ADCY10

Summary

ADCY10 (adenylate cyclase 10, HGNC:21285) is a protein-coding gene on chromosome 1q24.2, encoding Adenylate cyclase type 10 (Q96PN6). Catalyzes the formation of the signaling molecule cAMP.

The protein encoded by this gene belongs to a distinct class of adenylyl cyclases that is soluble and insensitive to G protein or forskolin regulation. Activity of this protein is regulated by bicarbonate. Variation at this gene has been observed in patients with absorptive hypercalciuria. Alternatively spliced transcript variants encoding different isoforms have been observed. There is a pseudogene of this gene on chromosome 6.

Source: NCBI Gene 55811 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypercalciuria, absorptive, 2 (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 692 total — 27 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 8
• Druggable target: yes
• MANE Select transcript: NM_018417

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21285
Approved symbol	ADCY10
Name	adenylate cyclase 10
Location	1q24.2
Locus type	gene with protein product
Status	Approved
Aliases	SAC, Sacy, SACI, HCA2, RP1-313L4.2
Ensembl gene	ENSG00000143199
Ensembl biotype	protein_coding
OMIM	605205
Entrez	55811

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 nonsense_mediated_decay

ENST00000367848, ENST00000367851, ENST00000476818, ENST00000485964, ENST00000545172

RefSeq mRNA: 3 — MANE Select: NM_018417 NM_001167749, NM_001297772, NM_018417

CCDS: CCDS1265, CCDS53426, CCDS72977

Canonical transcript exons

ENST00000367851 — 33 exons

Exon	Start	End
ENSE00000958614	167896595	167896691
ENSE00000958617	167883437	167883628
ENSE00000958618	167880491	167880609
ENSE00000958624	167859807	167859893
ENSE00000958625	167856165	167856439
ENSE00001157277	167836309	167836540
ENSE00001157282	167837249	167837318
ENSE00001157306	167854353	167854489
ENSE00001157320	167860871	167861063
ENSE00001157327	167870257	167870410
ENSE00001157333	167875131	167875186
ENSE00001157341	167878446	167878635
ENSE00001157351	167880115	167880191
ENSE00001157372	167893853	167893941
ENSE00001157395	167901662	167901805
ENSE00001771820	167809386	167809839
ENSE00003460449	167822024	167822141
ENSE00003485882	167902016	167902054
ENSE00003525851	167904993	167905198
ENSE00003536879	167903887	167903991
ENSE00003540452	167833970	167834077
ENSE00003553259	167824651	167824855
ENSE00003555540	167818072	167818267
ENSE00003567920	167823008	167823123
ENSE00003579781	167829267	167829423
ENSE00003582024	167810725	167810913
ENSE00003592377	167899423	167899628
ENSE00003640805	167824476	167824572
ENSE00003679575	167832987	167833162
ENSE00003705763	167845563	167845853
ENSE00003706924	167845985	167846263
ENSE00003708154	167848361	167848489
ENSE00003895715	167913976	167914134

Expression profiles

Bgee: expression breadth ubiquitous, 154 present calls, max score 89.14.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0973 / max 57.2878, expressed in 10 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
15794	0.0569	8
15793	0.0404	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	89.14	gold quality
male germ cell	CL:0000015	86.83	gold quality
left testis	UBERON:0004533	83.49	gold quality
right testis	UBERON:0004534	82.51	gold quality
testis	UBERON:0000473	81.10	gold quality
buccal mucosa cell	CL:0002336	78.64	silver quality
right lobe of liver	UBERON:0001114	78.16	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	74.69	silver quality
pancreatic ductal cell	CL:0002079	68.40	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	67.94	gold quality
liver	UBERON:0002107	66.90	gold quality
cerebellar hemisphere	UBERON:0002245	61.99	gold quality
cerebellar cortex	UBERON:0002129	61.77	gold quality
adult organism	UBERON:0007023	61.76	gold quality
right hemisphere of cerebellum	UBERON:0014890	61.35	gold quality
cerebellum	UBERON:0002037	59.98	gold quality
mucosa of transverse colon	UBERON:0004991	58.03	gold quality
granulocyte	CL:0000094	56.67	gold quality
ileal mucosa	UBERON:0000331	53.28	silver quality
hindlimb stylopod muscle	UBERON:0004252	53.05	gold quality
lower esophagus mucosa	UBERON:0035834	53.01	gold quality
epithelial cell of pancreas	CL:0000083	52.65	gold quality
right coronary artery	UBERON:0001625	52.17	gold quality
anterior cingulate cortex	UBERON:0009835	52.16	gold quality
cingulate cortex	UBERON:0003027	52.15	gold quality
islet of Langerhans	UBERON:0000006	51.96	gold quality
mucosa of urinary bladder	UBERON:0001259	51.70	gold quality
metanephros cortex	UBERON:0010533	51.70	gold quality
deltoid	UBERON:0001476	51.26	gold quality
stromal cell of endometrium	CL:0002255	51.25	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.95

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF1B

miRNA regulators (miRDB)

20 targeting ADCY10, 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-196A-1-3P	99.99	72.15	2772
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-520F-3P	99.82	71.32	1216
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-19A-5P	99.36	66.93	1675
HSA-MIR-19B-1-5P	99.36	67.07	1669
HSA-MIR-19B-2-5P	99.36	67.07	1669
HSA-MIR-2054	99.20	68.89	1699
HSA-MIR-1253	99.12	67.08	1688
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-5197-3P	98.71	67.05	1905
HSA-MIR-5011-3P	98.63	64.81	638
HSA-MIR-4457	98.09	67.12	1274
HSA-MIR-3620-5P	97.42	63.95	792
HSA-MIR-1587	96.95	64.03	932
HSA-MIR-125B-2-3P	96.69	68.38	1210
HSA-MIR-4790-3P	96.63	67.08	806
HSA-MIR-3974	96.56	66.22	928
HSA-MIR-3914	94.91	65.77	643

Literature-anchored findings (GeneRIF, showing 21)

