PDE2A

Summary

PDE2A (phosphodiesterase 2A, HGNC:8777) is a protein-coding gene on chromosome 11q13.4, encoding cGMP-dependent 3’,5’-cyclic phosphodiesterase (O00408). cGMP-activated cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.

Enables several functions, including 3’,5’-cyclic-nucleotide phosphodiesterase activity; anion binding activity; and metal ion binding activity. Involved in several processes, including cGMP catabolic process; cellular response to cytokine stimulus; and regulation of vascular permeability. Located in several cellular components, including cytosol; mitochondrial membrane; and perinuclear region of cytoplasm.

Source: NCBI Gene 5138 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• Gene–disease (curated): intellectual developmental disorder with paroxysmal dyskinesia or seizures (Strong, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 382 total — 5 pathogenic, 3 likely-pathogenic (top 9% of genes corpus-wide)
• Regional missense constraint (gnomAD): 2 of 7 regions constrained (≈9% of expected missense variation)
• GTEx eGene: eQTL in 24 tissues, sQTL in 10 (q < 0.05)
• Phenotypes (HPO): 25
• ChEMBL bioactivity: 12 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.02 (LoF-tolerant), LOEUF 0.56 (moderately constrained)
• MANE Select transcript: NM_002599

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8777
Approved symbol	PDE2A
Name	phosphodiesterase 2A
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000186642
Ensembl biotype	protein_coding
OMIM	602658
Entrez	5138

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 15 protein_coding, 8 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000334456

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 5, TSL 3: 2, TSL 4: 8, TSL 5: 10

ENST00000334456, ENST00000376450, ENST00000418754, ENST00000420501, ENST00000441209, ENST00000444035, ENST00000475807, ENST00000485058, ENST00000490749, ENST00000535701, ENST00000536308, ENST00000536458, ENST00000536918, ENST00000537631, ENST00000538299, ENST00000538749, ENST00000539367, ENST00000540345, ENST00000540380, ENST00000541998, ENST00000542223, ENST00000542969, ENST00000543575, ENST00000543750, ENST00000544239, ENST00000544570, ENST00000546038, ENST00001016162

RefSeq mRNA: 4 — MANE Select: NM_002599 NM_001143839, NM_001146209, NM_001243784, NM_002599

CCDS: CCDS44670, CCDS53678, CCDS73345, CCDS8216

Canonical transcript exons

ENST00000334456 — 31 exons

Exon	Start	End
ENSE00001836179	72576141	72577594
ENSE00001920521	72674137	72674422
ENSE00003509911	72582444	72582566
ENSE00003527140	72589175	72589240
ENSE00003539877	72584872	72584944
ENSE00003542819	72590427	72590580
ENSE00003544701	72579534	72579608
ENSE00003552170	72578233	72578339
ENSE00003562606	72608662	72608751
ENSE00003563206	72581357	72581479
ENSE00003577129	72597510	72597619
ENSE00003591282	72578897	72579009
ENSE00003594101	72585554	72585593
ENSE00003600020	72578476	72578514
ENSE00003600335	72589751	72589792
ENSE00003607412	72580577	72580624
ENSE00003612344	72585371	72585434
ENSE00003617818	72590192	72590244
ENSE00003620083	72642254	72642326
ENSE00003635557	72581877	72581947
ENSE00003640580	72579284	72579383
ENSE00003641523	72584201	72584313
ENSE00003646487	72583438	72583515
ENSE00003657003	72589907	72589981
ENSE00003657645	72596593	72596648
ENSE00003679062	72586070	72586181
ENSE00003679787	72580886	72580973
ENSE00003683488	72591297	72591356
ENSE00003686558	72588784	72588914
ENSE00003784190	72605138	72605226
ENSE00003791334	72584551	72584728

Expression profiles

Bgee: expression breadth ubiquitous, 224 present calls, max score 98.38.

FANTOM5 (CAGE): breadth broad, TPM avg 5.2001 / max 187.2796, expressed in 509 samples.

Highest expression (Bgee): spleen, frontal lobe, prefrontal cortex, omental fat pad, peritoneum.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PDE2A is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 24 tissues and its splicing (sQTL) in 10 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 34 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Spinal cord cervical c-1	eqtl	1.2e-31	+0.99	11:72654619:C:G
Brain Cerebellar Hemisphere	eqtl	6.5e-18	+0.90	11:72629642:C:G
Brain Cerebellum	eqtl	4.2e-16	+1.04	11:72629642:C:G
Pituitary	eqtl	2.1e-11	+0.60	11:72653361:C:G
Thyroid	eqtl	6.4e-09	+0.20	11:72641602:G:C
Brain Substantia nigra	eqtl	1.5e-08	+0.44	11:72650324:AC:A
Esophagus Muscularis	eqtl	5.6e-07	+0.23	11:72626542:C:T
Adipose Subcutaneous	sqtl	2.8e-06	+0.36	11:72579585:G:A
Muscle Skeletal	sqtl	9.3e-06	+0.38	11:72583396:G:A
Thyroid	sqtl	1.9e-05	+0.37	11:72597159:A:G
Esophagus Mucosa	eqtl	1.9e-05	+0.13	11:72643346:T:C
Heart Atrial Appendage	sqtl	3.9e-05	+0.47	11:72581752:C:T
Nerve Tibial	sqtl	2.0e-04	+0.38	11:72606513:C:T
Whole Blood	eqtl	2.1e-04	+0.17	11:72681858:A:G
Testis	eqtl	3.3e-04	+0.17	11:72648743:C:G
Adipose Visceral Omentum	sqtl	1.8e-03	+0.31	11:72583396:G:A
Muscle Skeletal	eqtl	1.8e-03	+0.15	11:72639551:T:C
Brain Cortex	eqtl	2.6e-03	+0.10	11:72608476:T:C
Adipose Subcutaneous	eqtl	3.2e-03	+0.09	11:72650839:T:C
Colon Sigmoid	eqtl	4.3e-03	+0.21	11:72650849:TCCCTGAC:T

FANTOM5 promoters

showing 10 of 11 alternative TSS:

Promoter ID	TPM avg	Samples expressed
121176	2.6306	390
121178	1.7756	128
121177	0.3036	110
121180	0.1856	42
121179	0.1034	57
121166	0.0672	28
121172	0.0615	15
121173	0.0427	13
121171	0.0193	4
121174	0.0089	3

