CAMK2A

Summary

CAMK2A (calcium/calmodulin dependent protein kinase II alpha, HGNC:1460) is a protein-coding gene on chromosome 5q32, encoding Calcium/calmodulin-dependent protein kinase type II subunit alpha (Q9UQM7). Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in various processes, such as synaptic plasticity, neurotransmitter release and long-term potentiation.

The product of this gene belongs to the serine/threonine protein kinases family, and to the Ca(2+)/calmodulin-dependent protein kinases subfamily. Calcium signaling is crucial for several aspects of plasticity at glutamatergic synapses. This calcium calmodulin-dependent protein kinase is composed of four different chains: alpha, beta, gamma, and delta. The alpha chain encoded by this gene is required for hippocampal long-term potentiation (LTP) and spatial learning. In addition to its calcium-calmodulin (CaM)-dependent activity, this protein can undergo autophosphorylation, resulting in CaM-independent activity. Several transcript variants encoding distinct isoforms have been identified for this gene.

Source: NCBI Gene 815 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 191 total — 13 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 51
• Druggable target: yes — 25 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_015981

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1460
Approved symbol	CAMK2A
Name	calcium/calmodulin dependent protein kinase II alpha
Location	5q32
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0968, CaMKIINalpha, CaMKIIα
Ensembl gene	ENSG00000070808
Ensembl biotype	protein_coding
OMIM	114078
Entrez	815

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 18 protein_coding, 5 protein_coding_CDS_not_defined, 4 retained_intron, 2 nonsense_mediated_decay

ENST00000348628, ENST00000351010, ENST00000398376, ENST00000507995, ENST00000508662, ENST00000510347, ENST00000515758, ENST00000671881, ENST00000672089, ENST00000672396, ENST00000672404, ENST00000672479, ENST00000672752, ENST00000672785, ENST00000672829, ENST00000682786, ENST00000683115, ENST00000683273, ENST00000683332, ENST00000683506, ENST00000684093, ENST00000684431, ENST00000684465, ENST00000856239, ENST00000856240, ENST00000856241, ENST00000856242, ENST00000856243, ENST00000856244

RefSeq mRNA: 5 — MANE Select: NM_015981 NM_001363989, NM_001363990, NM_001369025, NM_015981, NM_171825

CCDS: CCDS43386, CCDS43387, CCDS93803

Canonical transcript exons

ENST00000671881 — 19 exons

Exon	Start	End
ENSE00001532987	150219491	150222713
ENSE00003478430	150253444	150253546
ENSE00003482247	150273065	150273159
ENSE00003507431	150239704	150239736
ENSE00003517992	150250226	150250309
ENSE00003533562	150222989	150223217
ENSE00003538138	150251982	150252065
ENSE00003545447	150247772	150247814
ENSE00003552768	150250688	150250810
ENSE00003565600	150228192	150228286
ENSE00003575513	150251750	150251844
ENSE00003606932	150264956	150265015
ENSE00003635197	150256766	150256831
ENSE00003649385	150238700	150238748
ENSE00003676691	150231305	150231380
ENSE00003681672	150245161	150245201
ENSE00003686280	150256573	150256645
ENSE00003791267	150257563	150257617
ENSE00003889782	150289564	150289773

Expression profiles

Bgee: expression breadth ubiquitous, 184 present calls, max score 98.52.

FANTOM5 (CAGE): breadth broad, TPM avg 23.4634 / max 1795.6695, expressed in 308 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
64203	16.7222	150
64202	5.6909	126
64187	0.3426	109
64192	0.1816	54
64204	0.0973	44
64189	0.0633	22
64205	0.0596	35
64207	0.0573	40
64200	0.0542	37
64191	0.0452	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
amygdala	UBERON:0001876	98.52	gold quality
prefrontal cortex	UBERON:0000451	98.46	gold quality
right frontal lobe	UBERON:0002810	98.40	gold quality
CA1 field of hippocampus	UBERON:0003881	98.36	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.21	gold quality
cingulate cortex	UBERON:0003027	98.19	gold quality
anterior cingulate cortex	UBERON:0009835	98.12	gold quality
Ammon’s horn	UBERON:0001954	97.71	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.62	gold quality
frontal pole	UBERON:0002795	97.42	gold quality
orbitofrontal cortex	UBERON:0004167	97.13	gold quality
temporal lobe	UBERON:0001871	97.12	gold quality
frontal cortex	UBERON:0001870	96.75	gold quality
primary visual cortex	UBERON:0002436	96.44	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.44	gold quality
Brodmann (1909) area 10	UBERON:0013541	96.44	gold quality
nucleus accumbens	UBERON:0001882	96.40	gold quality
postcentral gyrus	UBERON:0002581	96.29	gold quality
neocortex	UBERON:0001950	96.20	gold quality
cerebral cortex	UBERON:0000956	96.14	gold quality
parietal lobe	UBERON:0001872	95.99	gold quality
superior frontal gyrus	UBERON:0002661	95.93	gold quality
occipital lobe	UBERON:0002021	95.90	gold quality
telencephalon	UBERON:0001893	95.70	gold quality
entorhinal cortex	UBERON:0002728	95.46	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.33	gold quality
putamen	UBERON:0001874	95.04	gold quality
caudate nucleus	UBERON:0001873	94.70	gold quality
diaphragm	UBERON:0001103	93.86	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.16	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	82.41
E-HCAD-35	yes	50.54
E-ANND-3	yes	4.04
E-HCAD-30	no	1076.20

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF1, DLX5, EGR1, HESX1, KCNIP3, MEF2A, SP7, ZIC2, ZNF91

miRNA regulators (miRDB)

147 targeting CAMK2A, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6739-5P	99.80	67.87	2806