• Soluble adenylyl cyclase is localized to motile airway cilia and it contributes to the regulation of human airway ciliary beat frequency. (PMID:17591988)
• These results show that bicarbonate-controlled sAC stimulation must be taken into account in cell physiology and that basal CFTR expression depends on an ionic parameter. (PMID:18209474)
• a modest association between an ADCY10 polymorphism and the spinal areal BMD in premenopausal white women. (PMID:19093065)
• sAC may play a role in the pathogenesis of certain hyperproliferative skin disorders via modulation of gene expression (PMID:20130594)
• Regulation of anterior chamber drainage by bicarbonate-sensitive soluble adenylyl cyclase in the ciliary body. (PMID:21994938)
• a haem-binding domain within the C-terminus of the human soluble adenylate cyclase (PMID:22775536)
• Significant overexpression of soluble type 10 adenylyl cyclase (sAC), an alternative source of cAMP, was found in human prostate carcinoma. (PMID:23255611)
• sAC is necessary for normal glucose-stimulated insulin secretion in vitro and in vivo. (PMID:24100033)
• sAC is a regulator of gene expression involved in aldosterone signaling and an important regulator of endothelial stiffness. (PMID:24420537)
• Evaluation of soluble adenylyl cyclase expression using R21 antibody is a useful diagnostic adjunct in the evaluation of margins of LM during slow Mohs surgery. (PMID:24698940)
• Soluble adenylyl cyclase plays a role in the regulation of basal cCMP and cUMP. (PMID:24792377)
• Crystal structures of human ADCY10 catalytic domains in complex with nucleotides. (PMID:25040695)
• shows that in fibroblast cultures inhibition by KH7 of production in the mitochondrial matrix by soluble adenylyl cyclase (PMID:25409931)
• The data support an important role for prostaglandin activation of sAC and PKA in H2O2-induced barrier disruption. (PMID:26857816)
• results thus provide 1) novel insights into the communication between allosteric regulatory and active sites, 2) a novel mechanism for sAC inhibition, and 3) pharmacological compounds targeting this allosteric site and utilizing this mode of inhibition. (PMID:26961873)
• the higher level of cyclic AMP observed in Parkin-mutant fibroblasts can contribute to a higher level of activity/expression by soluble adenylyl cyclase. (PMID:30875974)
• Soluble adenylyl cyclase links Ca(2+) entry to Ca(2+)/cAMP-response element binding protein (CREB) activation in vascular smooth muscle. (PMID:31086231)
• Study provides the first report of a homozygous frameshift variation (c.1205_1206del; dbSNP rs779944215) in the exonic region of ADCY10 associated with recessive asthenozoospermia, in an inbred family from Iran. Noticeably, all relatives who were heterozygous or homozygous for the variant had a history of developing calcium kidney stones, confirming the association with absorptive hypercalciuria (OMIM#143870). (PMID:31119281)
• Soluble adenylyl cyclase regulates the cytosolic NADH/NAD(+) redox state and the bioenergetic switch between glycolysis and oxidative phosphorylation. (PMID:33412125)
• Endogenous glutamate determines ferroptosis sensitivity via ADCY10-dependent YAP suppression in lung adenocarcinoma. (PMID:33897873)
• Two novel heterozygous ADCY10 variants identified in Chinese pediatric patients with absorptive hypercalciuria: case report and literature review. (PMID:38258300)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Adcy10	ENSMUSG00000026567
rattus_norvegicus	Adcy10	ENSRNOG00000053410

Protein

Protein identifiers

Adenylate cyclase type 10 — Q96PN6 (reviewed: Q96PN6)

Alternative names: AH-related protein, Adenylate cyclase homolog, Germ cell soluble adenylyl cyclase, Testicular soluble adenylyl cyclase

All UniProt accessions (4): Q96PN6, A0A0K0K1J8, U3KPS9, V9GY51

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the formation of the signaling molecule cAMP. May function as sensor that mediates responses to changes in cellular bicarbonate and CO(2) levels. Has a critical role in mammalian spermatogenesis by producing the cAMP which regulates cAMP-responsive nuclear factors indispensable for sperm maturation in the epididymis. Induces capacitation, the maturational process that sperm undergo prior to fertilization. Involved in ciliary beat regulation.

Subcellular location. Cell membrane. Cytoplasm. Cytoskeleton. Perinuclear region. Nucleus. Cell projection. Cilium. Mitochondrion.

Tissue specificity. Detected in airway epithelial cells and testis (at protein level). Weakly expressed in multiple tissues. Expressed in brain, heart, kidney, liver, lung, pancreas, peripheral blood leukocytes, placenta, skeletal muscle, stomach, thymus, airway epithelial cells, duodenum, jejunum and ileum. Very low level of expression in bone.

Post-translational modifications. Cleavage may occur to generate the active 48 kDa form.

Disease relevance. Hypercalciuria absorptive 2 (HCA2) [MIM:143870] A common type of hypercalciuria, a condition characterized by excessive urinary calcium excretion. Absorptive hypercalciuria is due to gastrointestinal hyperabsorption of calcium and is a frequent cause of calcium oxalate nephrolithiasis. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. Activated by manganese or magnesium ions. In the presence of magnesium ions, the enzyme is activated by bicarbonate. In the presence of manganese ions, the enzyme is inhibited by bicarbonate. In the absence of magnesium and bicarbonate, the enzyme is weakly activated by calcium. Calcium mildly increases the enzyme activity, also in the presence of magnesium ions.

Cofactor. Binds 2 magnesium ions per subunit. Is also active with manganese (in vitro).

Domain organisation. The N-terminal guanylate cyclase domains are required for enzyme activity. Fragments or isoforms containing the first 470 amino acid residues are fully active.

Similarity. Belongs to the adenylyl cyclase class-4/guanylyl cyclase family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q96PN6-1	1	yes
Q96PN6-2	2
Q96PN6-3	3
Q96PN6-4	4

RefSeq proteins (3): NP_001161221, NP_001284701, NP_060887* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001054	A/G_cyclase	Domain
IPR016577	Adenylate_cyclase_typ10	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR029787	Nucleotide_cyclase	Homologous_superfamily

Pfam: PF00211

Enzyme classification (BRENDA):

• EC 4.6.1.1 — adenylate cyclase (BRENDA: 120 organisms, 167 substrates, 404 inhibitors, 155 Km, 27 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0005–8.78	135
MGATP2-	0.009–2.2	4
MNATP2-	0.067–0.086	2
ADENYLIMIDODIPHOSPHATE	0.33	1
CAMP	14	1
DATP	0.44	1
DEOXYCAMP	13	1
DIPHOSPHATE	1.9	1
GTP	1.38	1

Catalyzed reactions (Rhea), 1 shown:

• ATP = 3’,5’-cyclic AMP + diphosphate (RHEA:15389)

UniProt features (71 total): helix 21, strand 18, binding site 14, splice variant 6, turn 3, domain 2, sequence variant 2, mutagenesis site 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