Top tissues by expression

showing 100 of 278 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
spleen	UBERON:0002106	98.38	gold quality
right frontal lobe	UBERON:0002810	97.34	gold quality
prefrontal cortex	UBERON:0000451	97.32	gold quality
omental fat pad	UBERON:0010414	97.28	gold quality
peritoneum	UBERON:0002358	97.20	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.83	gold quality
frontal cortex	UBERON:0001870	96.66	gold quality
cingulate cortex	UBERON:0003027	96.59	gold quality
anterior cingulate cortex	UBERON:0009835	96.59	gold quality
adipose tissue of abdominal region	UBERON:0007808	96.56	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.56	gold quality
orbitofrontal cortex	UBERON:0004167	96.19	gold quality
neocortex	UBERON:0001950	96.12	gold quality
CA1 field of hippocampus	UBERON:0003881	96.06	gold quality
nucleus accumbens	UBERON:0001882	96.04	gold quality
subcutaneous adipose tissue	UBERON:0002190	95.92	gold quality
cortical plate	UBERON:0005343	95.88	gold quality
putamen	UBERON:0001874	95.76	gold quality
caudate nucleus	UBERON:0001873	95.71	gold quality
amygdala	UBERON:0001876	95.70	gold quality
cerebral cortex	UBERON:0000956	95.65	gold quality
postcentral gyrus	UBERON:0002581	95.65	gold quality
superior frontal gyrus	UBERON:0002661	95.42	gold quality
telencephalon	UBERON:0001893	95.28	gold quality
parietal lobe	UBERON:0001872	95.19	gold quality
temporal lobe	UBERON:0001871	95.13	gold quality
entorhinal cortex	UBERON:0002728	95.12	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.90	gold quality
frontal pole	UBERON:0002795	94.68	gold quality
Ammon’s horn	UBERON:0001954	94.54	gold quality
sural nerve	UBERON:0015488	94.38	gold quality
body of uterus	UBERON:0009853	94.17	gold quality
endocervix	UBERON:0000458	93.99	gold quality
Brodmann (1909) area 10	UBERON:0013541	93.95	gold quality
left uterine tube	UBERON:0001303	93.92	gold quality
mucosa of stomach	UBERON:0001199	93.72	gold quality
forebrain	UBERON:0001890	93.65	gold quality
adipose tissue	UBERON:0001013	93.40	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.29	gold quality
right adrenal gland	UBERON:0001233	93.28	gold quality
right atrium auricular region	UBERON:0006631	93.23	gold quality
metanephros cortex	UBERON:0010533	93.16	gold quality
ectocervix	UBERON:0012249	92.55	gold quality
cardiac atrium	UBERON:0002081	92.49	gold quality
connective tissue	UBERON:0002384	92.45	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.43	gold quality
right adrenal gland cortex	UBERON:0035827	92.42	gold quality
left adrenal gland cortex	UBERON:0035825	92.27	gold quality
adrenal cortex	UBERON:0001235	92.05	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.02	gold quality
lower esophagus	UBERON:0013473	91.99	gold quality
left adrenal gland	UBERON:0001234	91.95	gold quality
adrenal gland	UBERON:0002369	91.90	gold quality
gall bladder	UBERON:0002110	91.88	gold quality
tibial nerve	UBERON:0001323	91.73	gold quality
primary visual cortex	UBERON:0002436	91.12	gold quality
ganglionic eminence	UBERON:0004023	91.10	gold quality
right lobe of thyroid gland	UBERON:0001119	90.93	gold quality
left lobe of thyroid gland	UBERON:0001120	90.90	gold quality
apex of heart	UBERON:0002098	90.70	gold quality
middle frontal gyrus	UBERON:0002702	90.68	gold quality
occipital lobe	UBERON:0002021	90.31	gold quality
heart left ventricle	UBERON:0002084	90.27	gold quality
brain	UBERON:0000955	90.14	gold quality
thyroid gland	UBERON:0002046	90.08	gold quality
central nervous system	UBERON:0001017	89.82	gold quality
cardiac ventricle	UBERON:0002082	89.70	gold quality
heart	UBERON:0000948	89.34	gold quality
calcaneal tendon	UBERON:0003701	89.34	gold quality
lower esophagus mucosa	UBERON:0035834	89.18	gold quality
gastrocnemius	UBERON:0001388	89.06	gold quality
muscle of leg	UBERON:0001383	88.82	gold quality
esophagus	UBERON:0001043	88.11	gold quality
skin of leg	UBERON:0001511	87.95	gold quality
hindlimb stylopod muscle	UBERON:0004252	87.93	gold quality
hypothalamus	UBERON:0001898	87.33	gold quality
sigmoid colon	UBERON:0001159	87.13	gold quality
right uterine tube	UBERON:0001302	87.09	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.99	gold quality
left coronary artery	UBERON:0001626	86.94	gold quality
fundus of stomach	UBERON:0001160	86.90	gold quality
middle temporal gyrus	UBERON:0002771	86.77	gold quality
coronary artery	UBERON:0001621	86.64	gold quality
skin of abdomen	UBERON:0001416	86.63	gold quality
vagina	UBERON:0000996	86.40	gold quality
pericardium	UBERON:0002407	86.40	gold quality
body of stomach	UBERON:0001161	86.20	gold quality
right lung	UBERON:0002167	86.18	gold quality
diaphragm	UBERON:0001103	86.12	gold quality
myometrium	UBERON:0001296	86.01	gold quality
transverse colon	UBERON:0001157	85.95	gold quality
Brodmann (1909) area 23	UBERON:0013554	85.94	gold quality
right ovary	UBERON:0002118	85.82	gold quality
right coronary artery	UBERON:0001625	85.78	gold quality
right lobe of liver	UBERON:0001114	85.72	gold quality
cardiac muscle of right atrium	UBERON:0003379	85.69	silver quality
colonic epithelium	UBERON:0000397	85.61	gold quality
muscle organ	UBERON:0001630	85.44	gold quality
adenohypophysis	UBERON:0002196	85.30	gold quality
small intestine	UBERON:0002108	84.99	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.44
E-MTAB-9067	yes	7.13

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Caudate putamen	tissue	332.7
Basal ganglia	tissue	193.0	low
Putamen	tissue	177.1
Postcentral gyrus	tissue	162.9
Frontal cortex	tissue	146.6
Ventral forebrain	tissue	134.8
Hippocampus	tissue	127.0	medium
Spleen	tissue	125.2	not detected
Hippocampal formation	tissue	123.9
Prefrontal cortex	tissue	119.4
Cerebral cortex	tissue	119.4	medium
Nucleus accumbens	tissue	117.7
Entorhinal cortex	tissue	113.5
Amygdala	tissue	111.0
Insular cortex	tissue	109.6
Temporal cortex	tissue	105.9
Motor cortex	tissue	102.0
Retrosplenial and cingulate cortex	tissue	99.2
Occipital cortex	tissue	98.4
Somatosensory cortex	tissue	95.6
Retrosplenial cortex	tissue	92.4
Septum	tissue	84.9
Adipose tissue	tissue	52.2	not detected
Locus coeruleus	tissue	35.2
Adrenal gland	tissue	31.3	medium
Olfactory bulb	tissue	29.1
Tongue	tissue	26.8
Vagina	tissue	26.0	not detected
Gallbladder	tissue	21.3	low
Heart muscle	tissue	20.1	not detected
Fallopian tube	tissue	19.3	not detected
Liver	tissue	18.1	not detected
Esophagus	tissue	17.4	not detected
Smooth muscle	tissue	17.2	not detected
Endometrium 1	tissue	16.1	not detected
Hypothalamus	tissue	14.9
Cervix	tissue	14.4	not detected
Choroid plexus	tissue	14.0
Corpus callosum	tissue	13.4
Urinary bladder	tissue	13.0	not detected
Skeletal muscle	tissue	12.6	not detected
Breast	tissue	12.1	not detected
Thyroid gland	tissue	11.6	not detected
Placenta	tissue	11.3	not detected
Pituitary gland	tissue	10.9
Substantia nigra	tissue	10.7
Kidney	tissue	10.4	low
Seminal vesicle	tissue	10.1	not detected
Thalamus	tissue	9.2
Lung	tissue	8.6	not detected
Ovary	tissue	8.3	not detected
Rectum	tissue	8.3	low
Colon	tissue	8.3	low
Skin 1	tissue	8.1	not detected
Midbrain	tissue	7.9
Epididymis	tissue	7.8	not detected
Superior colliculi	tissue	7.7
Pons	tissue	7.6
Prostate	tissue	7.3	not detected
Medulla oblongata	tissue	7.0

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Olfactory area (257.9), Temporal pole (224.6), Claustrum (224.0), Perirhinal gyrus (222.5), Posterior insular cortex (209.8).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting PDE2A by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 67 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AN	99.97	70.91	2817
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-377-5P	99.70	65.28	712
HSA-MIR-6086	99.70	65.38	699
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119

Functional genomics

gnomAD constraint: pLI 0.0158, LOEUF 0.564, missense Z 3.88 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000334456 splits into 7 regions with different missense tolerance; 2 are missense-constrained (≈9% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
11:72,577,387–72,578,249	83 / 99.0	0.84	no
11:72,578,250–72,578,966	28 / 86.0	0.33	yes (p 4.0e-10)
11:72,578,967–72,579,004	19 / 16.0	1.18	no
11:72,579,005–72,584,897	218 / 465.9	0.47	no
11:72,584,898–72,585,377	0 / 20.0	0.00	yes (p 7.8e-06)
11:72,585,378–72,586,148	31 / 70.2	0.44	no
11:72,586,149–72,674,207	417 / 475.3	0.88	no

Literature-anchored findings (GeneRIF, showing 25)

• Inhibition of PDE2 resulted in higher levels of intracellular cAMP than inhibition of PDE3A suggesting this PDE may be the more important regulator of cAMP in human platelets. (PMID:12038792)
• TNF-alpha-mediated up-regulation of PDE2 may destabilize endothelial barrier function in sepsis (PMID:15650061)
• Phosphodiesterase 2 mediates redox-sensitive endothelial cell proliferation and angiogenesis by thrombin via Rac1 and NADPH oxidase 2. (PMID:19390057)
• report the X-ray crystal structures of a PDE protein that includes both catalytic and regulatory domains, namely, PDE2A containing the N-terminal GAF domains and the catalytic domain. (PMID:19828435)
• found in smooth muscle wall of blood vessels transversing the clitoral supepithelial and stromal space (PMID:21697861)
• the phosphodiesterase 2A isoform localized to mitochondria regulates respiration (PMID:21724846)
• Active site similarity between human and Plasmodium falciparum phosphodiesterases: considerations for antimalarial drug design (PMID:21766240)
• Our results demonstrated that the PDE2A2 variant carrying point mutations is expressed in PMP cells and may affect cell cycle progression by modulating cyclin A expression. (PMID:23381931)
• PDE2 overexpression in healthy cardiomyocytes reduces the rise in cyclic AMP levels and L-type calcium current amplitude, and abolishes the inotropic effect following acute beta-adrenergic receptor stimulation. (PMID:23810893)
• This study reports the X-ray crystal structure of PDE2A in complex with a highly selective, nanomolar inhibitor (BAY60-7550) at 1.9 A resolution, and the structure of apo PDE2 at 2.0 A resolution. (PMID:23899287)
• PDE2A is involved in growth and invasion of human malignant melanoma PMP cells. (PMID:24705027)
• curcumin exerts its in vitro anti-angiogenic and in vivo anti-tumour properties through combined PDE2 and PDE4 inhibition (PMID:25230992)
• Lu AF33241 represents a novel PDE2A/PDE10A inhibitor tool which can penetrate the blood brain barrier. (PMID:25941078)
• Epigenetic regulation of phosphodiesterases 2A and 3A underlies compromised beta-adrenergic Signaling in an induced pluripotent stem cell model of dilated cardiomyopathy. (PMID:26095046)
• the well-known interaction between AIP and 2 different isoforms of phosphodiesterases (PDEs), PDE2A3 and PDE4A5, is of particular interest. While the interaction with over-expressed AIP does not seem to affect PDE2A3 function, the reported effect on PDE4A5 is, in contrast, reduced enzymatic activity. (PMID:28427099)
• Phosphodiesterases PDE2A and PDE10A both change mRNA expression in the human brain with age, but only PDE2A changes in a region-specific manner with psychiatric disease. (PMID:32119913)
• A Homozygous Splicing Mutation in PDE2A in a Family With Atypical Rett Syndrome. (PMID:32196122)
• A Novel Inhibition Modality for Phosphodiesterase 2A. (PMID:32343157)
• Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia. (PMID:32467598)
• Phosphodiesterase 2A2 regulates mitochondria clearance through Parkin-dependent mitophagy. (PMID:33087821)
• Phosphodiesterase 2A and 3B variants are associated with primary aldosteronism. (PMID:33112806)
• miR-139/PDE2A-Notch1 feedback circuit represses stemness of gliomas by inhibiting Wnt/beta-catenin signaling. (PMID:34512162)
• Low Expression of Phosphodiesterase 2 (PDE2A) Promotes the Progression by Regulating Mitochondrial Morphology and ATP Content and Predicts Poor Prognosis in Hepatocellular Carcinoma. (PMID:36611861)
• Phosphodiesterase 2 and Its Isoform A as Therapeutic Targets in the Central Nervous System Disorders. (PMID:37855295)
• The phosphodiesterase 2A controls lymphatic junctional maturation via cGMP-dependent notch signaling. (PMID:38159569)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000079064
danio_rerio	pde2a	ENSDARG00000114444
mus_musculus	Pde2a	ENSMUSG00000110195
rattus_norvegicus	Pde2a	ENSRNOG00000019560
drosophila_melanogaster	Pde11	FBGN0085370
caenorhabditis_elegans		WBGENE00011146