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Four distinct isoforms of CAMKII were isolated. Two of them were characterized as CaMKII alpha and beta subunits.CaMKII expression is developmentally regulated in human fetal and adult brain (PMID:11710563)
• the NPY Y(1) receptor induces the expression of CRE containing target genes through the CaM kinase-CREB pathway (PMID:11814622)
• role in cell communication (PMID:11889801)
• CaMKII alpha mRNA expression is significantly reduced in the prefrontal cortex of patients with bipolar illness. (PMID:11930170)
• Calcium/calmodulin-dependent protein kinase II binds to Raf-1 and modulates integrin-stimulated ERK activation (PMID:12954639)
• measured differences in CaMKII binding affinities for CaM play a minor role in the autophosphorylation of the enzyme, largely dictated by autophosphorylation rate for alpha, beta, gamma and delta isoforms (PMID:14722083)
• CaMKII-alpha may be related with beta-amyloid more closely than being involved in tau hyperphosphorylation in Alzheimer’s disease (PMID:15621017)
• novel mechanism for Ca2+-dependent negative-feedback regulation of NR2B-containing NMDARs in a CaMKII activity- and autophosphorylation-dependent manner that may modulate NMDAR-mediated synaptic plasticity (PMID:15866054)
• activation of the IKK/NFkappaB signaling cascade by SSTR2 requires a complicated network consisting of Galpha(14), protein kinase C, CamkII, ERK, and c-Src (PMID:16115892)
• The expression of CaMKII alpha was significantly elevated in depression. (PMID:16247765)
• The expression of CaMKIIalpha is significantly elevated in depression (29%), but not in schizophrenia or bipolar disorder, compared to healthy controls. (PMID:16247765)
• EGF has the ability to abrogate the PP2A function in the maintenance of beta1 integrin-mediated cell adhesion by dissociation of PP2A-IQGAP1-CaMKII from beta1 integrin-Rac through activation of CaMKII (PMID:16557530)
• CD44 interaction with LARG and EGFR plays a pivotal role in Rho/Ras co-activation, PLC epsilon-Ca2+ signaling, and Raf/ERK up-regulation required for CaMKII-mediated cytoskeleton function and in head and neck squamous cell carcinoma progression (PMID:16565089)
• voltage-dependent facilitation of the Ca(v)1.2 channel depends on the phosphorylation of Ser1512/Ser1570 by calmodulin kinase II (PMID:16820363)
• To characterize the human alphaCaMKII promoter, a promoter-reporter gene assay using different cell lines, was developed. (PMID:17221287)
• Amphetamine sensitization in rats, an animal model of schizophrenia, results in significant increase in CaMKII beta and a nonsignificant increase in CaMKII alpha mRNA. (PMID:17603807)
• Skeletal muscle CaMKII kinase isoform expression and serum response factor phosphorylation is higher with endurance-type exercise training, adaptations that are restricted to active muscle. (PMID:17627985)
• alpha-CaMKII controls the growth of human osteosarcoma by regulating cell cycle progression (PMID:17632540)
• These findings revealed that TNF-alpha induced VCAM-1 expression via multiple signaling pathways. (PMID:18227124)
• Mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/-) have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (PMID:18803808)
• Phosphorylation or a phosphorylation mimicking mutation on NR2B (NR2B-S1303D) abolishes the Ca(2+)/calmodulin-independent binding whereas it allows the Ca(2+)/calmodulin-dependent binding of alpha-CaMKII in vitro. (PMID:19453375)
• Data show that data provide a novel mechanism whereby CaMKII may regulate the proteasome in neurons to facilitate remodeling of synaptic connections through protein degradation. (PMID:19638347)
• Knockdown of spinal CaMKIIalpha attentuates opioid-induced hyperalgesia. (PMID:20053885)
• Data show that he calmodulin-CKII peptide system allows the study of photounbinding under different dissociation constants without changing the molecular system. (PMID:21124984)
• Characterization of a central Ca2+/calmodulin-dependent protein kinase IIalpha/beta binding domain in densin that selectively modulates glutamate receptor subunit phosphorylation. (PMID:21610080)
• 20 single nucleotide polymorphisms had suggestive associations with conduct disorder, nine of which were located in known genes, including CAMK2A (PMID:21611732)
• Kv4.3 K channels contribute to cell apoptosis and necrosis through activating CaMKII. (PMID:22023388)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• Findigs show that the F-actin-binding protein alpha-actinin-2 targets CaMKIIalpha to F-actin in cells by binding to the CaMKII regulatory domain. (PMID:22427672)
• The role of CaMKII in regulating GLUT4 expression in skeletal muscle. (PMID:22496345)
• The decrease in CaMKII signaling in the absence of CAPN3 is associated with a reduction of muscle adaptation response. (PMID:22505582)
• Inactivating the alphaCamKII transgene eliminates both the IA-type potassium current-mediated firing decrease and the elevated behavioral response to cocaine. (PMID:22573680)
• Rem2 has a role in neuronal plasticity hrough co-trafficking with CaMKIIa (PMID:22815963)
• results suggest that the CAMK2A gene may influence spatial and non-SWM performance in humans without any corresponding gross changes in frontal cortex or hippocampal anatomy. (PMID:22824813)
• These results suggest that Osterix is a novel target of CaMKII and the activity of Osterix can be modulated by a novel mechanism involving CaMKII during osteoblast differentiation. (PMID:23402759)
• found seven significant associations between CAMK2A SNPs and alcohol dependence, one of which in an autophosphorylation-related area of the gene. (PMID:23459588)
• we describe for the first time, two patients with MFD and ID and for whom a deletion encompassing TCOF1 and CAMK2A has been identified (PMID:23695276)
• CAMK2A SNPs were associated with Alzheimer disease and mild cognitive impairment. AG genotype at the CAMK2A-rs3822606 was associated with AD risk. (PMID:24384746)
• Overexpression of a T253D phosphomimic form of calcium/calmodulin-dependent protein kinase type II subunit alpha significantly decreases proliferation, and cells accumulate in mitosis, specifically in metaphase. (PMID:24407174)
• CaMKII-mediated recruitment and upregulation of CYLD is expected to remove K63-linked polyubiquitins and facilitate proteasomal degradation at the postsynaptic density. (PMID:24614225)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	camk2a	ENSDARG00000053617
mus_musculus	Camk2a	ENSMUSG00000024617
rattus_norvegicus	Camk2a	ENSRNOG00000018712

Paralogs (22): CAMKK1 (ENSG00000004660), CAMK1G (ENSG00000008118), CAMK2B (ENSG00000058404), MYLK2 (ENSG00000101306), CAMKK2 (ENSG00000110931), STK11 (ENSG00000118046), STK33 (ENSG00000130413), PNCK (ENSG00000130822), DCLK1 (ENSG00000133083), CAMK1 (ENSG00000134072), MYLK3 (ENSG00000140795), CAMK2D (ENSG00000145349), MYLK4 (ENSG00000145949), PSKH2 (ENSG00000147613), CAMK2G (ENSG00000148660), PHKG2 (ENSG00000156873), PSKH1 (ENSG00000159792), DCLK3 (ENSG00000163673), CAMKV (ENSG00000164076), PHKG1 (ENSG00000164776), DCLK2 (ENSG00000170390), CAMK1D (ENSG00000183049)

Protein

Protein identifiers

Calcium/calmodulin-dependent protein kinase type II subunit alpha — Q9UQM7 (reviewed: Q9UQM7)

All UniProt accessions (13): Q9UQM7, A0A5F9ZH21, A0A5F9ZH50, A0A5F9ZHM9, A0A5F9ZHR5, A0A5F9ZHY2, A0A5K1VW76, A0A804HIC9, A0A804HLD1, A0A8V8TME7, A8K161, D6RFJ0, Q7LDD5

UniProt curated annotations — full annotation on UniProt →

Function. Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in various processes, such as synaptic plasticity, neurotransmitter release and long-term potentiation. Member of the NMDAR signaling complex in excitatory synapses, it regulates NMDAR-dependent potentiation of the AMPAR and therefore excitatory synaptic transmission. Regulates dendritic spine development. Also regulates the migration of developing neurons. Phosphorylates the transcription factor FOXO3 to activate its transcriptional activity. Phosphorylates the transcription factor ETS1 in response to calcium signaling, thereby decreasing ETS1 affinity for DNA. In response to interferon-gamma (IFN-gamma) stimulation, catalyzes phosphorylation of STAT1, stimulating the JAK-STAT signaling pathway. In response to interferon-beta (IFN-beta) stimulation, stimulates the JAK-STAT signaling pathway. In response to interferon-gamma (IFN-gamma) stimulation, catalyzes phosphorylation of PSAT1, inhibiting ferroptosis by promoting GPX4 hydroxylation and stability. Acts as a negative regulator of 2-arachidonoylglycerol (2-AG)-mediated synaptic signaling via modulation of DAGLA activity.