37 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
4CLF	X-RAY DIFFRACTION	1.7
4CLL	X-RAY DIFFRACTION	1.7
4OYB	X-RAY DIFFRACTION	1.7
4OYI	X-RAY DIFFRACTION	1.7
4OYM	X-RAY DIFFRACTION	1.7
4OYW	X-RAY DIFFRACTION	1.7
4OZ3	X-RAY DIFFRACTION	1.7
4OYZ	X-RAY DIFFRACTION	1.74
4OYO	X-RAY DIFFRACTION	1.75
5IV4	X-RAY DIFFRACTION	1.79
4CM2	X-RAY DIFFRACTION	1.8
8B75	X-RAY DIFFRACTION	1.82
4CLS	X-RAY DIFFRACTION	1.85
5IV3	X-RAY DIFFRACTION	1.86
4OYX	X-RAY DIFFRACTION	1.89
4CLP	X-RAY DIFFRACTION	1.9
4CLU	X-RAY DIFFRACTION	1.9
4CLZ	X-RAY DIFFRACTION	1.9
4UST	X-RAY DIFFRACTION	1.9
8CO7	X-RAY DIFFRACTION	1.9
4CLT	X-RAY DIFFRACTION	1.95
4USU	X-RAY DIFFRACTION	1.95
8IL7	X-RAY DIFFRACTION	1.95
4USV	X-RAY DIFFRACTION	2
8CNH	X-RAY DIFFRACTION	2
4OYA	X-RAY DIFFRACTION	2.03
4CLY	X-RAY DIFFRACTION	2.05
4USW	X-RAY DIFFRACTION	2.05
4OZ2	X-RAY DIFFRACTION	2.1
8COJ	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96PN6-F1	81.17	0.29

Functional residue map

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

Ligand- & substrate-binding residues (14): 99; 144; 167; 176; 337; 406; 412–416; 47–52; 47; 47; 48; 95 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
95	nearly abolishes bicarbonate-mediated increase of enzyme activity. abolishes bicarbonate-mediated increase of enzyme act
176	reduces bicarbonate-mediated increase of enzyme activity. abolishes bicarbonate-mediated increase of enzyme activity; wh

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5610787	Hedgehog ‘off’ state
R-HSA-162582	Signal Transduction
R-HSA-5358351	Signaling by Hedgehog

MSigDB gene sets: 339 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CONTRACTION, GOBP_POSITIVE_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_BIOSYNTHETIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS, MAZ_Q6, GOBP_GROWTH, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CAMP_BIOSYNTHETIC_PROCESS, GOBP_MONOSACCHARIDE_CATABOLIC_PROCESS

GO Biological Process (30): epithelial cilium movement involved in extracellular fluid movement (GO:0003351), glucose catabolic process (GO:0006007), cAMP biosynthetic process (GO:0006171), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), spermatid development (GO:0007286), positive regulation of cardiac muscle hypertrophy (GO:0010613), positive regulation of cardiac muscle cell apoptotic process (GO:0010666), negative regulation of mitochondrial membrane potential (GO:0010917), intracellular signal transduction (GO:0035556), positive regulation of axon extension (GO:0045773), positive regulation of ossification (GO:0045778), positive regulation of glycogen catabolic process (GO:0045819), positive regulation of mitochondrial depolarization (GO:0051901), regulation of membrane repolarization (GO:0060306), neuron projection retraction (GO:0106028), negative regulation of cardiac muscle cell contraction (GO:0106135), regulation of mitophagy (GO:1901524), positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway (GO:1903378), negative regulation of reactive oxygen species biosynthetic process (GO:1903427), positive regulation of reactive oxygen species biosynthetic process (GO:1903428), obsolete positive regulation of protein targeting to mitochondrion (GO:1903955), positive regulation of vascular associated smooth muscle cell apoptotic process (GO:1905461), neuron projection extension (GO:1990138), neuron projection maintenance (GO:1990535), mitochondrial ATP transmembrane transport (GO:1990544), positive regulation of ATP biosynthetic process (GO:2001171), spermatogenesis (GO:0007283), cyclic nucleotide biosynthetic process (GO:0009190), positive regulation of apoptotic process (GO:0043065), positive regulation of intrinsic apoptotic signaling pathway (GO:2001244)

GO Molecular Function (9): magnesium ion binding (GO:0000287), adenylate cyclase activity (GO:0004016), ATP binding (GO:0005524), manganese ion binding (GO:0030145), ATPase binding (GO:0051117), bicarbonate binding (GO:0071890), nucleotide binding (GO:0000166), lyase activity (GO:0016829), metal ion binding (GO:0046872)

GO Cellular Component (21): extracellular region (GO:0005576), nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), cilium (GO:0005929), dendrite (GO:0030425), neuronal cell body (GO:0043025), apical part of cell (GO:0045177), basal part of cell (GO:0045178), perinuclear region of cytoplasm (GO:0048471), central region of growth cone (GO:0090724), astrocyte end-foot (GO:0097450), microtubule cytoskeleton (GO:0015630), membrane (GO:0016020), axon (GO:0030424), growth cone (GO:0030426), motile cilium (GO:0031514), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by Hedgehog	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	8
cytoplasm	3
intracellular anatomical structure	2
reactive oxygen species biosynthetic process	2
regulation of reactive oxygen species biosynthetic process	2
intracellular membrane-bounded organelle	2
neuron projection	2
cilium movement	1
extracellular transport	1
microtubule-based transport	1
glucose metabolic process	1
hexose catabolic process	1
purine ribonucleotide biosynthetic process	1
cyclic nucleotide biosynthetic process	1
cAMP metabolic process	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
germ cell development	1
spermatid differentiation	1
cardiac muscle hypertrophy	1
regulation of cardiac muscle hypertrophy	1
positive regulation of muscle hypertrophy	1
cardiac muscle cell apoptotic process	1
positive regulation of striated muscle cell apoptotic process	1
regulation of cardiac muscle cell apoptotic process	1
negative regulation of membrane potential	1
regulation of mitochondrial membrane potential	1
signal transduction	1
positive regulation of cell growth	1
regulation of axon extension	1
positive regulation of developmental growth	1
axon extension	1
positive regulation of axonogenesis	1
ossification	1
regulation of ossification	1
positive regulation of multicellular organismal process	1
glycogen catabolic process	1
regulation of glycogen catabolic process	1
positive regulation of catabolic process	1
positive regulation of glycogen metabolic process	1

Protein interactions and networks

STRING

2172 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADCY10	EZR	P15311	810
ADCY10	PRKACA	P17612	790
ADCY10	PRKACG	P22612	790
ADCY10	PRKACB	P22694	788
ADCY10	GALT	P07902	768
ADCY10	CHD7	Q9P2D1	768
ADCY10	SLC9C1	Q4G0N8	752
ADCY10	PYDC1	Q8WXC3	720
ADCY10	SDHC	Q99643	720
ADCY10	TFPI	P10646	708
ADCY10	PXDNL	A1KZ92	679
ADCY10	PXDN	Q92626	677
ADCY10	PKM	P14618	675
ADCY10	LIPA	P38571	674
ADCY10	SCAI	Q8N9R8	654