Paralogs (20): PDE4A (ENSG00000065989), PDE8A (ENSG00000073417), PDE6C (ENSG00000095464), PDE4C (ENSG00000105650), PDE10A (ENSG00000112541), PDE8B (ENSG00000113231), PDE4D (ENSG00000113448), PDE1A (ENSG00000115252), PDE1B (ENSG00000123360), PDE11A (ENSG00000128655), PDE6A (ENSG00000132915), PDE6B (ENSG00000133256), PDE5A (ENSG00000138735), PDE3B (ENSG00000152270), PDE1C (ENSG00000154678), PDE9A (ENSG00000160191), PDE7B (ENSG00000171408), PDE3A (ENSG00000172572), PDE4B (ENSG00000184588), PDE7A (ENSG00000205268)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2446107) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 7 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased neutrophil cell number	1
decreased circulating triglyceride level	1
increased heart weight	1
increased circulating bilirubin level	1
lethality throughout fetal growth and development, complete penetrance	1
preweaning lethality, complete penetrance	1
preweaning lethality, incomplete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pan troglodytes	H2QL32	99.5%	Diamond
Drosophila erecta	B3P3K2	98.3%	Diamond
Drosophila simulans	B4QZU1	98.3%	Diamond
Drosophila yakuba	B4PSS5	96.8%	Diamond
Drosophila mojavensis	B4K9L4	96.7%	Diamond
Drosophila virilis	B4LVU6	96.7%	Diamond
Drosophila grimshawi	B4JXX2	95.6%	Diamond
Drosophila willistoni	B4NAL6	94.8%	Diamond
Drosophila pseudoobscura pseudoobscura	Q298P4	94.8%	Diamond
Bos taurus	P14099	94.7%	Diamond
Drosophila ananassae	B3LVW5	93.1%	Diamond
Takifugu rubripes	Q1KKS3	81.6%	Diamond
Dictyostelium discoideum	Q23917	39.3%	Diamond
Plasmodium falciparum 3D7	Q8I6Z7	38.9%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ARAP1-AS2	ncRNA	100506020
MIR4692	ncRNA	100616410
PDE2A-AS1	ncRNA	105369379
STARD10	protein-coding	10809
ARAP1	protein-coding	116985
LINC01537	ncRNA	101928555
PDE2A-AS2	ncRNA	105369378
MIR139	ncRNA	406931

Protein

Protein identifiers

cGMP-dependent 3’,5’-cyclic phosphodiesterase — O00408 (reviewed: O00408)

Alternative names: Cyclic GMP-stimulated phosphodiesterase

All UniProt accessions (16): C9JPD5, E9PEF1, F5GXX2, F5H130, F5H143, F5H1D7, F5H2R8, F5H2V7, F5H2Z0, F5H3Z7, F5H5P8, O00408, H0YFL1, H0YG13, H0YGL2, H7C009

UniProt curated annotations — full annotation on UniProt →

Function. cGMP-activated cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Has a higher efficiency with cGMP compared to cAMP. Plays a role in cell growth and migration. Regulates mitochondrial cAMP levels and respiration. Involved in the regulation of mitochondria morphology/dynamics and apoptotic cell death via local modulation of cAMP/PKA signaling in the mitochondrion, including the monitoring of local cAMP levels at the outer mitochondrial membrane and of PKA-dependent phosphorylation of DNM1L.

Subunit / interactions. Homodimer.

Subcellular location. Cell membrane Mitochondrion matrix. Mitochondrion inner membrane. Mitochondrion outer membrane Cytoplasm Mitochondrion.

Tissue specificity. Widely expressed. Expressed in brain, with high expression observed in the corpus striatum. Also expressed in heart, placenta, lung, skeletal muscle, kidney and pancreas.

Disease relevance. Intellectual developmental disorder with paroxysmal dyskinesia or seizures (IDDPADS) [MIM:619150] An autosomal recessive disorder characterized by global developmental delay, impaired intellectual development, language delay, and early-onset paroxysmal hyperkinetic movement disorder that manifests as sudden falls or backward propulsion, eye or head deviation, and dystonic limb posturing followed by chorea and dyskinetic movements. Some patients may also develop epileptic seizures or only have seizures without a movement disorder. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The 3’,5’-cyclic-AMP phosphodiesterase activity is stimulated by 3’,5’-cyclic GMP.

Cofactor. Binds 2 divalent metal cations per subunit. Site 1 may preferentially bind zinc ions. Binds 2 divalent metal cations per subunit. Site 2 has a preference for magnesium ions.

Domain organisation. The GAF 1 domain functions as a dimerization domain. The GAF 2 domains binds cGMP, which acts as an allosteric activator.

Miscellaneous. Soluble form. Contains a transit peptide at positions 1-17.

Similarity. Belongs to the cyclic nucleotide phosphodiesterase family. PDE2 subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
O00408-1	PDE2A3	yes
O00408-2	PDE2A1
O00408-3	PDE2A2
O00408-4	PDE2A4
O00408-5	5
O00408-6	6

RefSeq proteins (4): NP_001137311, NP_001139681, NP_001230713, NP_002590* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002073	PDEase_catalytic_dom	Domain
IPR003018	GAF	Domain
IPR003607	HD/PDEase_dom	Domain
IPR023088	PDEase	Family
IPR023174	PDEase_CS	Conserved_site
IPR029016	GAF-like_dom_sf	Homologous_superfamily
IPR036971	PDEase_catalytic_dom_sf	Homologous_superfamily

Pfam: PF00233, PF01590

Enzyme classification (BRENDA)

• EC 3.1.4.17 — 3’,5’-cyclic-nucleotide phosphodiesterase (BRENDA: 27 organisms, 83 substrates, 296 inhibitors, 106 Km, 31 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
3’,5’-CAMP	0.0001–7	41
3’,5’-CGMP	—	23
CAMP	0.0002–1.6	15
CGMP	0.0002–1	12
2’,3’-CAMP	0.0038–0.0052	2
5’-AMP	0.0014–0.0016	2
5’-ATP	0.0033–0.0125	2
5’-PAPA	0.204	1
5’-PAPG	0.355	1
ADENOSINE 3’,5’-CYCLIC PHOSPHATE	0.012	1
GUANOSINE 3’,5’-CYCLIC PHOSPHATE	0.025	1

Catalyzed reactions (Rhea)

• a nucleoside 3’,5’-cyclic phosphate + H2O = a nucleoside 5’-phosphate + H(+) (RHEA:14653)
• 3’,5’-cyclic GMP + H2O = GMP + H(+) (RHEA:16957)
• 3’,5’-cyclic AMP + H2O = AMP + H(+) (RHEA:25277)

UniProt features (111 total): helix 37, strand 17, mutagenesis site 12, binding site 10, turn 9, splice variant 6, domain 4, sequence variant 4, sequence conflict 4, lipid moiety-binding region 3, region of interest 2, initiator methionine 1, chain 1, active site 1

Structure

Experimental structures (PDB)

showing 30 of 44 structures by resolution:

PDB	Title	Method	Resolution (Å)
5U00	CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 2A IN COMPLEX WITH …	X-RAY DIFFRACTION	1.41
6C7E	Crystal structure of human phosphodiesterase 2A with …	X-RAY DIFFRACTION	1.43
6EZF	PDE2 in complex with molecule 5	X-RAY DIFFRACTION	1.5
6CYC	PDE2 in complex with compound 5	X-RAY DIFFRACTION	1.54
3ITU	hPDE2A catalytic domain complexed with IBMX	X-RAY DIFFRACTION	1.58
5TZW	CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 2A IN COMPLEX WITH …	X-RAY DIFFRACTION	1.59
5TZH	CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 2A IN COMPLEX WITH …	X-RAY DIFFRACTION	1.6
5TZZ	CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 2A IN COMPLEX WITH …	X-RAY DIFFRACTION	1.6
6CYB	PDE2 in complex with compound 7	X-RAY DIFFRACTION	1.62
6C7G	Crystal structure of human phosphodiesterase 2A with …	X-RAY DIFFRACTION	1.68
6CYD	PDE2 in complex with compound 7	X-RAY DIFFRACTION	1.69
1Z1L	The Crystal Structure of the Phosphodiesterase 2A Catalytic Domain	X-RAY DIFFRACTION	1.7
5TZA	CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 2A WITH …	X-RAY DIFFRACTION	1.7
6C7I	Crystal structure of human phosphodiesterase 2A with …	X-RAY DIFFRACTION	1.71
4JIB	Crystal structure of of PDE2-inhibitor complex	X-RAY DIFFRACTION	1.72
5TZ3	CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 2A IN COMPLEX with …	X-RAY DIFFRACTION	1.72
5U7D	PDE2 catalytic domain complexed with inhibitors	X-RAY DIFFRACTION	1.75
6B97	Crystal structure of PDE2 in complex with complex 9	X-RAY DIFFRACTION	1.76
6C7D	Crystal structure of human phosphodiesterase 2A with …	X-RAY DIFFRACTION	1.79
6C7F	Crystal structure of human phosphodiesterase 2A with …	X-RAY DIFFRACTION	1.82
6C7J	Crystal structure of human phosphodiesterase 2A with …	X-RAY DIFFRACTION	1.85
5VP1	Discovery of Clinical Candidate …	X-RAY DIFFRACTION	1.86
6B96	Crystal Structure of PDE2 in complex with compound 16	X-RAY DIFFRACTION	1.88
6ZQZ	[1,2,4]Triazolo[1,5-a]pyrimidine Phosphodiesterase 2 Inhibitors	X-RAY DIFFRACTION	1.88
4D08	PDE2a catalytic domain in complex with a brain penetrant inhibitor	X-RAY DIFFRACTION	1.9
4HTX	Crystal structure of PDE2 catalytic domain in complex with BAY60-7550	X-RAY DIFFRACTION	1.9
5TZX	CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 2A IN COMPLEX WITH …	X-RAY DIFFRACTION	1.9
5U7J	PDE2 catalytic domain complexed with inhibitors	X-RAY DIFFRACTION	1.9
6B98	PDE2 in complex with compound 1	X-RAY DIFFRACTION	1.97
4HTZ	Crystal structure of PDE2 catalytic domain in space group P1	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00408-F1	84.17	0.53

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Metabolic proteins, Predicted intracellular proteins, Disease related genes, Human disease related genes, Mental and behavioural disorders

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH enhanced · IF supported

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)

Position	Role
656	proton donor

Ligand- & substrate-binding residues (10)

Position	Role
446	3’,5’-cyclic GMP
465	3’,5’-cyclic GMP
488	3’,5’-cyclic GMP
499	3’,5’-cyclic GMP
660	Zn(2+)
696	Zn(2+)
697	Mg(2+)
697	Zn(2+)
808	Zn(2+)
431	3’,5’-cyclic GMP

Post-translational modifications (3)

Type	Positions
N-myristoyl glycine	2
S-palmitoyl cysteine	5, 11

Mutagenesis-validated functional residues (12)

Position	Phenotype
811	decreased 3’,5’-cyclic-amp phosphodiesterase activity. no effect on 3’,5’-cyclic-gmp phosphodiesterase activity.
812	no effect on 3’,5’-cyclic-amp phosphodiesterase activity. decreased 3’,5’-cyclic-gmp phosphodiesterase activity.
812	loss of 3’,5’-cyclic-amp phosphodiesterase activity. loss of 3’,5’-cyclic-gmp phosphodiesterase activity.
819	loss of 3’,5’-cyclic-amp phosphodiesterase activity. loss of 3’,5’-cyclic-gmp phosphodiesterase activity.
826	decreased 3’,5’-cyclic-amp phosphodiesterase activity. increased 3’,5’-cyclic-gmp phosphodiesterase activity.
827	decreased 3’,5’-cyclic-amp phosphodiesterase activity. loss of 3’,5’-cyclic-gmp phosphodiesterase activity.
827	loss of 3’,5’-cyclic-amp phosphodiesterase activity. decreased 3’,5’-cyclic-gmp phosphodiesterase activity.
827	loss of 3’,5’-cyclic-amp phosphodiesterase activity. loss of 3’,5’-cyclic-gmp phosphodiesterase activity.
847	decreased 3’,5’-cyclic-amp phosphodiesterase activity. loss of 3’,5’-cyclic-gmp phosphodiesterase activity.
858	decreased 3’,5’-cyclic-amp phosphodiesterase activity. decreased 3’,5’-cyclic-gmp phosphodiesterase activity.
858	loss of 3’,5’-cyclic-amp phosphodiesterase activity. decreased 3’,5’-cyclic-gmp phosphodiesterase activity.
907	decreased 3’,5’-cyclic-amp phosphodiesterase activity. loss of 3’,5’-cyclic-gmp phosphodiesterase activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 8; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

8 pathways:

ID	Pathway	Evidence
R-HSA-418555	G alpha (s) signalling events	curated
R-HSA-418457	cGMP effects	curated
R-HSA-388396	GPCR downstream signalling	—
R-HSA-109582	Hemostasis	—
R-HSA-392154	Nitric oxide stimulates guanylate cyclase	—
R-HSA-418346	Platelet homeostasis	—
R-HSA-162582	Signal Transduction	—
R-HSA-372790	Signaling by GPCR	—

MSigDB gene sets: 0 (showing top):

GO Biological Process (25): negative regulation of transcription by RNA polymerase II (GO:0000122), heart valve development (GO:0003170), ventricular septum development (GO:0003281), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), positive regulation of gene expression (GO:0010628), negative regulation of receptor guanylyl cyclase signaling pathway (GO:0010754), regulation of mitochondrion organization (GO:0010821), monocyte differentiation (GO:0030224), aorta development (GO:0035904), cellular response to macrophage colony-stimulating factor stimulus (GO:0036006), negative regulation of vascular permeability (GO:0043116), positive regulation of vascular permeability (GO:0043117), cGMP catabolic process (GO:0046069), positive regulation of inflammatory response (GO:0050729), establishment of endothelial barrier (GO:0061028), cellular response to mechanical stimulus (GO:0071260), cellular response to cAMP (GO:0071320), cellular response to cGMP (GO:0071321), cellular response to xenobiotic stimulus (GO:0071466), cellular response to transforming growth factor beta stimulus (GO:0071560), cellular response to granulocyte macrophage colony-stimulating factor stimulus (GO:0097011), negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0106072), negative regulation of cAMP/PKA signal transduction (GO:0141162), cellular response to 2,3,7,8-tetrachlorodibenzodioxine (GO:1904613), signal transduction (GO:0007165)

GO Molecular Function (17): magnesium ion binding (GO:0000287), 3’,5’-cyclic-AMP phosphodiesterase activity (GO:0004115), 3’,5’-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity (GO:0004118), zinc ion binding (GO:0008270), cAMP binding (GO:0030552), cGMP binding (GO:0030553), TPR domain binding (GO:0030911), phosphate ion binding (GO:0042301), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), 3’,5’-cyclic-GMP phosphodiesterase activity (GO:0047555), nucleotide binding (GO:0000166), 3’,5’-cyclic-nucleotide phosphodiesterase activity (GO:0004114), protein binding (GO:0005515), phosphoric diester hydrolase activity (GO:0008081), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (13): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrial outer membrane (GO:0005741), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), presynaptic membrane (GO:0042734), perinuclear region of cytoplasm (GO:0048471), synaptic membrane (GO:0097060), mitochondrion (GO:0005739)

Reactome top-level categories

6 top-level categories:

Category	Pathways
Nitric oxide stimulates guanylate cyclase	1
GPCR downstream signalling	1
Signal Transduction	1
Signaling by GPCR	1
Platelet homeostasis	1
Hemostasis	1

GO top-level categories

showing 60 of 75 GO namespaces:

Category	Terms
cytoplasm	5
intracellular membrane-bounded organelle	4
3’,5’-cyclic-nucleotide phosphodiesterase activity	3
anion binding	3
cellular anatomical structure	3
regulation of vascular permeability	2
cellular response to nitrogen compound	2
cellular response to oxygen-containing compound	2
cyclic nucleotide binding	2
mitochondrial membrane	2
endomembrane system	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
heart development	1
animal gross anatomical part developmental process	1
cardiac ventricle development	1
cardiac septum development	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
receptor guanylyl cyclase signaling pathway	1
negative regulation of signal transduction	1
mitochondrion organization	1
regulation of organelle organization	1
myeloid leukocyte differentiation	1
mononuclear cell differentiation	1
artery development	1
response to macrophage colony-stimulating factor	1
cellular response to cytokine stimulus	1
purine ribonucleotide catabolic process	1
cyclic nucleotide catabolic process	1
cGMP metabolic process	1
inflammatory response	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
endothelial cell development	1
response to mechanical stimulus	1
cellular response to abiotic stimulus	1
cellular response to external stimulus	1
response to cAMP	1
response to cGMP	1
response to xenobiotic stimulus	1
cellular response to chemical stimulus	1
cellular response to growth factor stimulus	1
response to transforming growth factor beta	1
metal ion binding	1
transition metal ion binding	1
adenyl ribonucleotide binding	1
guanyl ribonucleotide binding	1
protein domain specific binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
cyclic-nucleotide phosphodiesterase activity	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 32 of 55 annotations. The rest are phylogenetic / computational / electronic (IEA).