Subunit / interactions. There are 4 genes encoding calcium/calmodulin-dependent protein kinase type II chains: CAMK2A, CAMK2B, CAMK2G and CAMK2D. The corresponding proteins assemble into homo- or heteromultimeric holoenzymes composed of 12 subunits with two hexameric rings stacked one on top of the other. Interacts with BAALC. Interacts with MPDZ. Interacts with SYN1. Interacts with CAMK2N2. Interacts with SYNGAP1. Interacts with SYNPO2. Interacts with SHANK3. Interacts with GRIN2B. Interacts with CACNB2. Interacts with LRRC7. Interacts with GRM5. Interacts with DAGLA (via C-terminal); this interaction is enhanced by autophosphorylation of CAMK2A at Thr-286. Interacts with CAMK2N1; this interaction requires CAMK2A activation by Ca(2+).

Subcellular location. Synapse. Postsynaptic density. Cell projection. Dendritic spine. Dendrite.

Post-translational modifications. Autophosphorylation of Thr-286 following activation by Ca(2+)/calmodulin. Phosphorylation of Thr-286 locks the kinase into an activated state. Palmitoylated. Probably palmitoylated by ZDHHC3 and ZDHHC7.

Disease relevance. Intellectual developmental disorder, autosomal dominant 53 (MRD53) [MIM:617798] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. The disease is caused by variants affecting the gene represented in this entry. Intellectual developmental disorder, autosomal recessive 63 (MRT63) [MIM:618095] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT63 patients manifest global developmental delay, severe intellectual disability, and seizures. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by Ca(2+)/calmodulin. Binding of calmodulin results in conformational change that relieves intrasteric autoinhibition and allows autophosphorylation of Thr-286 which turns the kinase in a constitutively active form and confers to the kinase a Ca(2+)-independent activity.

Similarity. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UQM7-1	A	yes
Q9UQM7-2	B

RefSeq proteins (5): NP_001350918, NP_001350919, NP_001355954, NP_057065, NP_741960 (=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
IPR013543	Ca/CaM-dep_prot_kinase-assoc	Domain
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR032710	NTF2-like_dom_sf	Homologous_superfamily

Pfam: PF00069, PF08332

Enzyme classification (BRENDA):

• EC 2.7.11.17 — Ca2+/calmodulin-dependent protein kinase (BRENDA: 38 organisms, 300 substrates, 137 inhibitors, 35 Km, 17 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0071–178.29	13
BIOTINYLATED THR-ARG-SER-ALA-ILE-ARG-ARG-ALA-SER	0.0064–0.0158	4
GST-TAGGED GLUN2A	6.05–11.75	2
GST-TAGGED GLUN2B	0.35–5.93	2
MAP2	0.0007–0.0008	2
CALDESMON	0.0049	1
HISTONE IIIS	0.0445	1
LYS-LYS-ALA-LEU-ARG-ARG-GLN-GLU-ALA-VAL-ASP-ALA-	0.063	1
MICROTUBULE ASSOCIATED PROTEIN 2	0.0016	1
SYNTIDE-2	0.02	1
SYNTIDE-2 PEPTIDE	0.0221	1
MYELIN BASIC PROTEIN	—	0

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 (75 total): helix 22, strand 14, sequence variant 11, modified residue 9, mutagenesis site 5, region of interest 3, turn 3, binding site 2, chain 1, domain 1, splice variant 1, sequence conflict 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

22 structures.

PDB	Method	Resolution (Å)
6X5G	X-RAY DIFFRACTION	1.85
7UJR	X-RAY DIFFRACTION	1.95
6OF8	X-RAY DIFFRACTION	2.1
7UJT	X-RAY DIFFRACTION	2.1
9EOY	X-RAY DIFFRACTION	2.1
6X5Q	X-RAY DIFFRACTION	2.14
7REC	X-RAY DIFFRACTION	2.2
7UJQ	X-RAY DIFFRACTION	2.25
2VZ6	X-RAY DIFFRACTION	2.3
7KL0	X-RAY DIFFRACTION	2.4
7KL1	X-RAY DIFFRACTION	2.4
6VZK	X-RAY DIFFRACTION	2.55
7KL2	X-RAY DIFFRACTION	2.56
7UJP	X-RAY DIFFRACTION	2.56
7UIS	X-RAY DIFFRACTION	2.58
5IG3	X-RAY DIFFRACTION	2.75
7UJS	X-RAY DIFFRACTION	2.75
7UIR	X-RAY DIFFRACTION	3.1
7UIQ	X-RAY DIFFRACTION	3.11
3SOA	X-RAY DIFFRACTION	3.55
6W4O	ELECTRON MICROSCOPY	4.8
6W4P	ELECTRON MICROSCOPY	6.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UQM7-F1	86.44	0.62

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): 135 (proton acceptor)

Ligand- & substrate-binding residues (2): 19–27; 42

Post-translational modifications (9): 257, 286, 330, 331, 333, 336, 337, 404, 13

Mutagenesis-validated functional residues (5):

Position	Phenotype
42	no effect on protein stability or degradation. no effect on neuronal migration; when associated with p-286.
286	abolished autophosphorylation and activation. no effect on neuronal migration.
286	mimics phosphorylation; constitutively active. loss of neuronal migration.
286	no effect on neuronal migration; when associated with r-42.
466–478	loss of oligomerization.

Function

Pathways and Gene Ontology

Reactome pathways

63 pathways

ID	Pathway
R-HSA-111932	CaMK IV-mediated phosphorylation of CREB
R-HSA-3371571	HSF1-dependent transactivation
R-HSA-399719	Trafficking of AMPA receptors
R-HSA-4086398	Ca2+ pathway
R-HSA-438066	Unblocking of NMDA receptors, glutamate binding and activation
R-HSA-442982	Ras activation upon Ca2+ influx through NMDA receptor
R-HSA-5576892	Phase 0 - rapid depolarisation
R-HSA-5578775	Ion homeostasis
R-HSA-5673000	RAF activation
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6802946	Signaling by moderate kinase activity BRAF mutants
R-HSA-6802952	Signaling by BRAF and RAF1 fusions
R-HSA-6802955	Paradoxical activation of RAF signaling by kinase inactive BRAF
R-HSA-877300	Interferon gamma signaling
R-HSA-9022692	Regulation of MECP2 expression and activity
R-HSA-936837	Ion transport by P-type ATPases
R-HSA-9609736	Assembly and cell surface presentation of NMDA receptors
R-HSA-9617324	Negative regulation of NMDA receptor-mediated neuronal transmission
R-HSA-9620244	Long-term potentiation
R-HSA-9649948	Signaling downstream of RAS mutants
R-HSA-9656223	Signaling by RAF1 mutants
R-HSA-9918481	Dengue Virus-Host Interactions
R-HSA-111885	Opioid Signalling
R-HSA-111933	Calmodulin induced events
R-HSA-111996	Ca-dependent events
R-HSA-111997	CaM pathway
R-HSA-112040	G-protein mediated events
R-HSA-112043	PLC beta mediated events
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-112315	Transmission across Chemical Synapses

MSigDB gene sets: 493 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_DENDRITE_DEVELOPMENT, RNGTGGGC_UNKNOWN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOBP_REGULATION_OF_NEURONAL_SYNAPTIC_PLASTICITY, PID_NETRIN_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_HYDROLASE_ACTIVITY, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_RESPONSE_TO_ANGIOTENSIN, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_NEUROGENESIS