IntAct

5 interactions, top by confidence:

A	B	Type	Score
ADCY10	TPR	psi-mi:“MI:0915”(physical association)	0.400
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
ZNF692	IFI30	psi-mi:“MI:0914”(association)	0.350
ZNF692	U2SURP	psi-mi:“MI:0914”(association)	0.350

BioGRID (5): ADCY10 (Affinity Capture-MS), ADCY10 (Proximity Label-MS), ADCY10 (Affinity Capture-MS), ADCY10 (Affinity Capture-MS), TPR (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A140LIF8, A3QNZ8, A3QNZ9, A3QP00, A3QP01, A3QP07, A3QP08, A3QP09, A6H684, A6NIM6, E1BPQ3, E9Q4J9, E9Q6I0, O62714, O70410, P35384, P41180, P48442, Q28478, Q28660, Q3UX83, Q497L9, Q49HI0, Q5T6X5, Q5U9X3, Q6AYC2, Q6GV17, Q6TAC4, Q70VB1, Q7RTX1, Q811Q4, Q8IUA7, Q8K441, Q8K4Z6, Q8N139, Q8TE23, Q91ZE5, Q923K1, Q925D8, Q925I4

Diamond homologs: P0A4Y1, P0A4Y3, P40137, P40138, P59972, P63528, P9WQ28, P9WQ29, P9WQ30, P9WQ31, P9WQ32, P9WQ33, P9WQ34, P9WQ35, Q866F4, Q96PN6, Q9Z286, Q8C0T9

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
NF1	up-regulates	ADCY10
ADCY10	“up-regulates quantity”	“3’,5’-cyclic AMP”	“chemical modification”
hydrogencarbonate	“up-regulates activity”	ADCY10	“chemical activation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	12
Uncertain significance	323
Likely benign	155
Benign	120

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073111	NM_018417.6(ADCY10):c.1825G>T (p.Glu609Ter)	Pathogenic
1074185	NM_018417.6(ADCY10):c.581G>A (p.Trp194Ter)	Pathogenic
1075582	NM_018417.6(ADCY10):c.4438G>T (p.Glu1480Ter)	Pathogenic
1076639	NM_018417.6(ADCY10):c.4477del (p.Leu1493fs)	Pathogenic
1454870	NM_018417.6(ADCY10):c.952dup (p.Tyr318fs)	Pathogenic
1527348	GRCh37/hg19 1q23.3-24.3(chr1:162330810-171532331)	Pathogenic
1527359	GRCh37/hg19 1q24.2-24.3(chr1:167391422-171843613)	Pathogenic
155225	GRCh38/hg38 1q23.3-25.1(chr1:163382523-175877022)x1	Pathogenic
1942986	NM_018417.6(ADCY10):c.2779C>T (p.Arg927Ter)	Pathogenic
2060623	NM_018417.6(ADCY10):c.3961C>T (p.Arg1321Ter)	Pathogenic
2070996	NM_018417.6(ADCY10):c.325C>T (p.Arg109Ter)	Pathogenic
2154138	NM_018417.6(ADCY10):c.2859T>A (p.Cys953Ter)	Pathogenic
2161374	NM_018417.6(ADCY10):c.3823G>T (p.Glu1275Ter)	Pathogenic
2685754	GRCh37/hg19 1q23.3-25.1(chr1:164571371-175708060)x1	Pathogenic
2705159	NM_018417.6(ADCY10):c.3193_3302dup (p.Asn1101delinsLysArgLeuSerSerCysLeuTrpProThrIlePheTrpLeuTrpGluLysMetThrLysProTyrIleThrSerTer)	Pathogenic
3248011	NC_000001.10:g.(?167823571)(167823747_?)del	Pathogenic
3248012	NC_000001.10:g.(?167798485)(167798681_?)del	Pathogenic
3614616	NM_018417.6(ADCY10):c.3094dup (p.Glu1032fs)	Pathogenic
3659936	NM_018417.6(ADCY10):c.1738dup (p.Leu580fs)	Pathogenic
4703156	NM_018417.6(ADCY10):c.3629_3632del (p.Val1210fs)	Pathogenic
4775993	NM_018417.6(ADCY10):c.864del (p.Glu288fs)	Pathogenic
544683	NM_018417.6(ADCY10):c.1205_1206del (p.His402fs)	Pathogenic
60042	GRCh38/hg38 1q23.3-25.1(chr1:161740907-173965154)x1	Pathogenic
688465	GRCh37/hg19 1q23.3-24.2(chr1:163093021-168991239)x1	Pathogenic
846484	NM_018417.6(ADCY10):c.2101C>T (p.Gln701Ter)	Pathogenic
933870	NM_018417.6(ADCY10):c.2402del (p.Arg801fs)	Pathogenic
948647	NM_018417.6(ADCY10):c.4000C>T (p.Arg1334Ter)	Pathogenic
1066395	NM_018417.6(ADCY10):c.4168+1G>A	Likely pathogenic
1179048	NM_018417.6(ADCY10):c.2215G>T (p.Glu739Ter)	Likely pathogenic
2001177	NM_018417.6(ADCY10):c.253+1G>A	Likely pathogenic

SpliceAI

5224 predictions. Top by Δscore:

Variant	Effect	Δscore
1:167810723:A:AC	donor_gain	1.0000
1:167810724:C:CC	donor_gain	1.0000
1:167823006:A:AC	donor_gain	1.0000
1:167823006:AC:A	donor_gain	1.0000
1:167823007:C:CA	donor_gain	1.0000
1:167823007:CC:C	donor_gain	1.0000
1:167823007:CCAGA:C	donor_gain	1.0000
1:167823123:TC:T	acceptor_loss	1.0000
1:167823124:C:CC	acceptor_gain	1.0000
1:167823124:CTATG:C	acceptor_loss	1.0000
1:167823125:T:A	acceptor_loss	1.0000
1:167823126:A:C	acceptor_gain	1.0000
1:167824471:AATAC:A	donor_loss	1.0000
1:167824472:ATACC:A	donor_loss	1.0000
1:167824473:TAC:T	donor_loss	1.0000
1:167824474:ACCT:A	donor_loss	1.0000
1:167824475:C:A	donor_loss	1.0000
1:167824475:CCTG:C	donor_gain	1.0000
1:167824573:CT:C	acceptor_loss	1.0000
1:167824574:T:A	acceptor_loss	1.0000
1:167824645:CCTTA:C	donor_loss	1.0000
1:167824646:CTTA:C	donor_loss	1.0000
1:167824647:TTACC:T	donor_loss	1.0000
1:167824648:TACCT:T	donor_loss	1.0000
1:167824650:C:CT	donor_loss	1.0000
1:167824650:CCTAA:C	donor_gain	1.0000
1:167824654:A:C	donor_gain	1.0000
1:167824658:AATGG:A	donor_gain	1.0000
1:167834090:C:T	acceptor_gain	1.0000
1:167845561:A:AC	donor_gain	1.0000