32 experimentally-supported GO terms:

GO term	NS	Evidence
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	BP	direct assay
cGMP catabolic process	BP	direct assay
cellular response to 2,3,7,8-tetrachlorodibenzodioxine	BP	direct assay
cellular response to cAMP	BP	direct assay
cellular response to cGMP	BP	direct assay
cellular response to granulocyte macrophage colony-stimulating factor stimulus	BP	direct assay
cellular response to macrophage colony-stimulating factor stimulus	BP	direct assay
cellular response to transforming growth factor beta stimulus	BP	expression pattern
cellular response to xenobiotic stimulus	BP	expression pattern
monocyte differentiation	BP	expression pattern
negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	BP	mutant phenotype
negative regulation of transcription by RNA polymerase II	BP	direct assay
negative regulation of vascular permeability	BP	mutant phenotype
positive regulation of vascular permeability	BP	mutant phenotype
cytoplasm	CC	direct assay
cytosol	CC	direct assay
mitochondrial inner membrane	CC	direct assay
mitochondrial outer membrane	CC	direct assay
nucleus	CC	direct assay
perinuclear region of cytoplasm	CC	direct assay
plasma membrane	CC	direct assay
3’,5’-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity	MF	direct assay
3’,5’-cyclic-AMP phosphodiesterase activity	MF	direct assay
3’,5’-cyclic-GMP phosphodiesterase activity	MF	direct assay
TPR domain binding	MF	physical interaction
cAMP binding	MF	mutant phenotype
cGMP binding	MF	direct assay
identical protein binding	MF	physical interaction
magnesium ion binding	MF	direct assay
phosphate ion binding	MF	direct assay
protein homodimerization activity	MF	physical interaction
zinc ion binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 930 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDE2A	ALDH7A1	P49419	652
PDE2A	ARAP1	Q96P48	536
PDE2A	CNGA2	Q16280	521
PDE2A	PDE6D	O43924	487
PDE2A	CNGA3	Q16281	483
PDE2A	CNGA4	Q8IV77	454
PDE2A	ADCY5	O95622	423
PDE2A	RAPGEF3	O95398	420
PDE2A	CA2	P00918	417
PDE2A	OR4D2	P58180	406
PDE2A	GUCY1B1	Q02153	400
PDE2A	CRACDL	Q6NV74	393
PDE2A	OR2Y1	Q8NGV0	389
PDE2A	BAG4	O95429	370
PDE2A	GUCA2A	Q02747	369

IntAct

Human interaction partners of PDE2A in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

12 partners by confidence:

Partner	Interaction type	MIscore	Records
AIP	physical association	0.600	6
NUFIP1	association	0.530	1
ACKR3	association	0.350	1
CXCL1	association	0.350	1
DEFA5	association	0.350	1
DHCR24	association	0.350	1
FAF2	association	0.350	1
FZD10	association	0.350	1
LPCAT4	association	0.350	1
UXS1	association	0.350	1
ITSN1	physical association	0.000	1
OBI1	physical association	0.000	1

BioGRID (123 interactions; top human partners by supporting records): IMMT (Affinity Capture-Western; 3 records), NUFIP1 (Affinity Capture-MS; 3 records), SAMM50 (Affinity Capture-Western; 3 records), CHCHD3 (Affinity Capture-Western; 2 records), MTX2 (Affinity Capture-Western; 2 records), A2M (Affinity Capture-MS), ABCB10 (Affinity Capture-MS), ABCC1 (Affinity Capture-MS), ABCC5 (Affinity Capture-MS), ANO6 (Affinity Capture-MS), APAF1 (Affinity Capture-MS), ATAD3A (Affinity Capture-MS), ATG14 (Affinity Capture-MS), ATG3 (Affinity Capture-MS), ATG9A (Affinity Capture-MS)

SIGNOR signaling

3 signaling interactions:

A	Effect	B	Mechanism
caffeine	“down-regulates activity”	PDE2A	“chemical inhibition”
PDE2A	“down-regulates activity”	PRKACA	binding
PDE2A	“down-regulates activity”	PKA	binding

Protein complexes (CORUM) (3)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

3 complexes by size:

Complex	Subunits	Members
★ NUFIP1-PDE2A complex	2	NUFIP1, PDE2A
★ AIP-PDE2A complex	2	AIP, PDE2A
★ PDE2A homodimer	1	PDE2A

Disease & clinical

Genetic variants

Variant evidence for PDE2A: 382 ClinVar records (8 pathogenic / likely pathogenic); 3 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	3
Uncertain significance	150
Likely benign	170
Benign	20

Top pathogenic / likely-pathogenic (8)

Showing all 8 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
689477	NM_002599.5(PDE2A):c.1180C>T (p.Gln394Ter)	Pathogenic	criteria provided, single submitter	2
2217721	NM_002599.5(PDE2A):c.574_592dup (p.Gly198fs)	Pathogenic	criteria provided, single submitter	1
1696651	NM_002599.5(PDE2A):c.2134-2A>G	Likely pathogenic	criteria provided, single submitter	1
3337442	NM_002599.5(PDE2A):c.2256+1G>A	Likely pathogenic	criteria provided, single submitter	1
3337443	NM_002599.5(PDE2A):c.2123A>C (p.Gln708Pro)	Likely pathogenic	criteria provided, single submitter	1
995830	NM_002599.5(PDE2A):c.1922+5G>A	Pathogenic	no assertion criteria provided	1
995831	NM_002599.5(PDE2A):c.446C>T (p.Pro149Leu)	Pathogenic	no assertion criteria provided	1
995832	NM_002599.5(PDE2A):c.323+1G>A	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore PDE2A’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 3,115):

Position(s)	Effect	Δscore	Sites
11:72577595–72577596	acceptor_loss	1.0000	6
11:72577601	acceptor_gain	1.0000
11:72577605	acceptor_gain	1.0000
11:72578232	donor_loss	1.0000	2
11:72578895	donor_loss	1.0000
11:72579010–72579011	acceptor_loss	1.0000	3
11:72579289	donor_gain	1.0000
11:72580884–72580885	donor_loss	1.0000	5
11:72580974–72580975	acceptor_loss	1.0000	6
11:72580977–72580978	acceptor_gain	1.0000	2

AlphaMissense

3,111 missense substitutions predicted likely pathogenic (of 6,244 scored), across 643 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M848	9	0.991	1.000
M847	9	0.970	0.998
M804	9	0.945	0.999
M571	9	0.891	0.997
M622	9	0.870	0.997
H656	8	1.000	1.000
D697	8	1.000	1.000
D699	8	1.000	1.000
H700	8	1.000	1.000
H730	8	1.000	1.000
D769	8	1.000	1.000
D808	8	1.000	1.000
D492	8	0.999	1.000
H660	8	0.999	1.000
H696	8	0.999	1.000
H729	8	0.999	1.000
D811	8	0.999	1.000
D835	8	0.999	1.000
F862	8	0.999	1.000
F433	8	0.998	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

7 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.91e-08
Liver Hepatocellular Carcinoma (validation)	favorable	1.36e-07
Kidney Renal Clear Cell Carcinoma (validation)	favorable	9.4e-06
Liver Hepatocellular Carcinoma (TCGA)	favorable	8.83e-05
Glioblastoma Multiforme (validation)	favorable	0.00014
Ovary Serous Cystadenocarcinoma (TCGA)	unfavorable	0.000489
Stomach Adenocarcinoma (TCGA)	unfavorable	0.000643

Disease associations

OMIM: gene MIM:602658 | disease phenotypes: MIM:619150

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
intellectual developmental disorder with paroxysmal dyskinesia or seizures	Strong	Autosomal recessive	2

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (4 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

4 panels:

Panel	Rating
Dystonia, chorea or related movement disorder, childhood onset	green
Adult-onset neurological disorders	amber
Dystonia, chorea or related movement disorder, adult onset	amber
Paroxysmal central nervous system disorders	amber

Mondo (3): intellectual developmental disorder with paroxysmal dyskinesia or seizures (MONDO:0030900), choreatic disease (MONDO:0001595), paroxysmal dystonia (MONDO:0016058)

Orphanet (2): Benign hereditary chorea (Orphanet:1429), Paroxysmal dystonia (Orphanet:200037)

HPO phenotypes

25 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000273	Facial grimacing
HP:0000718	Aggressive behavior
HP:0000733	Motor stereotypy
HP:0000748	Inappropriate laughter
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0001332	Dystonia
HP:0002072	Chorea
HP:0002119	Ventriculomegaly
HP:0002311	Incoordination
HP:0002342	Moderate intellectual disability
HP:0002353	EEG abnormality
HP:0002376	Developmental regression
HP:0002527	Falls
HP:0003593	Infantile onset
HP:0003763	Bruxism
HP:0007166	Paroxysmal dyskinesia
HP:0007359	Focal-onset seizure
HP:0008936	Axial hypotonia
HP:0032663	Focal motor status epilepticus
HP:0100785	Insomnia