GO Biological Process (23): G1/S transition of mitotic cell cycle (GO:0000082), response to ischemia (GO:0002931), protein phosphorylation (GO:0006468), calcium ion transport (GO:0006816), positive regulation of cardiac muscle cell apoptotic process (GO:0010666), cellular response to interferon-beta (GO:0035458), angiotensin-activated signaling pathway (GO:0038166), positive regulation of receptor signaling pathway via JAK-STAT (GO:0046427), regulation of neurotransmitter secretion (GO:0046928), regulation of neuronal synaptic plasticity (GO:0048168), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), negative regulation of hydrolase activity (GO:0051346), positive regulation of calcium ion transport (GO:0051928), long-term synaptic potentiation (GO:0060291), dendritic spine development (GO:0060996), cellular response to type II interferon (GO:0071346), negative regulation of ferroptosis (GO:0110076), regulation of mitochondrial membrane permeability involved in apoptotic process (GO:1902108), regulation of protein localization to plasma membrane (GO:1903076), peptidyl-threonine autophosphorylation (GO:1990443), regulation of endocannabinoid signaling pathway (GO:2000124), regulation of neuron migration (GO:2001222), cell surface receptor signaling pathway via JAK-STAT (GO:0007259)

GO Molecular Function (14): protein serine/threonine kinase activity (GO:0004674), calcium/calmodulin-dependent protein kinase activity (GO:0004683), calmodulin binding (GO:0005516), ATP binding (GO:0005524), kinase activity (GO:0016301), glutamate receptor binding (GO:0035254), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (13): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), calcium- and calmodulin-dependent protein kinase complex (GO:0005954), postsynaptic density (GO:0014069), endocytic vesicle membrane (GO:0030666), neuron projection (GO:0043005), dendritic spine (GO:0043197), dendrite (GO:0030425), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Activation of NMDA receptors and postsynaptic events	3
Oncogenic MAPK signaling	3
Cardiac conduction	2
Calmodulin induced events	1
Cellular response to heat stress	1
Glutamate binding, activation of AMPA receptors and synaptic plasticity	1
Beta-catenin independent WNT signaling	1
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	1
RAF/MAP kinase cascade	1
MAPK1/MAPK3 signaling	1
Interferon Signaling	1
Transcriptional Regulation by MECP2	1
Ion channel transport	1
Post NMDA receptor activation events	1
Signaling by RAS mutants	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cellular response to cytokine stimulus	2
regulation of synaptic plasticity	2
protein kinase activity	2
protein binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G1/S phase transition	1
response to stress	1
phosphorylation	1
protein modification process	1
metal ion transport	1
cardiac muscle cell apoptotic process	1
positive regulation of striated muscle cell apoptotic process	1
regulation of cardiac muscle cell apoptotic process	1
response to interferon-beta	1
G protein-coupled receptor signaling pathway	1
cellular response to angiotensin	1
cell surface receptor signaling pathway via JAK-STAT	1
regulation of receptor signaling pathway via JAK-STAT	1
positive regulation of receptor signaling pathway via STAT	1
neurotransmitter secretion	1
modulation of chemical synaptic transmission	1
regulation of neurotransmitter transport	1
regulation of secretion by cell	1
hydrolase activity	1
negative regulation of catalytic activity	1
regulation of hydrolase activity	1
calcium ion transport	1
positive regulation of monoatomic ion transport	1
regulation of calcium ion transport	1
positive regulation of synaptic transmission	1
dendrite development	1
anatomical structure development	1
response to type II interferon	1
negative regulation of programmed cell death	1
ferroptosis	1
regulation of ferroptosis	1

Protein interactions and networks

STRING

3314 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CAMK2A	CALM1	P02593	994
CAMK2A	CALML3	P27482	994
CAMK2A	CALML5	Q9NZT1	994
CAMK2A	CALML6	Q8TD86	993
CAMK2A	CALML4	Q96GE6	993
CAMK2A	GRIN2B	Q13224	965
CAMK2A	GRIN2A	Q12879	919
CAMK2A	LRRC7	Q96NW7	917
CAMK2A	CAMK2B	Q13554	901
CAMK2A	GRIA1	P42261	891
CAMK2A	DLG4	P78352	833
CAMK2A	FMR1	Q06787	825
CAMK2A	CAMK2N2	Q96S95	770
CAMK2A	GRID1	Q9ULK0	734
CAMK2A	EGR1	P18146	727

IntAct

301 interactions, top by confidence:

A	B	Type	Score
CAMK2A	CAMK2D	psi-mi:“MI:0407”(direct interaction)	0.860
CAMK2B	CAMK2A	psi-mi:“MI:0915”(physical association)	0.850
CAMK2A	CAMK2G	psi-mi:“MI:0914”(association)	0.730
CALM1	CAMK2A	psi-mi:“MI:0407”(direct interaction)	0.680
TAB2	CAMK2A	psi-mi:“MI:0915”(physical association)	0.670
CDC37	CAMK2A	psi-mi:“MI:0915”(physical association)	0.670
HSP90AA1	CAMK2A	psi-mi:“MI:0915”(physical association)	0.670
CAMK2A	CAMK2A	psi-mi:“MI:0407”(direct interaction)	0.620
CAMK2A	MRPL11	psi-mi:“MI:0915”(physical association)	0.560
RHOXF2	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
GLB1L2	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
SPMIP9	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-3	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
KRTAP15-1	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
VARS1	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
KRTAP23-1	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
RALYL	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
KRTAP19-3	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
KRT75	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
C1orf94	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
CAMK2B	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
KRTAP8-1	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
ARID5A	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-1	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
LENG8	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
SOX5	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
RBFOX2	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
FAM168A	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
CAMK2A	TCAF1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (299): CAMK2D (Affinity Capture-MS), CAMK2G (Affinity Capture-MS), ZMYM1 (Affinity Capture-MS), CAMK2A (Affinity Capture-MS), CAMK2A (Affinity Capture-MS), CAMK2A (Affinity Capture-MS), CAMK2A (Affinity Capture-MS), CAMK2A (Affinity Capture-MS), CAMK2A (Affinity Capture-MS), CAMK2A (Affinity Capture-MS), GNAO1 (Co-fractionation), CAMK2A (Biochemical Activity), CAMK2A (Biochemical Activity), CAMK2A (Biochemical Activity), CAMK2A (Co-localization)

ESM2 similar proteins: A0A087WV53, A1CS92, A2ABU4, A2Q908, A2RUH7, A4QZL9, D3ZHA0, O01761, O70468, O75369, O88599, P05548, P11275, P11730, P11798, P13466, P21333, P56276, P56741, P70402, P79280, Q05623, Q13177, Q13203, Q13557, Q14315, Q2GM53, Q2HJF7, Q2URB7, Q5FW53, Q5PQM4, Q5RCC4, Q5VTT5, Q5ZJJ9, Q5ZKI0, Q62422, Q63518, Q6C1H8, Q6P686, Q6PHZ2

Diamond homologs: A0A509AFG4, A0A509AQE6, A0A5K1K8H0, A0AAR7, A2ZVI7, A5A7I7, A5A7I8, B9FKW9, O15865, O49717, O80673, P11275, P11798, P28582, P28583, P49101, P53681, P53682, P53683, P53684, P62345, P93759, Q00168, Q06850, Q0D715, Q0DYK7, Q10KY3, Q14012, Q1PE17, Q1PFH8, Q2QQR2, Q2QVG8, Q2QX45, Q2QY37, Q2RAV0, Q38868, Q38869, Q38870, Q38871, Q38872

SIGNOR signaling

121 interactions.