AlphaMissense

10816 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:167901785:A:G	W105R	0.999
1:167901785:A:T	W105R	0.999
1:167878635:A:T	V406D	0.998
1:167883443:A:C	F338L	0.998
1:167883443:A:T	F338L	0.998
1:167883445:A:G	F338L	0.998
1:167878629:C:A	G408V	0.997
1:167883441:T:A	D339V	0.997
1:167901729:G:C	S123R	0.997
1:167901729:G:T	S123R	0.997
1:167901731:T:G	S123R	0.997
1:167901783:C:A	W105C	0.997
1:167901783:C:G	W105C	0.997
1:167901790:G:T	A103D	0.997
1:167901793:A:G	L102P	0.997
1:167901800:C:G	A100P	0.997
1:167903987:A:C	F51L	0.997
1:167903987:A:T	F51L	0.997
1:167903989:A:G	F51L	0.997
1:167878611:G:T	A414D	0.996
1:167878630:C:G	G408R	0.996
1:167880128:T:A	R401S	0.996
1:167880128:T:G	R401S	0.996
1:167880141:C:T	G397E	0.996
1:167883569:A:C	F296L	0.996
1:167883569:A:T	F296L	0.996
1:167883571:A:G	F296L	0.996
1:167901784:C:G	W105S	0.996
1:167901802:T:A	D99V	0.996
1:167901802:T:C	D99G	0.996

dbSNP variants (sampled 300 via entrez): RS1000010148 (1:167910092 G>T), RS1000024035 (1:167867244 G>A), RS1000029623 (1:167826439 C>T), RS1000089911 (1:167901732 A>G,T), RS1000092435 (1:167825766 G>A), RS1000115878 (1:167882943 G>T), RS1000117672 (1:167819429 C>G,T), RS1000139599 (1:167866881 C>T), RS1000145768 (1:167832211 G>C), RS1000164158 (1:167915915 A>G), RS1000178907 (1:167912949 C>G), RS1000193982 (1:167906713 C>T), RS1000209918 (1:167912704 C>G), RS1000278844 (1:167878971 C>T), RS1000330794 (1:167879277 G>A,T)

Disease associations

OMIM: gene MIM:605205 | disease phenotypes: MIM:143870, MIM:610163

GenCC curated gene-disease

Disease	Classification	Inheritance
hypercalciuria, absorptive, 2	Strong	Autosomal dominant
idiopathic inherited hypercalciuria	Supportive	Autosomal dominant

Mondo (4): hypercalciuria, absorptive, 2 (MONDO:0007748), immunodeficiency 25 (MONDO:0012426), male infertility (MONDO:0005372), (MONDO:0016352)

Orphanet (0):

HPO phenotypes

8 total (8 of 8 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0002150	Hypercalciuria
HP:0003529	Parathormone-independent increased renal tubular calcium reabsorption
HP:0004363	Abnormal circulating calcium concentration
HP:0008672	Calcium oxalate nephrolithiasis
HP:0012637	Renal calcium wasting

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D007248	Infertility, Male	C12.100.500.430; C12.100.750.700; C12.200.294.430
C562790	Hypercalciuria, Absorptive, 2 (supp.)
C565712	Immunodeficiency due to Defect in CD3-Zeta (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5854 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Adenylyl cyclases (ACs)

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
TDI-11861	Binding	8.85	pKd
KH7	Inhibition	5.52	pIC50
LRE1	Inhibition	5.0	pIC50

ChEMBL bioactivities

72 potent at pChembl≥5 of 73 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL5220685
8.96	Kd	1.1	nM	CHEMBL5219579
8.85	Kd	1.4	nM	CHEMBL5219830
8.77	Kd	1.7	nM	CHEMBL5220685
8.68	IC50	2.1	nM	CHEMBL5218878
8.68	Kd	2.1	nM	CHEMBL5218615
8.66	IC50	2.2	nM	CHEMBL5218552
8.64	Kd	2.3	nM	CHEMBL5220647
8.62	IC50	2.4	nM	CHEMBL5218615
8.60	Kd	2.5	nM	CHEMBL5218552
8.48	IC50	3.3	nM	CHEMBL5219579
8.48	IC50	3.33	nM	CHEMBL5219830
8.48	Kd	3.3	nM	CHEMBL5218698
8.44	Kd	3.6	nM	CHEMBL5218702
8.43	Kd	3.7	nM	CHEMBL5219443
8.41	IC50	3.9	nM	CHEMBL5218698
8.40	IC50	4	nM	CHEMBL5218702
8.34	IC50	4.6	nM	CHEMBL5220647
8.33	Kd	4.7	nM	CHEMBL5220632
8.26	IC50	5.5	nM	CHEMBL5219443
8.26	Kd	5.5	nM	CHEMBL5218878
8.17	IC50	6.7	nM	CHEMBL5220895
8.11	IC50	7.8	nM	CHEMBL5220347
7.91	IC50	12.3	nM	CHEMBL5220723
7.77	IC50	16.9	nM	CHEMBL5219922
7.68	IC50	21	nM	CHEMBL5219530
7.62	IC50	24.2	nM	CHEMBL5220632
7.55	IC50	28	nM	CHEMBL4878379
7.19	IC50	64	nM	CHEMBL5221008
7.17	IC50	67	nM	CHEMBL5220075
7.13	IC50	74	nM	CHEMBL4848035
7.06	IC50	87.1	nM	CHEMBL5221093
7.04	IC50	92	nM	CHEMBL4854762
6.99	IC50	102	nM	CHEMBL4848035
6.97	IC50	107	nM	CHEMBL4868801
6.95	IC50	112	nM	CHEMBL5219193
6.90	IC50	126	nM	CHEMBL4864668
6.88	IC50	132	nM	CHEMBL4857305
6.85	IC50	141	nM	CHEMBL4849033
6.80	IC50	160	nM	CHEMBL4854762
6.80	IC50	159	nM	CHEMBL4854762
6.75	Kd	175.6	nM	CHEMBL4854762
6.71	IC50	195	nM	CHEMBL4854762
6.71	IC50	196	nM	CHEMBL4849033
6.65	IC50	225	nM	CHEMBL4874288
6.49	IC50	325	nM	CHEMBL4866319
6.47	IC50	342	nM	CHEMBL4864843
6.46	IC50	351	nM	CHEMBL4867202
6.41	IC50	392	nM	CHEMBL4874288
6.41	IC50	389	nM	CHEMBL5219159