GWAS associations

3 associations:

Study	Trait	p-value
GCST001454_7	Rheumatoid arthritis	6e-10
GCST009524_339	Household income (MTAG)	2e-8
GCST000659_6	Optic nerve measurement (cup area)	5e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0009695	household income

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D002819	Chorea	C10.228.662.262.249; C10.597.350.250; C23.888.592.350.250

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2111470 (SELECTIVITY GROUP), CHEMBL2363066 (PROTEIN FAMILY), CHEMBL2652 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 210,724 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

12 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL760	ANAGRELIDE	4	24,027
CHEMBL1750	CLOFARABINE	4	32,296
CHEMBL932	DIPYRIDAMOLE	4	52,091
CHEMBL192	SILDENAFIL	4	42,240
CHEMBL1520	VARDENAFIL	4	21,263
CHEMBL19224	PAPAVERINE	3	22,318
CHEMBL150764	BUFROLIN	2	131
CHEMBL28079	ZAPRINAST	2	16,287
CHEMBL2180408	JNJ-42396302	1	12
CHEMBL3770459	LENRISPODUN PHOSPHATE	1	14
CHEMBL3092562	PF-05180999	1	31
CHEMBL4060569	TAK-915	1	14

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Phosphodiesterases, 3’,5’-cyclic nucleotide (PDEs)

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
PF-05180999	Inhibition	8.8	pIC50
BAY607550	Inhibition	8.8	pIC50
example 368 [WO2015164508]	Inhibition	7.0	pIC50
milrinone	Inhibition	6.52	pIC50
EHNA	Inhibition	5.3	pIC50

Binding affinities (BindingDB)

1669 measured of 2188 human assays (3063 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[cyclopropyl-[4-(1,1-difluoroethyl)-3-fluorophenyl]methyl]-6-(dimethylamino)-3-(hydroxymethyl)-3,3a,5,6,7,7a-hexahydro-2H-pyrazolo[3,4-d]pyrimidin-4-one	KI	0.02 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
Chf-6001	IC50	0.026 nM
1-[1-[4-(difluoromethyl)-2-fluorophenyl]propyl]-6-(dimethylamino)-3-(fluoromethyl)-3,3a,5,6,7,7a-hexahydro-2H-pyrazolo[3,4-d]pyrimidin-4-one	KI	0.03 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
(R)- or (S)-1- (Cyclopropyl(4-(1,1- difluoroethyl)-2- fluorophenyl)methyl)- 6-(dimethylamino)-3- (hydroxymethyl)-1H- pyrazolo[3,4- d]pyrimidin-4(5H)-one	KI	0.05 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
CHEMBL2206219	IC50	0.056 nM
CHEMBL4071033	IC50	0.06 nM
CHEMBL1916129	IC50	0.06 nM
2-(dimethylamino)-N-{(1S)-2- hydroxy-2-methyl-1-[4- (pentafluoro-lambda6- sulfanyl)phenyl]propyl}-6-oxo- 1,6-dihydropyrimidine-4- carboxamide	KI	0.073 nM	US-10285989: Pyrimidinone amide compounds as PDE2 inhibitors
CHEMBL2206215	IC50	0.075 nM
1-[1-[4-(difluoromethyl)phenyl]propyl]-6-(dimethylamino)-3-(fluoromethyl)-3,3a,5,6,7,7a-hexahydro-2H-pyrazolo[3,4-d]pyrimidin-4-one	KI	0.08 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
CHEMBL2206218	IC50	0.092 nM
CHEMBL2206214	IC50	0.097 nM
(R)- or (S)-1-(1-(4- (Difluoromethoxy)-2- fluorophenyl)propyl)- 6-(dimethylamino)-3- (fluoromethyl)-1H- pyrazolo[3,4- d]pyrimidin-4(5H)- one	KI	0.1 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
CHEMBL1916127	IC50	0.1 nM
N-{(1R)-2,2-dimethyl-1-[4- (trifluoromethyl)phenyl]propyl}-2- [(3S)-3- methoxypyrrolidin-1-yl]-6-oxo-1,6- dihydropyrimidine-4-carboxamide	KI	0.11 nM	US-10285989: Pyrimidinone amide compounds as PDE2 inhibitors
2-(dimethylamino)-N-{(1S)-1-[3- fluoro-4- (trifluoromethoxy)phenyl]-2- hydroxy-2-methylpropyl}-6-oxo- 1,6-dihydropyrimidine-4- carboxamide	KI	0.12 nM	US-10285989: Pyrimidinone amide compounds as PDE2 inhibitors
(R)- or (S)-1-(1-(4- (Difluoromethyl)-3- fluorophenyl)propyl)- 6-(dimethylamino)-3- (fluoromethyl)-1H- pyrazolo[3,4- d]pyrimidin-4(5H)- one	KI	0.13 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
(R)- or (S)-1-(1-(4- (Difluoromethoxy)-3- fluorophenyl)propyl)- 6-(dimethylamino)-3- (fluoromethyl)-1H- pyrazolo[3,4- d]pyrimidin-4(5H)- one	KI	0.15 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
CHEMBL4077126	IC50	0.16 nM
CHEMBL2206221	IC50	0.199 nM
CHEMBL4076642	IC50	0.2 nM
CHEMBL4092829	IC50	0.23 nM
3-(difluoromethyl)-6-(dimethylamino)-1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]-3,3a,5,6,7,7a-hexahydro-2H-pyrazolo[3,4-d]pyrimidin-4-one	KI	0.25 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
6-(azetidin-1-yl)-3-(difluoromethyl)-1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]-3,3a,5,6,7,7a-hexahydro-2H-pyrazolo[3,4-d]pyrimidin-4-one	KI	0.26 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
CHEMBL2069321	IC50	0.28 nM
4-(azetidin-1-yl)-7-methyl-5-[1-methyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]imidazo[5,1-f][1,2,4]triazine	IC50	0.3 nM	US-8598155: Imidazo[5,1-f][1,2,4]triazines for the treatment of neurological disorders
CHEMBL4062397	IC50	0.3 nM
1-[(1S)-1-[4-(1,1-difluoroethyl)phenyl]-2-methylpropyl]-3-(hydroxymethyl)-6-(methylamino)-3,3a,5,6,7,7a-hexahydro-2H-pyrazolo[3,4-d]pyrimidin-4-one	KI	0.33 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
CHEMBL1916117	IC50	0.35 nM
(R)- or (S)-N-{(1R)-2,2- dimethyl-1-[4- (trifluoromethyl)phenyl] propyl}-2-[3-(methoxy- methyl)pyrrolidin-1-yl]- 6-oxo-1,6-dihydro- pyrimidine-4-carboxamide	KI	0.38 nM	US-10285989: Pyrimidinone amide compounds as PDE2 inhibitors
N-{(1R)-1-[4-(1,1- difluoroethyl)phenyl]-2- methylpropyl}-2-(dimethylamino)-6- oxo-1,6-dihydropyrimidine-4- carboxamide	KI	0.39 nM	US-10285989: Pyrimidinone amide compounds as PDE2 inhibitors
5-(hydroxymethyl)-2-methyl-7-[1-[4-(1-methylcyclopropyl)phenyl]ethyl]-2,3-dihydro-1H-imidazo[5,1-f][1,2,4]triazin-4-one	KI	0.4 nM	US-10287293: Bicyclic heterocyclic compounds as PDE2 inhibitors
6-[4-[(1S)-1-[2-chloro-4-(trifluoromethyl)phenyl]ethyl]triazol-1-yl]-2-methyl-1,3-diazinan-4-one	KI	0.42 nM	US-10358435: Triazolyl pyrimidinone compounds as PDE2 inhibitors
2-fluoro-4-[3-[1-(7-fluoroquinolin-2-yl)azetidin-3-yl]pyrazin-2-yl]-N-methylbenzamide	IC50	0.5 nM	US-8691986: Azetidine and piperidine compounds useful as PDE10 inhibitors
N-[(2S)-2-[2-chloro-4-(trifluoromethyl)phenyl]-1-hydroxypropan-2-yl]-6-oxo-2-phenyl-1,3-diazinane-4-carboxamide	KI	0.5 nM	US-9815796: Pyrimidone carboxamide compounds as PDE2 inhibitors
N-[(1R)-1-(4-cyclopropylphenyl)-2,2-dimethylpropyl]-6-oxo-2-phenyl-1,3-diazinane-4-carboxamide	KI	0.51 nM	US-9815796: Pyrimidone carboxamide compounds as PDE2 inhibitors
CHEMBL5268162	IC50	0.51 nM
CHEMBL2206220	IC50	0.513 nM
4-(azetidin-1-yl)-5-[5-(4-ethylphenyl)-1-methylpyrazol-4-yl]-7-methylimidazo[5,1-f][1,2,4]triazine	IC50	0.517 nM	US-8598155: Imidazo[5,1-f][1,2,4]triazines for the treatment of neurological disorders
N-{(1S)-1-[2-chloro-4- (trifluoromethyl)phenyl]-2- hydroxy-1-methylethyl}-2- (dimethylamino)-6-oxo-1,6- dihydropyrimidine-4-carboxamide	KI	0.52 nM	US-10285989: Pyrimidinone amide compounds as PDE2 inhibitors
CHEMBL2206216	IC50	0.521 nM
N-{(1S)-1-[2-chloro-4- (trifluoromethoxy)phenyl]-2- hydroxy-2-methylpropyl}-2- (dimethylamino)-6-oxo- 1,6-dihydropyrimidine-4- carboxamide	KI	0.54 nM	US-10285989: Pyrimidinone amide compounds as PDE2 inhibitors
6-[7-[2-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-5,6-dihydro-4H-triazolo[1,5-a]pyridin-3-yl]-2-[(3-methoxyphenyl)methyl]-1,3-diazinan-4-one	KI	0.56 nM	US-10358435: Triazolyl pyrimidinone compounds as PDE2 inhibitors
4-(azetidin-1-yl)-5-[5-(4-methoxy-2-methylphenyl)-1-methylpyrazol-4-yl]-7-methylimidazo[5,1-f][1,2,4]triazine	IC50	0.578 nM	US-8598155: Imidazo[5,1-f][1,2,4]triazines for the treatment of neurological disorders
CHEMBL4160171	IC50	0.6 nM
CHEMBL4794209	IC50	0.6 nM
6-amino-1-[(1S)-1-[4-(1,1-difluoroethyl)phenyl]-2-methylpropyl]-3-(hydroxymethyl)-3,3a,5,6,7,7a-hexahydro-2H-pyrazolo[3,4-d]pyrimidin-4-one	KI	0.68 nM	US-10174037: Dihydropyrazolopyrimidinone compounds as PDE2 inhibitors
N-methyl-3-[3-(1-quinolin-2-ylazetidin-3-yl)pyrazin-2-yl]benzamide	IC50	0.7 nM	US-8957073: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
{Cyclohexyl-[4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]quinolin-7-yloxy)-butyryl]-amino}-acetic acid methyl ester	EC50	0.7 nM
CHEMBL2180775	IC50	0.7 nM