A	Effect	B	Mechanism
CAMK2A	up-regulates	RIMS1	phosphorylation
CAMK2A	“up-regulates activity”	CD44	phosphorylation
CAMK2A	down-regulates	CREB1	phosphorylation
PPM1F	down-regulates	CAMK2A	dephosphorylation
CAMK2A	down-regulates	HRH1	phosphorylation
CAMK2A	up-regulates	PTK2	phosphorylation
CAMK2A	up-regulates	PEA15	phosphorylation
CAMK2A	down-regulates	STMN1	phosphorylation
CAMK2A	down-regulates	CACNA1B	phosphorylation
CAMK2A	down-regulates	RCHY1	phosphorylation
CAMK2A	up-regulates	GFPT1	phosphorylation
CAMK2A	down-regulates	GABBR1	phosphorylation
CAMK2A	down-regulates	CAMK2A	phosphorylation
CAMK2A	down-regulates	ETS2	phosphorylation
CAMK2A	down-regulates	NCOR2	phosphorylation
CAMK2A	up-regulates	TH	phosphorylation
CAMK2A	up-regulates	CAMK2A	phosphorylation
CAMK2A	down-regulates	CALD1	phosphorylation
CAMK2A	“down-regulates activity”	MAPT	phosphorylation
CAMK2A	“up-regulates activity”	ATP2A2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 93 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	42.0×	1e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	40.0×	1e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	40.0×	1e-05
Long-term potentiation	5	35.0×	2e-05
Transcriptional Regulation by MECP2	6	28.0×	1e-05
Ion transport by P-type ATPases	5	15.3×	5e-04
Ion homeostasis	5	15.0×	5e-04
AURKA Activation by TPX2	6	13.4×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
long-term synaptic potentiation	6	20.3×	3e-04
regulation of alternative mRNA splicing, via spliceosome	5	14.7×	4e-03
keratinization	5	14.1×	4e-03
nervous system development	9	5.0×	7e-03
negative regulation of apoptotic process	11	4.6×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	15
Uncertain significance	96
Likely benign	44
Benign	7

Top pathogenic / likely-pathogenic (28)

Variant ID	HGVS	Classification
1722922	NM_015981.4(CAMK2A):c.901G>A (p.Gly301Arg)	Pathogenic
1804079	NM_015981.4(CAMK2A):c.666C>A (p.Tyr222Ter)	Pathogenic
430912	NM_015981.4(CAMK2A):c.293T>C (p.Phe98Ser)	Pathogenic
430913	NM_015981.4(CAMK2A):c.327G>C (p.Glu109Asp)	Pathogenic
430914	NM_015981.4(CAMK2A):c.548A>T (p.Glu183Val)	Pathogenic
430916	NM_015981.4(CAMK2A):c.635C>T (p.Pro212Leu)	Pathogenic
430917	NM_015981.4(CAMK2A):c.845A>G (p.His282Arg)	Pathogenic
430918	NM_015981.4(CAMK2A):c.856A>C (p.Thr286Pro)	Pathogenic
560170	NM_015981.4(CAMK2A):c.1429C>T (p.His477Tyr)	Pathogenic
560171	NM_015981.4(CAMK2A):c.635C>A (p.Pro212Gln)	Pathogenic
560173	NM_015981.4(CAMK2A):c.817-1G>A	Pathogenic
932398	NM_015981.4(CAMK2A):c.502C>T (p.Gln168Ter)	Pathogenic
988756	NM_015981.4(CAMK2A):c.220C>T (p.Arg74Ter)	Pathogenic
1162321	NM_015981.4(CAMK2A):c.524G>C (p.Gly175Ala)	Likely pathogenic
1285567	NM_015981.4(CAMK2A):c.59G>A (p.Gly20Asp)	Likely pathogenic
1700224	NM_015981.4(CAMK2A):c.785_790del (p.Ala262_Ala263del)	Likely pathogenic
2438786	NM_015981.4(CAMK2A):c.851_857delinsTGCATG (p.Gln284fs)	Likely pathogenic
2442355	NM_015981.4(CAMK2A):c.415G>C (p.Glu139Gln)	Likely pathogenic
2442356	NM_015981.4(CAMK2A):c.755T>C (p.Leu252Pro)	Likely pathogenic
2662703	NM_015981.4(CAMK2A):c.857C>A (p.Thr286Asn)	Likely pathogenic
3237497	NM_015981.4(CAMK2A):c.290T>C (p.Leu97Pro)	Likely pathogenic
3731164	NM_015981.4(CAMK2A):c.1219C>T (p.Arg407Ter)	Likely pathogenic
430911	NM_171825.2(CAMK2A):c.65del	Likely pathogenic
430915	NM_015981.4(CAMK2A):c.598+2dup	Likely pathogenic
4814056	NM_015981.4(CAMK2A):c.325G>A (p.Glu109Lys)	Likely pathogenic
620277	NM_015981.4(CAMK2A):c.809G>A (p.Trp270Ter)	Likely pathogenic
666572	NM_015981.4(CAMK2A):c.49G>A (p.Glu17Lys)	Likely pathogenic
870768	NM_015981.4(CAMK2A):c.902G>A (p.Gly301Glu)	Likely pathogenic

SpliceAI

3486 predictions. Top by Δscore:

Variant	Effect	Δscore
5:150231303:A:AC	donor_gain	1.0000
5:150231304:C:CC	donor_gain	1.0000
5:150231379:CA:C	acceptor_gain	1.0000
5:150231381:C:CC	acceptor_gain	1.0000
5:150238694:CCCTA:C	donor_loss	1.0000
5:150238695:CCTAC:C	donor_loss	1.0000
5:150238696:CTACC:C	donor_loss	1.0000
5:150238697:TA:T	donor_loss	1.0000
5:150238698:ACCTT:A	donor_loss	1.0000
5:150245197:CCCTC:C	acceptor_gain	1.0000
5:150245198:CCTCC:C	acceptor_gain	1.0000
5:150245199:CTC:C	acceptor_gain	1.0000
5:150245200:TC:T	acceptor_gain	1.0000
5:150245201:CC:C	acceptor_gain	1.0000
5:150245202:CTGTG:C	acceptor_loss	1.0000
5:150245203:T:G	acceptor_loss	1.0000
5:150248528:T:TA	donor_gain	1.0000
5:150250222:TTAC:T	donor_loss	1.0000
5:150250224:A:C	donor_loss	1.0000
5:150250225:CCTTC:C	donor_loss	1.0000
5:150250237:T:TA	donor_gain	1.0000
5:150250305:CGGTG:C	acceptor_gain	1.0000
5:150250306:GGTG:G	acceptor_gain	1.0000
5:150250307:GTG:G	acceptor_gain	1.0000
5:150250308:TG:T	acceptor_gain	1.0000
5:150250309:GCTG:G	acceptor_loss	1.0000
5:150250310:C:CC	acceptor_gain	1.0000
5:150250310:C:T	acceptor_loss	1.0000
5:150250311:T:C	acceptor_loss	1.0000
5:150250682:GCTCA:G	donor_loss	1.0000