PubChem BioAssay actives

67 with measured affinity, of 96 total; 47 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
methyl (3R)-4-[2-[2-[[3-(2-amino-6-chloropyrimidin-4-yl)-1-(difluoromethyl)pyrazol-4-yl]methyl]phenoxy]ethyl]morpholine-3-carboxylate	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	0.0010	uM
[(2R)-4-[2-[2-[[3-(2-amino-6-chloropyrimidin-4-yl)-1-(difluoromethyl)pyrazol-4-yl]methyl]phenoxy]ethyl]morpholin-2-yl]methanol	1918569: Binding affinity to human recombinant His-tagged ADCY10 assessed as dissociation constant and measured for 600 sec by SPR analysis	kd	0.0011	uM
[(3R)-4-[2-[2-[[3-(2-amino-6-chloropyrimidin-4-yl)-1-(difluoromethyl)pyrazol-4-yl]methyl]phenoxy]ethyl]morpholin-3-yl]methanol	1918569: Binding affinity to human recombinant His-tagged ADCY10 assessed as dissociation constant and measured for 600 sec by SPR analysis	kd	0.0014	uM
4-[2-[2-[[3-(2-amino-6-chloropyrimidin-4-yl)-1-(difluoromethyl)pyrazol-4-yl]methyl]phenoxy]ethyl]piperazin-2-one	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	0.0021	uM
4-chloro-6-[1-(difluoromethyl)-4-[[2-[2-(1,1-dioxo-1,4-thiazinan-4-yl)ethoxy]phenyl]methyl]pyrazol-3-yl]pyrimidin-2-amine	1918569: Binding affinity to human recombinant His-tagged ADCY10 assessed as dissociation constant and measured for 600 sec by SPR analysis	kd	0.0021	uM
methyl (3S)-4-[2-[2-[[3-(2-amino-6-chloropyrimidin-4-yl)-1-(difluoromethyl)pyrazol-4-yl]methyl]phenoxy]ethyl]morpholine-3-carboxylate	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	0.0022	uM
[(3S)-4-[2-[2-[[3-(2-amino-6-chloropyrimidin-4-yl)-1-(difluoromethyl)pyrazol-4-yl]methyl]phenoxy]ethyl]morpholin-3-yl]methanol	1918569: Binding affinity to human recombinant His-tagged ADCY10 assessed as dissociation constant and measured for 600 sec by SPR analysis	kd	0.0023	uM
4-chloro-6-[1-(difluoromethyl)-4-[[2-(2-morpholin-4-ylethoxy)phenyl]methyl]pyrazol-3-yl]pyrimidin-2-amine	1918569: Binding affinity to human recombinant His-tagged ADCY10 assessed as dissociation constant and measured for 600 sec by SPR analysis	kd	0.0033	uM
1-[2-[2-[[3-(2-amino-6-chloropyrimidin-4-yl)-1-(difluoromethyl)pyrazol-4-yl]methyl]phenoxy]ethyl]-4-methylpiperidin-4-ol	1918569: Binding affinity to human recombinant His-tagged ADCY10 assessed as dissociation constant and measured for 600 sec by SPR analysis	kd	0.0036	uM
[(2S)-4-[2-[2-[[3-(2-amino-6-chloropyrimidin-4-yl)-1-(difluoromethyl)pyrazol-4-yl]methyl]phenoxy]ethyl]morpholin-2-yl]methanol	1918569: Binding affinity to human recombinant His-tagged ADCY10 assessed as dissociation constant and measured for 600 sec by SPR analysis	kd	0.0037	uM
2-[2-[[3-(2-amino-6-chloropyrimidin-4-yl)-1-(difluoromethyl)pyrazol-4-yl]methyl]phenoxy]-1-morpholin-4-ylethanone	1918569: Binding affinity to human recombinant His-tagged ADCY10 assessed as dissociation constant and measured for 600 sec by SPR analysis	kd	0.0047	uM
4-chloro-6-[1-methyl-4-[[2-[2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)ethoxy]phenyl]methyl]pyrazol-3-yl]pyrimidin-2-amine	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	0.0067	uM
4-chloro-6-[1-methyl-4-[[2-[2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy]phenyl]methyl]pyrazol-3-yl]pyrimidin-2-amine	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	0.0078	uM
4-chloro-6-[1-methyl-4-[[2-(2-morpholin-4-ylethoxy)phenyl]methyl]pyrazol-3-yl]pyrimidin-2-amine	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	0.0123	uM
4-[2-[2-[[3-(2-amino-6-chloropyrimidin-4-yl)-1-methylpyrazol-4-yl]methyl]phenoxy]ethyl]piperazin-2-one	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	0.0169	uM
methyl 2-[[3-(2-amino-6-chloropyrimidin-4-yl)-1-methylpyrazol-4-yl]methyl]benzoate	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	0.0210	uM
methyl 3-(2-amino-6-chloropyrimidin-4-yl)-4-benzyl-1-methylpyrazole-5-carboxylate	1779676: Inhibition of human soluble adenylyl cyclase assessed as reduction in cAMP levels in the presence of alpha-32p labeled ATP by biochemical assay	ic50	0.0280	uM
4-chloro-6-[4-[(2-chlorophenyl)methyl]-1-methylpyrazol-3-yl]pyrimidin-2-amine	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	0.0640	uM
4-chloro-6-[4-[(2-methoxyphenyl)methyl]-1-methylpyrazol-3-yl]pyrimidin-2-amine	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	0.0670	uM
4-chloro-6-[1,5-dimethyl-4-(thiophen-2-ylmethyl)pyrazol-3-yl]pyrimidin-2-amine	1779676: Inhibition of human soluble adenylyl cyclase assessed as reduction in cAMP levels in the presence of alpha-32p labeled ATP by biochemical assay	ic50	0.0740	uM
4-chloro-6-[1-methyl-4-[(2-phenoxyphenyl)methyl]pyrazol-3-yl]pyrimidin-2-amine	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	0.0871	uM
4-(4-benzyl-1,5-dimethylpyrazol-3-yl)-6-chloropyrimidin-2-amine	1779678: Inhibition of human soluble adenylyl cyclase transfected (4-4 clones)in human HEK293 cells assessed as reduction in cAMP levels preincubated for 5 mins with test compounds in the presence of IBMX by ELISA	ic50	0.0920	uM
4-chloro-6-[4-[(3-chlorophenyl)methyl]-1,5-dimethylpyrazol-3-yl]pyrimidin-2-amine	1779676: Inhibition of human soluble adenylyl cyclase assessed as reduction in cAMP levels in the presence of alpha-32p labeled ATP by biochemical assay	ic50	0.1070	uM
4-(3-benzylpyrazolo[1,5-a]pyridin-2-yl)-6-chloropyrimidin-2-amine	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	0.1120	uM
4-chloro-6-[4-[(3-fluorophenyl)methyl]-1,5-dimethylpyrazol-3-yl]pyrimidin-2-amine	1779676: Inhibition of human soluble adenylyl cyclase assessed as reduction in cAMP levels in the presence of alpha-32p labeled ATP by biochemical assay	ic50	0.1260	uM
4-chloro-6-[4-[(2-fluorophenyl)methyl]-1-methylpyrazol-3-yl]pyrimidin-2-amine	1779676: Inhibition of human soluble adenylyl cyclase assessed as reduction in cAMP levels in the presence of alpha-32p labeled ATP by biochemical assay	ic50	0.1320	uM
4-chloro-6-[1-methyl-4-(thiophen-2-ylmethyl)pyrazol-3-yl]pyrimidin-2-amine	1779676: Inhibition of human soluble adenylyl cyclase assessed as reduction in cAMP levels in the presence of alpha-32p labeled ATP by biochemical assay	ic50	0.1410	uM
4-chloro-6-[4-[(3-fluorophenyl)methyl]-1-methylpyrazol-3-yl]pyrimidin-2-amine	1779678: Inhibition of human soluble adenylyl cyclase transfected (4-4 clones)in human HEK293 cells assessed as reduction in cAMP levels preincubated for 5 mins with test compounds in the presence of IBMX by ELISA	ic50	0.2250	uM
4-chloro-6-[1,5-dimethyl-4-(pyrazol-1-ylmethyl)pyrazol-3-yl]pyrimidin-2-amine	1779676: Inhibition of human soluble adenylyl cyclase assessed as reduction in cAMP levels in the presence of alpha-32p labeled ATP by biochemical assay	ic50	0.3250	uM
4-chloro-6-[4-[(4-fluorophenyl)methyl]-1-methylpyrazol-3-yl]pyrimidin-2-amine	1779676: Inhibition of human soluble adenylyl cyclase assessed as reduction in cAMP levels in the presence of alpha-32p labeled ATP by biochemical assay	ic50	0.3420	uM
4-chloro-6-[4-[(3-methoxyphenyl)methyl]-1-methylpyrazol-3-yl]pyrimidin-2-amine	1779676: Inhibition of human soluble adenylyl cyclase assessed as reduction in cAMP levels in the presence of alpha-32p labeled ATP by biochemical assay	ic50	0.3510	uM
4-chloro-6-[4-[(3-chlorophenyl)methyl]-1-methylpyrazol-3-yl]pyrimidin-2-amine	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	0.3890	uM
methyl 3-[[3-(2-amino-6-chloropyrimidin-4-yl)-1-methylpyrazol-4-yl]methyl]benzoate	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	0.4360	uM
4-[4-benzyl-1-(trifluoromethyl)pyrazol-3-yl]-6-chloropyrimidin-2-amine	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	0.4690	uM
4-chloro-6-[1-methyl-4-(1,3-thiazol-5-ylmethyl)pyrazol-3-yl]pyrimidin-2-amine	1779676: Inhibition of human soluble adenylyl cyclase assessed as reduction in cAMP levels in the presence of alpha-32p labeled ATP by biochemical assay	ic50	0.5760	uM
3-(2-amino-6-chloropyrimidin-4-yl)-4-benzyl-1-methylpyrazole-5-carboxylic acid	1779676: Inhibition of human soluble adenylyl cyclase assessed as reduction in cAMP levels in the presence of alpha-32p labeled ATP by biochemical assay	ic50	0.7000	uM
[(2R,3S,5R)-5-(6-aminopurin-9-yl)-2-methyloxolan-3-yl] [hydroxy(phosphonooxy)phosphoryl] hydrogen phosphate	366252: Inhibition of human recombinant soluble adenylyl cyclase	ic50	0.7000	uM
4-(3-benzylimidazo[1,2-a]pyridin-2-yl)-6-chloropyrimidin-2-amine	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	0.7160	uM
4-[4-benzyl-1-(difluoromethyl)pyrazol-3-yl]-6-chloropyrimidin-2-amine	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	0.8290	uM
4-(4-benzyl-1-methylpyrazol-3-yl)-6-chloropyrimidin-2-amine	1779676: Inhibition of human soluble adenylyl cyclase assessed as reduction in cAMP levels in the presence of alpha-32p labeled ATP by biochemical assay	ic50	0.9890	uM
[2-[(8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethyl] 4-bromobenzenesulfonate	366252: Inhibition of human recombinant soluble adenylyl cyclase	ic50	1.1000	uM
2-[[3-(2-amino-6-chloropyrimidin-4-yl)-1-methylpyrazol-4-yl]methyl]-N-methylbenzamide	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	1.2450	uM
6-chloro-4-N-cyclopropyl-4-N-(thiophen-2-ylmethyl)pyrimidine-2,4-diamine	1779676: Inhibition of human soluble adenylyl cyclase assessed as reduction in cAMP levels in the presence of alpha-32p labeled ATP by biochemical assay	ic50	1.5000	uM
[3-(2-amino-6-chloropyrimidin-4-yl)-4-benzyl-1-methylpyrazol-5-yl]methanol	1779676: Inhibition of human soluble adenylyl cyclase assessed as reduction in cAMP levels in the presence of alpha-32p labeled ATP by biochemical assay	ic50	1.6400	uM
3-[[3-(2-amino-6-chloropyrimidin-4-yl)-1-methylpyrazol-4-yl]methyl]-N-methylbenzamide	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	1.8760	uM
4-chloro-6-[4-[(4-chlorophenyl)methyl]-1-methylpyrazol-3-yl]pyrimidin-2-amine	1918566: Inhibition of human ADCY10 assessed as cAMP accumulation preincubated for 15 mins followed by substrate addition using alpha-32P labelled ATP as substrate by sequential chromatographic analysis	ic50	2.5770	uM
(8R,9S,13S,14S,17S)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-2,3,17-triol	366252: Inhibition of human recombinant soluble adenylyl cyclase	ic50	3.0000	uM

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	2
Aflatoxin B1	increases methylation, decreases expression, decreases methylation	2
aristolochic acid I	increases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
sodium arsenite	affects methylation	1
aflatoxin B2	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
Atrazine	increases expression	1
Bicarbonates	increases expression	1
Formaldehyde	increases expression	1
Methapyrilene	decreases expression, increases methylation	1
Tobacco Smoke Pollution	increases expression	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

14 unique, capped per target: 14 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4839263	Binding	Inhibition of human soluble adenylyl cyclase assessed as reduction in cAMP levels in the presence of alpha-32p labeled ATP by biochemical assay	Discovery of TDI-10229: A Potent and Orally Bioavailable Inhibitor of Soluble Adenylyl Cyclase (sAC, ADCY10). — ACS Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02202382	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Male Infertility
NCT02204826	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Semen Parameters in Male Infertility Patients: a Randomized, Placebo-controlled, Double-blind Clinical Study
NCT03802864	PHASE4	COMPLETED	Post-operative Pain Control of Testicular Sperm Extraction Using Liposomal Bupivacaine
NCT06100432	PHASE4	ACTIVE_NOT_RECRUITING	Effect of Eurycoma Longifolia (DLBS5055) and Multivitamins (Vitamin C+Vitamin E+ β-carotene) for Infertile Males
NCT07523022	PHASE4	ENROLLING_BY_INVITATION	Comparison of the Effect of Gonadotropin and Clomiphene Citrate Treatment on Sperm Parameters and the Outcome of Assisted Reproductive Procedures in Subfertile Men Based on the APHRODITE Groups
NCT00975117	PHASE3	COMPLETED	Spermotrend in the Treatment of Male Infertility
NCT01407432	PHASE3	COMPLETED	Impact of Folates in the Care of the Male Infertility
NCT01895816	PHASE3	COMPLETED	Herbal Tonic Fertile Supplement(ZO2C5)
NCT02605070	PHASE3	TERMINATED	Pilot Study on the Effects of FSH Treatment on the Epigenetic Characteristics of Spermatozoa in Infertile Patients With Severe Oligozoospermia
NCT07402759	PHASE3	ACTIVE_NOT_RECRUITING	Impact of tdrd9 Gene Mutations in the Therapeutic Response to L-carnitine in Oligoasthenozoospermic Men
NCT01880086	PHASE2	COMPLETED	Clomiphene Citrate for the Treatment of Low Testosterone Associated With Chronic Opioid Pain Medication Administration
NCT02061384	PHASE2	COMPLETED	RA-2 13-cis Retinoic Acid (Isotretinoin)
NCT02421887	PHASE2	COMPLETED	Males, Antioxidants, and Infertility Trial
NCT05200663	PHASE2	UNKNOWN	Efficacy Comparison of Tamoxifen and Tamoxifen With Antioxidants on Semen Quality of Male With Idiopathic Infertility
NCT05290558	PHASE2	ACTIVE_NOT_RECRUITING	The Therapeutic Effects of Bu Shen Yi Jing Pill on Semen Quality in Sub Fertile Males: a Randomized Controlled Trial
NCT06091969	PHASE2	NOT_YET_RECRUITING	Supplementation for Male Subfertility
NCT01595308	PHASE1	COMPLETED	A Pilot Study to Evaluate the Effect of Pomegranate Juice on Semen Parameters in Healthy Male Volunteers
NCT02122211	PHASE1	COMPLETED	Choline Dehydrogenase and Sperm Function: Effects of Betaine
NCT02575924	PHASE1	UNKNOWN	Influence of Culture Media on Clinical Outcomes in Poor Responders or Severe Male Infertility
NCT01304927	PHASE2/PHASE3	COMPLETED	Vitamin D Supplementation and Male Infertility: The CBG-study a Randomized Clinical Trial
NCT02349945	PHASE2/PHASE3	COMPLETED	FSH Receptor Polymorphism p.N680S and Efficacy of FSH Therapy
NCT05222841	PHASE2/PHASE3	COMPLETED	The Effectiveness of Spermotrend Food Supplement in the Treatment of Male Infertility
NCT05616598	PHASE2/PHASE3	COMPLETED	Effect of New Oral Treatment for Hepatitis C Virus on Seminal Parameters
NCT02025270	PHASE1/PHASE2	COMPLETED	MSCs For Treatment of Azoospermic Patients
NCT04541459	EARLY_PHASE1	UNKNOWN	Validation of New Devices Against Ambient Electromagnetic Radiation
NCT05792813	EARLY_PHASE1	UNKNOWN	Efficacy and Safety of Linggui Yangyuan Paste in Patients With Male Infertility
NCT06188936	EARLY_PHASE1	COMPLETED	Home Semen Analysis Tests As a Screening Tool for Fertility Patients
NCT00012480	Not specified	COMPLETED	Effect of Environmental Exposures on the Egg Fertilizing Ability of Human Sperm
NCT00044369	Not specified	COMPLETED	Role of the Toxic Metal Cadmium in the Mechanism Producing Infertility With a Varicocele
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists
NCT00178516	Not specified	COMPLETED	Vitamin E and Male Infertility
NCT00315029	Not specified	COMPLETED	Patient-Centered Implementation Trial for Single Embryo Transfer
NCT00341120	Not specified	COMPLETED	Genetic Causes of Male Infertility
NCT00481403	Not specified	COMPLETED	Study of Sperm Molecular Factors Implicated in Male Fertility
NCT00548977	Not specified	COMPLETED	Genetic Studies Spermatogenic Failure
NCT00596739	Not specified	COMPLETED	A Study of the Pre- and Post-operative Semen Analyses and Reproductive Hormone Levels of Men Undergoing Weight-reduction Surgery
NCT00756561	Not specified	COMPLETED	HOP-2A - Intratesticular Hormone Levels
NCT00961558	Not specified	TERMINATED	Canadian Varicocelectomy Initiative (CVI): Effects on Male Fertility and Testicular Function of Varicocelectomy
NCT01075334	Not specified	UNKNOWN	Is a Carnitine Based Food Supplement (PorimoreTM) for Infertile Men Superior to Folate and Zinc With Regard to Pregnancy Rates in Intrauterine Insemination Cycles?
NCT01178463	Not specified	UNKNOWN	Spermatogonial Stem Cells in Azoospermic Patients: a Comparison Between Obstructive and Non-obstructive Azoospermia