ChEMBL bioactivities

3698 potent at pChembl≥5 of 3803 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.80	Ki	0.016	nM	CHEMBL5827044
10.77	Ki	0.017	nM	CHEMBL5773913
10.70	Ki	0.02	nM	CHEMBL6019094
10.66	Ki	0.022	nM	CHEMBL5867733
10.62	Ki	0.024	nM	CHEMBL6027642
10.52	IC50	0.03	nM	CHEMBL370962
10.52	Ki	0.03	nM	CHEMBL5948981
10.52	Ki	0.03	nM	CHEMBL6040588
10.52	Ki	0.03	nM	CHEMBL5847109
10.42	Ki	0.038	nM	CHEMBL6032923
10.40	Ki	0.04	nM	CHEMBL6028983
10.39	Ki	0.041	nM	CHEMBL5774777
10.38	Ki	0.042	nM	CHEMBL5880032
10.36	Ki	0.044	nM	CHEMBL6045656
10.36	Ki	0.044	nM	CHEMBL5871807
10.35	Ki	0.045	nM	CHEMBL5827382
10.34	Ki	0.046	nM	CHEMBL5771360
10.33	Ki	0.047	nM	CHEMBL5912514
10.33	Ki	0.047	nM	CHEMBL5869948
10.32	Ki	0.048	nM	CHEMBL6050934
10.32	Ki	0.048	nM	CHEMBL6032101
10.30	Ki	0.05	nM	CHEMBL5886652
10.28	Ki	0.053	nM	CHEMBL5748229
10.25	Ki	0.056	nM	CHEMBL5963263
10.24	Ki	0.057	nM	CHEMBL6047592
10.24	Ki	0.058	nM	CHEMBL5937033
10.22	IC50	0.06	nM	CHEMBL4071033
10.20	Ki	0.063	nM	CHEMBL5866384
10.19	Ki	0.064	nM	CHEMBL5899608
10.19	Ki	0.064	nM	CHEMBL5788813
10.17	Ki	0.068	nM	CHEMBL5773913
10.16	Ki	0.069	nM	CHEMBL5928367
10.16	Ki	0.069	nM	CHEMBL6057847
10.15	Ki	0.071	nM	CHEMBL5952104
10.15	Ki	0.07	nM	CHEMBL5906907
10.14	Ki	0.073	nM	CHEMBL6029400
10.14	Ki	0.072	nM	CHEMBL5938025
10.14	Ki	0.073	nM	CHEMBL5808459
10.11	Ki	0.077	nM	CHEMBL5851735
10.10	Ki	0.08	nM	CHEMBL5988705
10.05	Ki	0.09	nM	CHEMBL5755097
10.00	IC50	0.1	nM	CHEMBL5081214
10.00	Ki	0.099	nM	CHEMBL5893408
10.00	Ki	0.1	nM	CHEMBL5963424
9.96	Ki	0.11	nM	CHEMBL6045656
9.96	Ki	0.11	nM	CHEMBL6047592
9.96	Ki	0.11	nM	CHEMBL5744255
9.96	Ki	0.11	nM	CHEMBL5842060
9.92	Ki	0.12	nM	CHEMBL6023089
9.92	Ki	0.12	nM	CHEMBL6048289