AlphaMissense

3202 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:150223038:A:G	W462R	1.000
5:150223038:A:T	W462R	1.000
5:150223059:A:G	W455R	1.000
5:150223059:A:T	W455R	1.000
5:150223064:C:G	R453P	1.000
5:150223124:C:G	R433P	1.000
5:150231336:C:G	A360P	1.000
5:150231344:A:G	L357P	1.000
5:150247804:A:G	L304P	1.000
5:150250230:A:G	L299P	1.000
5:150250235:C:A	R297S	1.000
5:150250235:C:G	R297S	1.000
5:150250236:C:A	R297M	1.000
5:150250236:C:G	R297T	1.000
5:150250247:G:C	F293L	1.000
5:150250247:G:T	F293L	1.000
5:150250248:A:G	F293S	1.000
5:150250249:A:G	F293L	1.000
5:150250257:A:G	L290P	1.000
5:150250696:A:G	W270R	1.000
5:150250696:A:T	W270R	1.000
5:150250749:A:G	L252P	1.000
5:150250749:A:T	L252Q	1.000
5:150250764:A:G	L247P	1.000
5:150250769:C:A	K245N	1.000
5:150250769:C:G	K245N	1.000
5:150250785:A:T	V240D	1.000
5:150250793:C:A	W237C	1.000
5:150250793:C:G	W237C	1.000
5:150250794:C:G	W237S	1.000

dbSNP variants (sampled 300 via entrez): RS1000062059 (5:150256171 G>A), RS1000074503 (5:150270455 C>G,T), RS1000142892 (5:150270291 C>A,T), RS1000228684 (5:150231197 G>A), RS1000310130 (5:150264891 G>A,T), RS1000324230 (5:150258573 T>A), RS1000372889 (5:150275915 C>G), RS1000409834 (5:150255293 C>G,T), RS1000462060 (5:150248642 A>G), RS1000485931 (5:150277055 C>A,T), RS1000533294 (5:150287243 C>T), RS1000535511 (5:150291310 C>A,T), RS1000549122 (5:150281014 C>T), RS1000660469 (5:150265190 G>A), RS1000662201 (5:150243237 C>G)

Disease associations

OMIM: gene MIM:114078 | disease phenotypes: MIM:617798, MIM:618095

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal dominant 53	Strong	Autosomal dominant
autosomal dominant non-syndromic intellectual disability	Supportive	Autosomal dominant
intellectual disability, autosomal recessive 63	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (6): intellectual disability, autosomal dominant 53 (MONDO:0030919), intellectual disability, autosomal recessive 63 (MONDO:0054861), autism spectrum disorder (MONDO:0005258), intellectual disability (MONDO:0001071), neurodevelopmental disorder (MONDO:0700092), autosomal dominant non-syndromic intellectual disability (MONDO:0015802)

Orphanet (2): NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000126	Hydronephrosis
HP:0000154	Wide mouth
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000286	Epicanthus
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000505	Visual impairment
HP:0000601	Hypotelorism
HP:0000737	Irritability
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001344	Absent speech
HP:0001382	Joint hypermobility
HP:0001510	Growth delay
HP:0001548	Overgrowth
HP:0001629	Ventricular septal defect
HP:0002069	Bilateral tonic-clonic seizure
HP:0002121	Generalized non-motor (absence) seizure
HP:0002194	Delayed gross motor development
HP:0002236	Frontal upsweep of hair
HP:0002247	Duodenal atresia

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001762_865	Obesity-related traits	5.000000e-07
GCST004131_58	Inflammatory bowel disease	5.000000e-09
GCST004133_75	Ulcerative colitis	2.000000e-08
GCST010396_58	Gut microbiota (bacterial taxa, hurdle binary method)	8.000000e-06
GCST90011892_3	Retinitis pigmentosa	7.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005116	urinary metabolite measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2097164 (PROTEIN FAMILY), CHEMBL4147 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

25 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 377,160 (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
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1342	OXYBATE	4	111,544
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL2103743	TOFACITINIB CITRATE	4	1,672
CHEMBL221959	TOFACITINIB	4	10,408
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL300138	ENZASTAURIN	3	3,209
CHEMBL140	CURCUMIN	3	93,882
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL105442	CI-1040	2	3,936
CHEMBL1721885	SU-014813	2	363
CHEMBL1967878	CENISERTIB	2	358
CHEMBL384304	RG-547	2	93
CHEMBL475251	R-406	2	762
CHEMBL513909	BI-2536	2	895
CHEMBL565612	SOTRASTAURIN	2
CHEMBL1908394	GSK-461364	1
CHEMBL1908397	KW-2449	1
CHEMBL1969664	AZD-1080	1
CHEMBL482967	CYC-116	1

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — CAMK2 family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
KN-93	Inhibition	6.43	pIC50

Binding affinities (BindingDB)

6 measured of 7 human assays (7 total across all organisms); most potent 6 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Staurosporine	KD	1.7 nM
PKC-412	KD	190 nM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1^{7,14}.0^{2,6}.0^{8,13}.0^{22,27}]nonacosa-1(28),2(6),7(29),8(13),9,11,22(27),23,25-nonaene-3,5-dione	KD	700 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	KD	3500 nM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S)-3-hydroxy-1-methyl-4-piperidinyl]-1-benzopyran-4-one	KD	5300 nM

ChEMBL bioactivities

217 potent at pChembl≥5 of 265 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.53	IC50	0.0297	nM	STAUROSPORINE
10.51	IC50	0.0307	nM	STAUROSPORINE
10.20	IC50	0.0635	nM	STAUROSPORINE
10.00	Kd	0.1	nM	STAUROSPORINE
9.80	Kd	0.16	nM	STAUROSPORINE
8.70	IC50	2	nM	STAUROSPORINE
8.50	Ki	3.162	nM	CHEMBL1980995
8.40	IC50	4	nM	STAUROSPORINE
8.22	IC50	6	nM	STAUROSPORINE
8.10	IC50	8	nM	CHEMBL573578
8.05	Kd	9	nM	CHEMBL4576489
8.00	Kd	10	nM	LESTAURTINIB
7.82	Kd	15	nM	CHEMBL4465866
7.70	Kd	20	nM	MIDOSTAURIN
7.60	IC50	25	nM	CHEMBL312292
7.60	IC50	25	nM	STAUROSPORINE AGLYCON
7.52	IC50	30	nM	CHEMBL2335444
7.50	IC50	32	nM	CHEMBL2369378
7.46	Ki	35	nM	CHEMBL5175277
7.44	IC50	36	nM	CHEMBL385035
7.40	IC50	40	nM	CHEMBL2335442
7.40	Ki	39.81	nM	CHEMBL1988581
7.34	IC50	46	nM	CHEMBL75368
7.34	Kd	46	nM	RUXOLITINIB
7.31	IC50	49	nM	CHEMBL73764
7.30	IC50	50	nM	CHEMBL2335479
7.24	IC50	58	nM	CHEMBL59785
7.21	IC50	62	nM	CHEMBL307630
7.20	Ki	63.1	nM	CHEMBL1980407
7.16	IC50	70	nM	CHEMBL1231206
7.10	Kd	80	nM	SUNITINIB
7.09	IC50	82	nM	CHEMBL292021
7.09	IC50	81	nM	CHEMBL72808
7.05	IC50	90	nM	CHEMBL308979
7.04	IC50	92	nM	CHEMBL293157
7.02	IC50	95	nM	CHEMBL76326
7.01	IC50	97	nM	CHEMBL264406
6.80	Ki	158.5	nM	CHEMBL1986943
6.80	Ki	158.5	nM	CHEMBL2002099
6.80	Ki	158.5	nM	CHEMBL1990885
6.80	Ki	158.5	nM	CHEMBL1988141
6.76	IC50	174	nM	CHEMBL293898
6.76	IC50	174	nM	CHEMBL72076
6.75	IC50	177	nM	CHEMBL306047
6.74	IC50	184	nM	STAUROSPORINONE
6.70	Ki	199.5	nM	CHEMBL1973720
6.70	Ki	199.5	nM	CHEMBL1973359
6.67	IC50	216	nM	CHEMBL307152
6.66	Kd	219	nM	CHEMBL5191835
6.66	Kd	219	nM	CHEMBL5196669

