GPATCH11	Q8N954	417
CDKL4	ARHGEF33	A8MVX0	362
CDKL4	KIF19	Q2TAC6	347
CDKL4	DHX57	Q6P158	328
CDKL4	NBPF14	Q5TI25	315
CDKL4	DRC1	Q96MC2	308
CDKL4	TMEM116	Q8NCL8	305
CDKL4	MORN2	Q502X0	296
CDKL4	RASGEF1C	Q8N431	294
CDKL4	NPHP1	O15259	285
CDKL4	YWHAB	P31946	283
CDKL4	ZNF496	Q96IT1	277
CDKL4	LCE1F	Q5T754	270
CDKL4	TMEM17	Q86X19	266

IntAct

8 interactions, top by confidence:

A	B	Type	Score
CDKL1	FKBP5	psi-mi:“MI:0914”(association)	0.640
CDKL1	TRIP6	psi-mi:“MI:0914”(association)	0.530
CDKL1	SUPT5H	psi-mi:“MI:0914”(association)	0.350
CDKL4	HSP90AA1	psi-mi:“MI:0914”(association)	0.350

BioGRID (27): HSP90AA1 (Affinity Capture-MS), HSP90AB1 (Affinity Capture-MS), HSP90AB4P (Affinity Capture-MS), HSP90AB3P (Affinity Capture-MS), HSP90AA5P (Affinity Capture-MS), POTEI (Affinity Capture-MS), FKBP5 (Affinity Capture-MS), DNMT1 (Affinity Capture-MS), MYO18A (Affinity Capture-MS), ZNF703 (Affinity Capture-MS), CDKL4 (Reconstituted Complex), HSP90AB3P (Affinity Capture-MS), POTEI (Affinity Capture-MS), CDKL4 (Affinity Capture-MS), HSP90AB4P (Affinity Capture-MS)

ESM2 similar proteins: A4IIW7, A8X5H5, B0VXE8, B0VXL7, B6A7Q3, G4NH08, G5EBT1, O04160, O23145, O44514, P18266, P21965, P38615, P43288, P43289, P49841, P51137, P51138, P51139, Q00532, Q09595, Q10452, Q11179, Q12222, Q388M1, Q39010, Q39011, Q39012, Q39019, Q3S406, Q3TZA2, Q40518, Q5MAI5, Q5YJC2, Q5Z7J0, Q60EZ2, Q6AXJ9, Q6DJM7, Q8CEQ0, Q8MXI4

Diamond homologs: A2X6X1, A2XFC8, A2XUW1, A2YCH5, A8WIP6, B0Y8W7, B3WFY8, G4N0Z0, G4NH08, G5EFV5, O04160, O23145, O42376, O42781, O80345, P16892, P18266, P20793, P20794, P21127, P23573, P24788, P27638, P38615, P39073, P43288, P43289, P43294, P46892, P47812, P49841, P51136, P51137, P51138, P51139, P54665, P54666, Q00532, Q00859, Q03957

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

52 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	47
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1543 predictions. Top by Δscore:

Variant	Effect	Δscore
2:39179320:CCCTT:C	acceptor_gain	1.0000
2:39187705:TTTTC:T	acceptor_gain	1.0000
2:39187706:TTTC:T	acceptor_gain	1.0000
2:39225837:A:AC	donor_gain	1.0000
2:39225838:C:CC	donor_gain	1.0000
2:39225956:AATTG:A	acceptor_gain	1.0000
2:39225957:ATTG:A	acceptor_gain	1.0000
2:39225958:TTG:T	acceptor_gain	1.0000
2:39225959:TG:T	acceptor_gain	1.0000
2:39225959:TGCTG:T	acceptor_loss	1.0000
2:39225960:GC:G	acceptor_loss	1.0000
2:39225961:C:CA	acceptor_loss	1.0000
2:39225961:C:CC	acceptor_gain	1.0000
2:39225962:T:A	acceptor_loss	1.0000
2:39225963:G:C	acceptor_gain	1.0000
2:39229362:TACCT:T	donor_loss	1.0000
2:39229364:C:CG	donor_loss	1.0000
2:39179317:CACCC:C	acceptor_gain	0.9900
2:39179319:CCC:C	acceptor_gain	0.9900
2:39179321:CCTT:C	acceptor_gain	0.9900
2:39179322:C:T	acceptor_gain	0.9900
2:39184587:GTAC:G	donor_loss	0.9900
2:39184588:TA:T	donor_loss	0.9900
2:39184589:A:AG	donor_loss	0.9900
2:39184590:C:CT	donor_loss	0.9900
2:39184644:TTTC:T	acceptor_gain	0.9900
2:39184645:TTCC:T	acceptor_loss	0.9900
2:39184646:TCC:T	acceptor_loss	0.9900
2:39184647:CCT:C	acceptor_loss	0.9900
2:39184648:C:CC	acceptor_gain	0.9900