PubChem BioAssay actives

672 with measured affinity, of 1520 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
2-[(3,4-dimethoxyphenyl)methyl]-7-[(2R,3R)-2-hydroxy-6-phenylhexan-3-yl]-5-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1480122: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	<0.0001	uM
5-(difluoromethyl)-7-[1,3-dimethyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-2-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1480122: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]sulfamoyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-[[N-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxycarbonyl]anilino]methyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0001	uM
7-[1,3-dimethyl-5-[3-methyl-4-(trifluoromethyl)phenyl]pyrazol-4-yl]-5-(hydroxymethyl)-2-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1480122: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0002	uM
7-[1,3-dimethyl-5-[3-methyl-4-(trifluoromethyl)phenyl]pyrazol-4-yl]-2,5-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1480122: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0002	uM
5-(difluoromethyl)-2-methyl-7-[5-methyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1480122: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0002	uM
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]amino]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0002	uM
7-[1,3-dimethyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-5-(hydroxymethyl)-2-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1480122: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0003	uM
4-(azetidin-1-yl)-7-methyl-5-[1-methyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]imidazo[5,1-f][1,2,4]triazine	1472968: Inhibition of full length human N-terminal FLAG-tagged PDE2A3 expressed in sf21 cells using [3H]cGMP as substrate after 30 mins by SPA	ic50	0.0003	uM
1-(2,6-dichlorophenyl)-N-ethyl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide	724277: Inhibition of human recombinant PDE2A expressed in Sf9 cells by scintillation proximity assay	ic50	0.0003	uM
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]amino]methyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0003	uM
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]sulfamoyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0003	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-[[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]amino]methyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0003	uM
N-benzyl-1-(2-chlorophenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide	724277: Inhibition of human recombinant PDE2A expressed in Sf9 cells by scintillation proximity assay	ic50	0.0004	uM
1-(2-chlorophenyl)-4-methyl-N-(pyridin-2-ylmethyl)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide	724277: Inhibition of human recombinant PDE2A expressed in Sf9 cells by scintillation proximity assay	ic50	0.0004	uM
4-(3-fluoroazetidin-1-yl)-7-methyl-5-[1-methyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]imidazo[5,1-f][1,2,4]triazine	747976: Inhibition of full length recombinant human PDE2A expressed in Sf21 cells using [3H]-cGMP as substrate by scintillation proximity assay	ic50	0.0005	uM
1-(2-chlorophenyl)-4-methyl-N-(2-morpholin-4-ylethyl)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide	724277: Inhibition of human recombinant PDE2A expressed in Sf9 cells by scintillation proximity assay	ic50	0.0005	uM
N-[(1S)-2-hydroxy-2-methyl-1-[4-(trifluoromethoxy)phenyl]propyl]-6-methyl-5-(3-methyl-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide	1923556: Inhibition of PDE2A (unknown origin)	ic50	0.0005	uM
7-[1,3-dimethyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-2,5-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1350143: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate measured after 30 mins by Yttrium silicate scintillation proximity assay	ic50	0.0006	uM
1-benzofuran-5-yl-[(3S,4R)-3-[5-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]-4-methylpiperidin-1-yl]methanone	1678216: Inhibition of 6xHis-tagged human recombinant PDE2A expressed in Sf9 cells in presence of [3H]-cGMP and cGMP incubated for 40 mins by scintillation counting method	ic50	0.0006	uM
4-(azetidin-1-yl)-5-[5-(4-methoxy-2-methylphenyl)-1-methylpyrazol-4-yl]-7-methylimidazo[5,1-f][1,2,4]triazine	747976: Inhibition of full length recombinant human PDE2A expressed in Sf21 cells using [3H]-cGMP as substrate by scintillation proximity assay	ic50	0.0006	uM
1-(2-chlorophenyl)-N-ethyl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide	724277: Inhibition of human recombinant PDE2A expressed in Sf9 cells by scintillation proximity assay	ic50	0.0006	uM
N-[(1S)-1-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl]-7-methoxy-2-oxo-1,3-dihydropyrido[2,3-b]pyrazine-4-carboxamide	1458906: Inhibition of recombinant human full-length His-tagged PDE2A3 expressed in fall armyworm Sf9 cells using [3H]cGMP as substrate preincubated for 30 mins followed by substrate addition measured after 60 mins by scintillation counting	ic50	0.0006	uM
[(3S)-3-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl]-naphthalen-2-ylmethanone	1440918: Inhibition of human full length GST-tagged PDE2a using FAM-labeled cAMP as substrate preincubated for 5 mins followed by substrate addition measured after 30 mins by IMAP assay	ic50	0.0008	uM
4-(azetidin-1-yl)-5-[5-(2-fluoro-4-methoxyphenyl)-1-methylpyrazol-4-yl]-7-methylimidazo[5,1-f][1,2,4]triazine	747976: Inhibition of full length recombinant human PDE2A expressed in Sf21 cells using [3H]-cGMP as substrate by scintillation proximity assay	ic50	0.0008	uM
1-(2-fluoroethyl)-3-[(1R)-1-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-5-methyl-6H-pyrazolo[4,5-d]pyrimidin-7-one	1776789: Inhibition of human PDE2	ki	0.0009	uM
7-[5-(4-chlorophenyl)-1,3-dimethylpyrazol-4-yl]-5-(hydroxymethyl)-2-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1480122: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0009	uM
3-(8-methoxy-1-methyl-2-oxo-7-phenyl-3H-1,4-benzodiazepin-5-yl)benzamide	1924473: Inhibition of PDE2A (unknown origin)	ic50	0.0010	uM
[3-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl]-naphthalen-2-ylmethanone	1440918: Inhibition of human full length GST-tagged PDE2a using FAM-labeled cAMP as substrate preincubated for 5 mins followed by substrate addition measured after 30 mins by IMAP assay	ic50	0.0010	uM
[3,3-difluoro-5-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl]-naphthalen-2-ylmethanone	1440918: Inhibition of human full length GST-tagged PDE2a using FAM-labeled cAMP as substrate preincubated for 5 mins followed by substrate addition measured after 30 mins by IMAP assay	ic50	0.0010	uM
5-(difluoromethyl)-7-[3-(hydroxymethyl)-1-methyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-2-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1480122: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0010	uM
(3S)-1-[7-methyl-5-[1-methyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]imidazo[5,1-f][1,2,4]triazin-4-yl]pyrrolidine-3-carboxylic acid	1411989: Inhibition of PDE2A (unknown origin)	ic50	0.0010	uM
4-(azetidin-1-yl)-7-methyl-5-[1-methyl-5-[5-(trifluoromethyl)-2-pyridinyl]pyrazol-4-yl]imidazo[5,1-f][1,2,4]triazine	1058003: Inhibition of recombinant human full length PDE2A3 expressed in insect SF-21 cells using [3H]-cGMP as substrate by scintillation proximity assay	ic50	0.0010	uM
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[N-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxycarbonyl]anilino]methyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0010	uM
4-[[1-(2-chloro-6-(18F)fluorophenyl)-4-methyl-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl]methyl]morpholine	1057995: Inhibition of recombinant human PDE2A expressed in baculovirus infected insect SF9 cells using [3H]-cGMP as substrate after 45 mins by scintillation proximity assay	ic50	0.0010	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]amino]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0010	uM
3-[(1R)-1-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-1-(2-hydroxyethyl)-5-methyl-6H-pyrazolo[4,5-d]pyrimidin-7-one	1776789: Inhibition of human PDE2	ki	0.0011	uM
5-(hydroxymethyl)-2-methyl-7-[5-methyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one	1480122: Inhibition of human PDE2A1 using 3’,5’-[3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0011	uM
1-benzofuran-5-yl-[3-[5-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]-4-methylpiperidin-1-yl]methanone	1678216: Inhibition of 6xHis-tagged human recombinant PDE2A expressed in Sf9 cells in presence of [3H]-cGMP and cGMP incubated for 40 mins by scintillation counting method	ic50	0.0011	uM
4-(azetidin-1-yl)-5-[5-(2,3-difluoro-4-methoxyphenyl)-1-methylpyrazol-4-yl]-7-methylimidazo[5,1-f][1,2,4]triazine	747976: Inhibition of full length recombinant human PDE2A expressed in Sf21 cells using [3H]-cGMP as substrate by scintillation proximity assay	ic50	0.0011	uM
3-tert-butyl-1-(2-hydroxyethyl)-5-[4-methoxy-3-(2-pyrrolidin-1-ylpyrimidin-5-yl)phenyl]-6,7-dihydropyrazolo[4,5-e][1,4]diazepin-8-one	749038: Inhibition of PDE2 catalytic domain (unknown origin)	ic50	0.0012	uM
3-[(1S)-1-(4-tert-butylphenyl)ethyl]-1-(2-fluoroethyl)-5-methyl-6H-pyrazolo[4,5-d]pyrimidin-7-one	2124203: Inhibition of PDE2A (unknown origin) using 3H-cGMP as substrate	ic50	0.0013	uM
3-[(1R)-1-(4-tert-butylphenyl)ethyl]-1-(2-fluoroethyl)-5-methyl-6H-pyrazolo[4,5-d]pyrimidin-7-one	1776789: Inhibition of human PDE2	ki	0.0013	uM
7-methyl-5-[1-methyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]imidazo[5,1-f][1,2,4]triazin-4-amine	1472968: Inhibition of full length human N-terminal FLAG-tagged PDE2A3 expressed in sf21 cells using [3H]cGMP as substrate after 30 mins by SPA	ic50	0.0013	uM
5-(difluoromethyl)-7-[(3S,4R)-4-methyl-1-(4-phenyl-2-pyridinyl)piperidin-3-yl]-[1,2,4]triazolo[1,5-a]pyrimidine	1678216: Inhibition of 6xHis-tagged human recombinant PDE2A expressed in Sf9 cells in presence of [3H]-cGMP and cGMP incubated for 40 mins by scintillation counting method	ic50	0.0013	uM
3-tert-butyl-5-[3-[6-(dimethylamino)-4-methyl-3-pyridinyl]-4-methoxyphenyl]-1-(2-hydroxyethyl)-6,7-dihydropyrazolo[4,5-e][1,4]diazepin-8-one	749038: Inhibition of PDE2 catalytic domain (unknown origin)	ic50	0.0013	uM
1-(2-chlorophenyl)-N-[2-(diethylamino)ethyl]-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide	724277: Inhibition of human recombinant PDE2A expressed in Sf9 cells by scintillation proximity assay	ic50	0.0014	uM
3-tert-butyl-1-(2-hydroxyethyl)-5-[4-methoxy-3-(2-morpholin-4-ylpyrimidin-5-yl)phenyl]-6,7-dihydropyrazolo[4,5-e][1,4]diazepin-8-one	749038: Inhibition of PDE2 catalytic domain (unknown origin)	ic50	0.0014	uM
(1-methylsulfonylindol-5-yl)-[(3S)-3-([1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl]methanone	1678216: Inhibition of 6xHis-tagged human recombinant PDE2A expressed in Sf9 cells in presence of [3H]-cGMP and cGMP incubated for 40 mins by scintillation counting method	ic50	0.0015	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	3
Aflatoxin B1	affects methylation, increases expression	3
bisphenol A	affects cotreatment, increases methylation, decreases expression	2
sulindac sulfone	affects binding, decreases activity	2
Resveratrol	decreases expression	2
Vorinostat	affects cotreatment, increases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	2
Nickel	decreases expression	2
Ozone	affects expression, increases abundance, increases expression	2
Cyclosporine	increases expression	2
TAK-243	increases sumoylation	1
Esketamine	increases expression	1
sotorasib	decreases expression, affects cotreatment	1
methylmercuric chloride	decreases expression	1
propionaldehyde	increases expression	1
titanium dioxide	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	affects methylation	1
pentanal	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
seocalcitol	increases expression	1
CGP 52608	affects binding, increases reaction	1
4,5-dimethoxy-2-nitrobenzyl-8-bromo-cAMP	affects localization, decreases reaction	1
(5-fluoro-2-methyl-1-(4-pyridyl)methylene-3-(N-benzyl)-indene)-acetamide hydrochloride	affects binding, decreases activity	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	increases expression	1

ChEMBL screening assays

346 unique, capped per target: 331 binding, 8 admet, 7 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4373090	Binding	Selectivity ratio of IC50 for PDE5 (unknown origin) to IC50 for PDE2 (unknown origin)	Design, synthesis of novel purin-6-one derivatives as phosphodiesterase 2 (PDE2) inhibitors: The neuroprotective and anxiolytic-like effects. — *Bioorg Med Chem Lett*
CHEMBL4680008	ADMET	Inhibition of PDE (unknown origin)	Fragment-Based Discovery of Novel Allosteric MEK1 Binders. — *ACS Med Chem Lett*
CHEMBL5723181	Functional	Affinity Biochemical interaction: (inhibition of enzyme activity with [3H]cGMP or [3H]cAMP as the substrate) EUB0002477a PDE2A	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C0TI	ACTOne cAMP-PDE2A	Transformed cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PDE2A across ~30M SureChEMBL compounds — explore on Sugi Predict.