PubChem BioAssay actives

145 with measured affinity, of 1260 total; 50 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
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1715428: Inhibition of human CAMK2A using KKALRRQETVDAL as substrate by [gamma-33P]-ATP assay	ic50	<0.0001	uM
1-tert-butyl-3-(naphthalen-1-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-amine	512631: Inhibition of CAMK2 F89G mutant	ic50	0.0080	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-methylamino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526298: Binding affinity to recombinant human full-length N-terminal GST-tagged CAMK2A expressed in baculovirus expression system using GS peptide as substrate incubated for 1 hr in presence of calmodulin by TR-FRET assay	kd	0.0090	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	507855: Binding affinity to CAMK2A	kd	0.0100	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526298: Binding affinity to recombinant human full-length N-terminal GST-tagged CAMK2A expressed in baculovirus expression system using GS peptide as substrate incubated for 1 hr in presence of calmodulin by TR-FRET assay	kd	0.0150	uM
Midostaurin	435520: Binding constant for CAMK2A kinase domain	kd	0.0200	uM
3,13,23-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1,4,6,8,10,15,17,19,21-nonaene-12,14-dione	45962: Inhibition of Calcium/calmodulin-dependent protein kinase type II	ic50	0.0250	uM
1-[2-(18-methyl-12,14-dioxo-3,13,18-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,21]tricosa-1(16),2(10),4,6,8,11(15),17(21),19,22-nonaen-5-yl)ethyl]piperidine-4-carboxamide	45968: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II	ic50	0.0250	uM
(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3S)-2-[[(2S)-5-amino-2-[[2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-1-[(2S)-1-[(2S)-2-[[(2S)-6-amino-2-[[(2R)-2-[[2-[[2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-6-amino-2-[[(2S,3S)-2-[[(2S)-5-amino-2-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]hexanoyl]amino]-3-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-5-oxopentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-4-methylsulfanylbutanoyl]amino]hexanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]hexanoyl]amino]hexanoyl]amino]acetyl]amino]acetyl]amino]-3-sulfanylpropanoyl]amino]hexanoyl]amino]-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]amino]hexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-methylpentanoic acid	733733: Inhibition of recombinant full length CAMK2alpha (unknown origin) using autocamtide-2 as substrate assessed as incorporation of 32P after 30 mins by scintillation counting analysis in presence of [gamma32P]ATP relative to control	ic50	0.0300	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-6-[(2-nitrophenyl)methoxycarbonylamino]hexanoyl]amino]-6-[(2-nitrophenyl)methoxycarbonylamino]hexanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-oxopentanoyl]amino]-4-carboxybutanoyl]amino]propanoyl]amino]-3-methylbutanoyl]amino]-3-carboxypropanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	220482: Inhibitory activity of compound against CaMKII	ic50	0.0320	uM
2-[2-(2,6-dichloroanilino)-4-hydroxyphenyl]acetic acid	1909936: Inhibition of [3H]NCS-382 binding to CaMK2alpha (unknown origin)	ki	0.0350	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[(2-nitrophenyl)methoxycarbonylamino]hexanoyl]amino]hexanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-oxopentanoyl]amino]-4-carboxybutanoyl]amino]-3-methylbutanoyl]amino]-3-carboxypropanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	220482: Inhibitory activity of compound against CaMKII	ic50	0.0360	uM
(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3S)-2-[[(2S)-5-amino-2-[[2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-1-[(2S)-1-[(2S)-2-[[(2S)-6-amino-2-[[(2R)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]hexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-sulfanylpropanoyl]amino]hexanoyl]amino]-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]amino]hexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-methylpentanoic acid	733733: Inhibition of recombinant full length CAMK2alpha (unknown origin) using autocamtide-2 as substrate assessed as incorporation of 32P after 30 mins by scintillation counting analysis in presence of [gamma32P]ATP relative to control	ic50	0.0400	uM
Ruxolitinib	624730: Binding constant for CAMK2A kinase domain	kd	0.0460	uM
5-[2-(4-hydroxypiperidin-1-yl)ethyl]-18-methyl-3,13,18-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,21]tricosa-1(16),2(10),4,6,8,11(15),17(21),19,22-nonaene-12,14-dione	45968: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II	ic50	0.0460	uM
5-[2-[(4-hydroxycyclohexyl)amino]ethyl]-18-methyl-3,13,18-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,21]tricosa-1(16),2(10),4,6,8,11(15),17(21),19,22-nonaene-12,14-dione	45968: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II	ic50	0.0490	uM
(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3S)-2-[[(2S)-5-amino-2-[[2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-1-[(2S)-1-[(2S)-5-carbamimidamido-2-[[(2S)-2,6-diaminohexanoyl]amino]pentanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]amino]hexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-methylpentanoyl]amino]-4-carboxybutanoyl]amino]-3-carboxypropanoyl]amino]-3-carboxypropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]hexanoic acid	733733: Inhibition of recombinant full length CAMK2alpha (unknown origin) using autocamtide-2 as substrate assessed as incorporation of 32P after 30 mins by scintillation counting analysis in presence of [gamma32P]ATP relative to control	ic50	0.0500	uM
8-bromo-3,13,23-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1,4(9),5,7,10,15,17,19,21-nonaene-12,14-dione	45967: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II using autocamtide as substrate	ic50	0.0580	uM
18-methyl-5-(2-piperidin-1-ylethyl)-3,13,18-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,21]tricosa-1(16),2(10),4,6,8,11(15),17(21),19,22-nonaene-12,14-dione	45968: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II	ic50	0.0620	uM
Sunitinib	435520: Binding constant for CAMK2A kinase domain	kd	0.0800	uM
methyl 1-[2-(18-methyl-12,14-dioxo-3,13,18-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,21]tricosa-1(16),2(10),4,6,8,11(15),17(21),19,22-nonaen-5-yl)ethyl]piperidine-4-carboxylate	45968: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II	ic50	0.0810	uM
6-methyl-3,13,23-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1,4(9),5,7,10,15,17,19,21-nonaene-12,14-dione	45967: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II using autocamtide as substrate	ic50	0.0820	uM
5-[2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]ethyl]-18-methyl-3,13,18-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,21]tricosa-1(16),2(10),4,6,8,11(15),17(21),19,22-nonaene-12,14-dione	45968: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II	ic50	0.0900	uM
6-fluoro-3,13,23-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1,4(9),5,7,10,15,17,19,21-nonaene-12,14-dione	45967: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II using autocamtide as substrate	ic50	0.0920	uM
5-[2-(2-hydroxyethylamino)ethyl]-18-methyl-3,13,18-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,21]tricosa-1(16),2(10),4,6,8,11(15),17(21),19,22-nonaene-12,14-dione	45968: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II	ic50	0.0950	uM
1-tert-butyl-3-naphthalen-1-ylpyrazolo[3,4-d]pyrimidin-4-amine	512631: Inhibition of CAMK2 F89G mutant	ic50	0.0970	uM
20-bromo-3-methyl-3,13,23-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1,4,6,8,10,15,17(22),18,20-nonaene-12,14-dione	45967: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II using autocamtide as substrate	ic50	0.1740	uM
5-[3-(diethylamino)propyl]-18-methyl-3,13,18-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,21]tricosa-1(16),2(10),4,6,8,11(15),17(21),19,22-nonaene-12,14-dione	45968: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II	ic50	0.1740	uM
18-methyl-5-(2-morpholin-4-ylethyl)-3,13,18-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,21]tricosa-1(16),2(10),4,6,8,11(15),17(21),19,22-nonaene-12,14-dione	45968: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II	ic50	0.1770	uM
3,13,23-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1,4,6,8,10,15,17,19,21-nonaen-12-one	45962: Inhibition of Calcium/calmodulin-dependent protein kinase type II	ic50	0.1840	uM
5-[3-[(4-hydroxycyclohexyl)amino]propyl]-18-methyl-3,13,18-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,21]tricosa-1(16),2(10),4,6,8,11(15),17(21),19,22-nonaene-12,14-dione	45968: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II	ic50	0.2160	uM
2-[2-(2,6-dichlorophenoxy)-4-hydroxyphenyl]acetic acid	1909905: Binding affinity to recombinant human CaMK2alpha Thr354Asn mutant expressed in Escherichia coli BL21 (DE3) assessed as dissociation constant by surface plasmon resonance assay	kd	0.2190	uM
2-[2-(2-chlorophenoxy)-4-hydroxyphenyl]acetic acid	1909905: Binding affinity to recombinant human CaMK2alpha Thr354Asn mutant expressed in Escherichia coli BL21 (DE3) assessed as dissociation constant by surface plasmon resonance assay	kd	0.2190	uM
6-methoxy-3,13,23-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1,4(9),5,7,10,15,17,19,21-nonaene-12,14-dione	45967: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II using autocamtide as substrate	ic50	0.2360	uM
5-[3-(2-hydroxyethylamino)propyl]-18-methyl-3,13,18-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,21]tricosa-1(16),2(10),4,6,8,11(15),17(21),19,22-nonaene-12,14-dione	45968: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II	ic50	0.2660	uM
4-[(E)-2-[3-[(E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-1H-pyrazol-5-yl]ethenyl]-2-methoxyphenol	687450: Inhibition of autophosphorylated alphaCaMK2 using GST-NR2A as substrate incubated for 1 min prior to substrate addition measured after 1 min in presence of EGTA	ic50	0.2900	uM
Fedratinib	624730: Binding constant for CAMK2A kinase domain	kd	0.3000	uM
18-methyl-5-(2-piperazin-1-ylethyl)-3,13,18-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,21]tricosa-1(16),2(10),4,6,8,11(15),17(21),19,22-nonaene-12,14-dione	45968: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II	ic50	0.3010	uM
(2S)-1-[[5-(3-methyl-2H-indazol-5-yl)-3-pyridinyl]oxy]-3-phenylpropan-2-amine	624730: Binding constant for CAMK2A kinase domain	kd	0.3200	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	435520: Binding constant for CAMK2A kinase domain	kd	0.3500	uM
2-(4-hydroxy-2-phenoxyphenyl)acetic acid	1909905: Binding affinity to recombinant human CaMK2alpha Thr354Asn mutant expressed in Escherichia coli BL21 (DE3) assessed as dissociation constant by surface plasmon resonance assay	kd	0.3530	uM
18-methyl-5-[3-(4-methylpiperazin-1-yl)propyl]-3,13,18-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,21]tricosa-1(16),2(10),4,6,8,11(15),17(21),19,22-nonaene-12,14-dione	45968: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II	ic50	0.3820	uM
18-methyl-5-(2-thiomorpholin-4-ylethyl)-3,13,18-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,21]tricosa-1(16),2(10),4,6,8,11(15),17(21),19,22-nonaene-12,14-dione	45968: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II	ic50	0.4030	uM
18-methyl-5-(3-morpholin-4-ylpropyl)-3,13,18-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,21]tricosa-1(16),2(10),4,6,8,11(15),17(21),19,22-nonaene-12,14-dione	45968: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II	ic50	0.5160	uM
3-[2-(2-hydroxyethylamino)ethyl]-6-methoxy-18-methyl-3,13,18-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,21]tricosa-1(16),2(10),4(9),5,7,11(15),17(21),19,22-nonaene-12,14-dione	45968: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II	ic50	0.5270	uM
4-(2-chlorophenoxy)-3-(2H-tetrazol-5-ylmethyl)phenol	1909905: Binding affinity to recombinant human CaMK2alpha Thr354Asn mutant expressed in Escherichia coli BL21 (DE3) assessed as dissociation constant by surface plasmon resonance assay	kd	0.6700	uM
4-[(E)-2-[3-[(E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-1,2-oxazol-5-yl]ethenyl]-2-methoxyphenol	687450: Inhibition of autophosphorylated alphaCaMK2 using GST-NR2A as substrate incubated for 1 min prior to substrate addition measured after 1 min in presence of EGTA	ic50	0.6800	uM
N-[(2S,3R,4R,6R,18S)-18-hydroxy-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-N-methylbenzamide	507855: Binding affinity to CAMK2A	kd	0.6900	uM
3-[3-(2-hydroxyethylamino)propyl]-6-methoxy-18-methyl-3,13,18-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,21]tricosa-1(16),2(10),4(9),5,7,11(15),17(21),19,22-nonaene-12,14-dione	45968: Inhibitory activity against Calcium/calmodulin-dependent protein kinase type II	ic50	0.7320	uM
(2E)-2-(5-hydroxy-2-phenyl-5,7,8,9-tetrahydrobenzo[7]annulen-6-ylidene)acetic acid	1848981: Binding affinity to recombinant human CaMK2alpha 6x hub domain (345 to 475 residues) expressed in Escherichia coli BL21 DE3 assessed as dissociation constant by surface plasmon resonance assay	kd	0.7570	uM