AlphaMissense

830 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:39179292:T:A	R274S	0.946
2:39179292:T:G	R274S	0.946
2:39179275:A:G	L280P	0.914
2:39179314:A:G	L267P	0.909
2:39187703:A:G	L220S	0.897
2:39179293:C:G	R274T	0.896
2:39179318:A:G	C266R	0.891
2:39184627:G:C	F252L	0.854
2:39184627:G:T	F252L	0.854
2:39184629:A:G	F252L	0.854
2:39187660:G:C	F234L	0.854
2:39187660:G:T	F234L	0.854
2:39187662:A:G	F234L	0.854
2:39187678:A:C	F228L	0.848
2:39187678:A:T	F228L	0.848
2:39187680:A:G	F228L	0.848
2:39179283:A:C	C277W	0.847
2:39179294:T:C	R274G	0.843
2:39179285:A:G	C277R	0.829
2:39187679:A:G	F228S	0.821
2:39179316:A:C	C266W	0.818
2:39179256:A:C	F286L	0.814
2:39179256:A:T	F286L	0.814
2:39179258:A:G	F286L	0.814
2:39184598:A:G	F262S	0.803
2:39187663:A:C	F233L	0.800
2:39187663:A:T	F233L	0.800
2:39187665:A:G	F233L	0.800
2:39179293:C:A	R274I	0.798
2:39184595:A:T	M263K	0.780

dbSNP variants (sampled 300 via entrez): RS1000024302 (2:39186349 T>C,G), RS1000073182 (2:39197841 C>T), RS1000080851 (2:39203365 T>C,G), RS1000207809 (2:39248035 A>G), RS1000221714 (2:39175258 A>G), RS1000233039 (2:39169862 G>C), RS1000260285 (2:39247831 C>G), RS1000265142 (2:39203121 G>A), RS1000269653 (2:39219721 T>A,C), RS1000311518 (2:39214223 A>G), RS1000320893 (2:39214019 G>T), RS1000417066 (2:39187838 C>A,T), RS1000488396 (2:39220488 A>G), RS1000516103 (2:39191512 G>A), RS1000593915 (2:39229405 A>G)

Disease associations

OMIM: gene `` | disease phenotypes: MIM:610733

GenCC curated gene-disease

Mondo (1): Noonan syndrome 4 (MONDO:0012547)

Orphanet (1): Noonan syndrome (Orphanet:648)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C548082	Noonan Syndrome 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523326 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 4 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL5426285	5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-	1	4

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Cyclin-dependent kinase-like (CDKL) family

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.10	IC50	0.8	nM	5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-
6.93	IC50	118	nM	CHEMBL5190023

PubChem BioAssay actives

2 with measured affinity, of 15 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(5Z)-5-(1,3-benzothiazol-6-ylmethylidene)-2-[(2R)-1-methoxy-4-methylpentan-2-yl]iminoimidazolidin-4-one	2024494: Inhibition of human CDKL4 assessed as remaining activity by eurofins-cerep kinase profiler analysis	ic50	0.0008	uM
cis-(1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide	1856717: Inhibition of CDKL4 (unknown origin)	ic50	0.1180	uM

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	increases expression	1
CGP 52608	affects binding, increases reaction	1
Valproic Acid	decreases methylation	1
Permethrin	increases expression	1
Particulate Matter	decreases expression	1

ChEMBL screening assays

20 unique, capped per target: 20 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4314625	Binding	Inhibition of human CDKL4 assessed as residual activity at 10 uM by radiometric method	Discovery of 3-(((9H-purin-6-yl)amino)methyl)-4,6-dimethylpyridin-2(1H)-one derivatives as novel tubulin polymerization inhibitors for treatment of cancer. — Eur J Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.