CTD chemical–gene interactions

33 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation, affects methylation	3
sodium arsenite	affects methylation, increases expression	2
1,2-bis(2-aminophenoxy)ethane N,N,N’,N’-tetraacetic acid acetoxymethyl ester	increases phosphorylation, decreases reaction	2
platycodin D	decreases reaction, increases phosphorylation	2
aminomethylphosphonic acid (AMPA)	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
VX-agent	increases expression	1
cypermethrin	increases expression	1
W 7	decreases reaction, increases phosphorylation	1
cobaltous chloride	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
2-chloroethyl ethyl sulfide	increases phosphorylation	1
cyfluthrin	increases expression	1
1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole	decreases reaction, increases phosphorylation	1
S-allylcysteine	increases phosphorylation	1
KN 93	decreases reaction, increases phosphorylation	1
N-(3-methoxyphenyl)-4-chlorocinnamanilide	decreases reaction, increases phosphorylation	1
1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone	decreases reaction, increases phosphorylation	1
rutacarpine	decreases reaction, increases phosphorylation	1
4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline	decreases reaction, increases phosphorylation	1
Resveratrol	affects cotreatment, decreases expression	1
Glyphosate	increases expression	1
Amiodarone	increases expression	1
Arsenic	affects methylation	1
Biological Products	increases phosphorylation	1
Cannabidiol	decreases expression	1
Copper	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Methapyrilene	increases methylation	1

ChEMBL screening assays

341 unique, capped per target: 340 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2422678	Binding	Inhibition of CaMK2alpha/CaMK2beta/CaMK2delta/CaMK2gamma in human PC3 cell lysates at 10 uM using desthiobiotin-tagged ATP probe AX9989 followed by trypsinization by LC/MS analysis	Hit-to-lead optimization and kinase selectivity of imidazo[1,2-a]quinoxalin-4-amine derived JNK1 inhibitors. — Bioorg Med Chem Lett
CHEMBL1964111	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: CAMK2A	PubChem BioAssay data set

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder