ADCY7

Summary

ADCY7 (adenylate cyclase 7, HGNC:238) is a protein-coding gene on chromosome 16q12.1, encoding Adenylate cyclase type 7 (P51828). Adenylate cyclase that mediates formation of both cyclic AMP (cAMP) and cyclic di-AMP (c-di-AMP).

This gene encodes a membrane-bound adenylate cyclase that catalyses the formation of cyclic AMP from ATP and is inhibitable by calcium. The product of this gene is a member of the adenylyl cyclase class-4/guanylyl cyclase enzyme family that is characterized by the presence of twelve membrane-spanning domains in its sequences. Several transcript variants have been observed for this gene, but the full-length natures of only two have been determined so far.

Source: NCBI Gene 113 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 176 total — 2 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001114

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:238
Approved symbol	ADCY7
Name	adenylate cyclase 7
Location	16q12.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0037, AC7
Ensembl gene	ENSG00000121281
Ensembl biotype	protein_coding
OMIM	600385
Entrez	113

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 9 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000254235, ENST00000394697, ENST00000537579, ENST00000563677, ENST00000564044, ENST00000564965, ENST00000566433, ENST00000566761, ENST00000567277, ENST00000568731, ENST00000568930, ENST00000568933, ENST00000569265, ENST00000570187, ENST00000673801, ENST00000673973

RefSeq mRNA: 2 — MANE Select: NM_001114 NM_001114, NM_001286057

CCDS: CCDS10741, CCDS73882

Canonical transcript exons

ENST00000673801 — 26 exons

Exon	Start	End
ENSE00000821462	50313958	50314062
ENSE00000821465	50311693	50311786
ENSE00000821466	50310687	50310880
ENSE00000821476	50300715	50300873
ENSE00000901699	50298904	50299031
ENSE00000901705	50304360	50304551
ENSE00000901719	50312036	50312191
ENSE00000901721	50312890	50313036
ENSE00001141904	50291736	50291897
ENSE00001141912	50290457	50290660
ENSE00001519264	50315359	50318135
ENSE00002590216	50266551	50266680
ENSE00002666645	50287912	50288350
ENSE00003461074	50307050	50307147
ENSE00003467413	50294640	50294751
ENSE00003469996	50314292	50314406
ENSE00003505503	50308667	50308792
ENSE00003525668	50315014	50315138
ENSE00003534890	50305503	50305586
ENSE00003542443	50301082	50301214
ENSE00003583724	50304925	50304959
ENSE00003593106	50305777	50305849
ENSE00003604456	50292676	50292825
ENSE00003624720	50309548	50309646
ENSE00003669651	50293354	50293502
ENSE00003671405	50308327	50308411

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 97.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.2541 / max 254.4711, expressed in 1515 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153990	7.0173	1179
153992	3.5256	453
153989	2.7791	1123
153995	0.5393	153
153993	0.1690	70
153996	0.1042	39
153994	0.0826	31
153997	0.0370	29

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	97.09	gold quality
monocyte	CL:0000576	96.43	gold quality
mononuclear cell	CL:0000842	96.36	gold quality
leukocyte	CL:0000738	96.30	gold quality
blood	UBERON:0000178	93.41	gold quality
vermiform appendix	UBERON:0001154	91.03	gold quality
secondary oocyte	CL:0000655	90.72	gold quality
lymph node	UBERON:0000029	90.17	gold quality
bone marrow cell	CL:0002092	89.52	gold quality
spleen	UBERON:0002106	89.51	gold quality
skin of hip	UBERON:0001554	89.01	gold quality
bone marrow	UBERON:0002371	87.67	gold quality
gall bladder	UBERON:0002110	87.04	gold quality
caecum	UBERON:0001153	86.45	gold quality
upper leg skin	UBERON:0004262	86.44	gold quality
placenta	UBERON:0001987	86.33	gold quality
upper lobe of left lung	UBERON:0008952	86.30	gold quality
trabecular bone tissue	UBERON:0002483	86.14	gold quality
upper lobe of lung	UBERON:0008948	85.96	gold quality
epithelium of nasopharynx	UBERON:0001951	85.10	gold quality
nasopharynx	UBERON:0001728	85.08	gold quality
left ovary	UBERON:0002119	84.95	gold quality
oocyte	CL:0000023	84.89	gold quality
right ovary	UBERON:0002118	84.51	gold quality
synovial joint	UBERON:0002217	84.39	gold quality
ovary	UBERON:0000992	84.29	gold quality
lung	UBERON:0002048	84.21	gold quality
esophagus mucosa	UBERON:0002469	83.78	gold quality
esophagus squamous epithelium	UBERON:0006920	83.55	gold quality
tonsil	UBERON:0002372	83.35	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.30

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

106 targeting ADCY7, 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-3163	100.00	77.23	8605
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4789-5P	99.98	70.76	2721
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-548N	99.98	71.94	4170
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942

Literature-anchored findings (GeneRIF, showing 13)

• construction of soluble adenylyl cyclase from human membrane-bound type 7 adenylyl cyclase (PMID:11665607)
• The first cytoplasmic domain (residues 506-584) of adenylyl cyclase (AC) type VII is an internal regulatory subunit, interacting with a cardinal activator of AC (Gs alpha) and with the conserved first catalytic domain of type VII AC. (PMID:15581358)
• Brain type VII adenylyl cyclase isoform plays a sex-specific role in the manifestation of a heritable form of depressive symptoms in genetically modified mice. (PMID:17135423)
• AC7 is a specific downstream effector of the G(12/13) pathway (PMID:18541530)
• soluble adenylyl cyclase is responsive to both CO(2) and bicarbonate ion (PMID:19008230)
• we found that single nucleotide polymorphisms in ADCY7 associate with alcohol dependence in women, and these markers are also associated with ADCY7 expression (messenger RNA) levels. (PMID:21481845)
• evidence implicates ADCY7 in the modulation of mood regulatory neural mechanisms and, possibly, risk for and pathophysiology of depression. (PMID:22264442)
• The stronger TNF-alpha responses in young males compared to females may be partly associated with male-specific down-regulation of ADCY7 and ADCY9. (PMID:25959651)
• The ADCY7 deficiency resulted in decreased cell growth, elevated apoptosis, and lower c-Myc expression in cultured leukemia cells obtained from acute myeloid leukemia patients. (PMID:26220344)
• We discovered a 0.6% frequency missense variant in ADCY7. (PMID:28067910)
• AC7 and miR-192 might be new biomarkers and therapeutic targets for patients with relapsed acute promyelocytic leukemia. (PMID:30366671)
• Hsa_circ_0008234 facilitates proliferation of cutaneous squamous cell carcinoma through targeting miR-127-5p to regulate ADCY7. (PMID:34143288)
• CRISPR/Cas9 ADCY7 Knockout Stimulates the Insulin Secretion Pathway Leading to Excessive Insulin Secretion. (PMID:34177802)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	adcy7	ENSDARG00000060070
mus_musculus	Adcy7	ENSMUSG00000031659
rattus_norvegicus	Adcy7	ENSRNOG00000014776

Paralogs (17): GUCY1B1 (ENSG00000061918), GUCY2C (ENSG00000070019), ADCY2 (ENSG00000078295), GUCY2F (ENSG00000101890), NPR3 (ENSG00000113389), ADCY4 (ENSG00000129467), GUCY2D (ENSG00000132518), ADCY3 (ENSG00000138031), GUCY1A2 (ENSG00000152402), ADCY8 (ENSG00000155897), NPR2 (ENSG00000159899), ADCY9 (ENSG00000162104), GUCY1A1 (ENSG00000164116), ADCY1 (ENSG00000164742), NPR1 (ENSG00000169418), ADCY5 (ENSG00000173175), ADCY6 (ENSG00000174233)

Protein

Protein identifiers

Adenylate cyclase type 7 — P51828 (reviewed: P51828)

Alternative names: ATP pyrophosphate-lyase 7, Adenylate cyclase type VII, Adenylyl cyclase 7, Cyclic di-AMP synthase ADCY7

All UniProt accessions (8): A0A669KBF7, F5H4D1, F5H699, H3BMA5, H3BQ93, I3L2Y1, I3L3Q5, P51828

UniProt curated annotations — full annotation on UniProt →

Function. Adenylate cyclase that mediates formation of both cyclic AMP (cAMP) and cyclic di-AMP (c-di-AMP). Acts as a key mediator of G protein-coupled receptor signaling by catalyzing the formation of cAMP downstream of G protein-coupled receptors. Functions in G protein-coupled receptor signaling cascades activated by thrombin, sphingosine 1-phosphate, dopamine and anaphylatoxin C5a. Mediates regulation of cAMP synthesis through synergistic action of the G alpha protein G(s) (GNAS) with G(13) (GNA13). Also involved in inflammation by acting as a diadenylate cyclase that catalyzes the condensation of 2 ATP molecules into c-di-AMP. Following activation by TLR9, mediates formation of c-di-AMP, which directly activates NLRP3, thereby promoting assembly and maturation of the NLRP3 inflammasome. It is also required for the optimal functions of B- and T cells during adaptive immune responses by regulating cAMP synthesis in both B- and T-cells.

Subunit / interactions. Interacts with TLR9; leading to ADCY7 activation and synthesis of cyclic di-AMP (c-di-AMP).

Subcellular location. Membrane.

Post-translational modifications. Phosphorylated by PRKCD.

Activity regulation. Activated by G(s) G alpha protein (GNAS). Inhibited by G(i) G alpha protein GNAI1. Activated by GNA13 and GNA12. Ethanol and phorbol 12,13-dibutanoate significantly potentiate adenylate cyclase activity generated in response to the activation of the prostanoid receptor by the agonist prostaglandin E1(1-) in a PKC-dependent manner. Inhibited by lithium. Activated by TLR9, promoting synthesis of cyclic di-AMP (c-di-AMP).

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

Domain organisation. The protein contains two modules with six transmembrane helices each; both are required for catalytic activity. Isolated N-terminal or C-terminal guanylate cyclase domains have no catalytic activity, but when they are brought together, enzyme activity is restored. The active site is at the interface of the two domains. Both contribute substrate-binding residues, but the catalytic metal ions are bound exclusively via the N-terminal guanylate cyclase domain.

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

RefSeq proteins (2): NP_001105, NP_001272986 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001054	A/G_cyclase	Domain
IPR009398	Adcy_conserved_dom	Domain
IPR018297	A/G_cyclase_CS	Conserved_site
IPR029787	Nucleotide_cyclase	Homologous_superfamily
IPR030672	Adcy	Family
IPR032628	AC_N	Domain

Pfam: PF00211, PF06327, PF16214

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), 2 shown:

• ATP = 3’,5’-cyclic AMP + diphosphate (RHEA:15389)
• 2 ATP = 3’,3’-c-di-AMP + 2 diphosphate (RHEA:35655)

UniProt features (44 total): transmembrane region 12, binding site 12, region of interest 5, mutagenesis site 5, topological domain 3, glycosylation site 3, domain 2, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51828-F1	77.32	0.33

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 (12): 284–289; 284; 284; 285; 326–328; 328; 328; 372; 931; 1010–1012; 1017–1021; 1057

Glycosylation sites (3): 701, 776, 781

Mutagenesis-validated functional residues (5):

Position	Phenotype
477–482	does not affect camp biosynthetic process in response to sphingosine 1-phosphate stimulation. reduces by 40% camp biosyn
485–489	reduces camp biosynthetic process in response to c5 alpha chain stimulation and more severely in response to sphingosine
491–496	does not affect camp biosynthetic process in response to c5 alpha chain stimulation. reduces by 40?60% camp biosynthetic
494–499	does not affect camp biosynthetic process in response to c5 alpha chain stimulation. reduces by 40?60% camp biosynthetic
564–569	reduces camp biosynthetic process in response to c5 alpha chain stimulation and more severely in response to sphingosine

Function

Pathways and Gene Ontology

Reactome pathways

46 pathways

ID	Pathway
R-HSA-163359	Glucagon signaling in metabolic regulation
R-HSA-163615	PKA activation
R-HSA-164378	PKA activation in glucagon signalling
R-HSA-170660	Adenylate cyclase activating pathway
R-HSA-170670	Adenylate cyclase inhibitory pathway
R-HSA-418555	G alpha (s) signalling events
R-HSA-418594	G alpha (i) signalling events
R-HSA-418597	G alpha (z) signalling events
R-HSA-432040	Vasopressin regulates renal water homeostasis via Aquaporins
R-HSA-5610787	Hedgehog ‘off’ state
R-HSA-9634597	GPER1 signaling
R-HSA-9660821	ADORA2B mediated anti-inflammatory cytokines production
R-HSA-9664323	FCGR3A-mediated IL10 synthesis
R-HSA-9856530	High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells
R-HSA-111885	Opioid Signalling
R-HSA-111931	PKA-mediated phosphorylation of CREB
R-HSA-111933	Calmodulin induced events
R-HSA-111996	Ca-dependent events
R-HSA-111997	CaM pathway
R-HSA-112040	G-protein mediated events
R-HSA-112043	PLC beta mediated events
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-1430728	Metabolism
R-HSA-1489509	DAG and IP3 signaling
R-HSA-162582	Signal Transduction
R-HSA-163685	Integration of energy metabolism
R-HSA-1643685	Disease
R-HSA-372790	Signaling by GPCR

MSigDB gene sets: 401 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, MULLIGHAN_NPM1_SIGNATURE_3_UP, BROWNE_HCMV_INFECTION_6HR_DN, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_INFLAMMATORY_RESPONSE, GOBP_TOLL_LIKE_RECEPTOR_9_SIGNALING_PATHWAY, GOBP_RESPONSE_TO_FLUID_SHEAR_STRESS, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, REACTOME_G_ALPHA_Z_SIGNALLING_EVENTS, MODULE_45, GOBP_CELLULAR_RESPONSE_TO_FLUID_SHEAR_STRESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, MORI_IMMATURE_B_LYMPHOCYTE_UP

GO Biological Process (12): regulation of adaptive immune response (GO:0002819), renal water homeostasis (GO:0003091), cAMP biosynthetic process (GO:0006171), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), intracellular signal transduction (GO:0035556), maternal process involved in female pregnancy (GO:0060135), cellular response to lithium ion (GO:0071285), cellular response to ethanol (GO:0071361), cellular response to glucagon stimulus (GO:0071377), vascular endothelial cell response to laminar fluid shear stress (GO:0097700), negative regulation of cytokine production involved in inflammatory response (GO:1900016), cyclic nucleotide biosynthetic process (GO:0009190)

GO Molecular Function (6): adenylate cyclase activity (GO:0004016), ATP binding (GO:0005524), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), lyase activity (GO:0016829), phosphorus-oxygen lyase activity (GO:0016849)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-18 pathways:

Category	Pathways
GPCR downstream signalling	3
G-protein mediated events	2
Anti-inflammatory response favouring Leishmania parasite infection	2
Integration of energy metabolism	1
PKA-mediated phosphorylation of CREB	1
Glucagon signaling in metabolic regulation	1
Activation of GABAB receptors	1
Aquaporin-mediated transport	1
Signaling by Hedgehog	1
G alpha (s) signalling events	1
Response of endothelial cells to shear stress	1
G alpha (i) signalling events	1
Calmodulin induced events	1
CaM pathway	1
PLC beta mediated events	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
adaptive immune response	1
regulation of immune response	1
renal system process	1
multicellular organismal-level water homeostasis	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 activator activity	1
intracellular anatomical structure	1
signal transduction	1
female pregnancy	1
multicellular organismal reproductive process	1
response to lithium ion	1
cellular response to metal ion	1
response to ethanol	1
cellular response to alcohol	1
response to glucagon	1
cellular response to peptide hormone stimulus	1
cellular response to laminar fluid shear stress	1
vascular endothelial cell response to fluid shear stress	1
negative regulation of cytokine production	1
cytokine production involved in inflammatory response	1
regulation of cytokine production involved in inflammatory response	1
nucleotide biosynthetic process	1
cyclic nucleotide metabolic process	1
cyclase activity	1
phosphorus-oxygen lyase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
lyase activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1174 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADCY7	SLC5A2	P31639	903
ADCY7	SLC6A2	P23975	840
ADCY7	CALML5	Q9NZT1	533
ADCY7	RAPGEF4	Q8WZA2	531
ADCY7	GNB1	P04697	498
ADCY7	GNG7	O60262	495
ADCY7	BRD7	Q9NPI1	493
ADCY7	PDE4B	Q07343	485
ADCY7	PDE7B	Q9NP56	484
ADCY7	NKD1	Q969G9	474
ADCY7	GNAI1	P04898	461
ADCY7	CLBA1	Q96F83	457
ADCY7	GNB2	P11016	439
ADCY7	DRD3	P35462	436
ADCY7	ADCY1	Q08828	432
ADCY7	POLR1D	P0DPB6	432

IntAct

15 interactions, top by confidence:

A	B	Type	Score
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
ADCY7	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
XRCC6	ADCY7	psi-mi:“MI:0915”(physical association)	0.370
BUD31	ADCY7	psi-mi:“MI:0915”(physical association)	0.370
ADCY7	PLSCR1	psi-mi:“MI:0915”(physical association)	0.370
PIGH	ILVBL	psi-mi:“MI:0914”(association)	0.350
ZDHHC12	FAAH	psi-mi:“MI:0914”(association)	0.350
CXCR3	RIMOC1	psi-mi:“MI:0914”(association)	0.350
CXCR4	ESYT2	psi-mi:“MI:0914”(association)	0.350
S1PR3	STXBP3	psi-mi:“MI:0914”(association)	0.350
MFSD5	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC2A7	GPR89A	psi-mi:“MI:0914”(association)	0.350
SLC31A1	DENND11	psi-mi:“MI:0914”(association)	0.350
SLC9A3	ESYT3	psi-mi:“MI:0914”(association)	0.350

BioGRID (24): HIST1H2BH (Proximity Label-MS), ADCY7 (Affinity Capture-MS), ADCY7 (Affinity Capture-MS), ADCY7 (Affinity Capture-MS), ADCY7 (Affinity Capture-RNA), ADCY7 (Cross-Linking-MS (XL-MS)), ALDH5A1 (Co-fractionation), ALDH6A1 (Co-fractionation), AMIGO2 (Co-fractionation), DMWD (Co-fractionation), HACL1 (Co-fractionation), KCTD12 (Co-fractionation), MME (Co-fractionation), MST1R (Co-fractionation), PNPT1 (Co-fractionation)

ESM2 similar proteins: A0JMH2, A5K3F9, A6XGL0, A8IRK7, B0BNM1, B7QDG3, C3YDS7, D3ZEY4, D3ZU57, E2QRY6, E7FCP8, F6W8I0, F7DL67, F7FIH8, O14976, O88444, P16386, P51828, P52333, P52824, P53370, P70563, Q08828, Q0PIT9, Q17QN2, Q2KI13, Q2KI24, Q3TIU4, Q4R4T6, Q5GA22, Q5RAR6, Q5ZHX9, Q6AXQ5, Q6DHK1, Q6L8Q7, Q6P5E8, Q6QRN6, Q8CH40, Q8K2J9, Q8K4Z3

Diamond homologs: A0A0U1RPR8, A0A509APX1, B1Q257, E7EAU8, G5EEE9, O02740, O16544, O16715, O19179, O54865, O60503, O62179, P0A4Y1, P16065, P16066, P16067, P16068, P18293, P18910, P19686, P19687, P20594, P20595, P23897, P25092, P26770, P46197, P51828, P51830, P51839, P51840, P51841, P51842, P52785, P55202, P55203, P55204, P55205, P70106, P91550

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
NF1	up-regulates	ADCY7
ADCY7	“up-regulates quantity”	“3’,5’-cyclic AMP”	“chemical modification”
PRKCD	“up-regulates activity”	ADCY7	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	129
Likely benign	11
Benign	7

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
148654	GRCh38/hg38 16q12.1-12.2(chr16:49570553-53467065)x1	Pathogenic
59489	GRCh38/hg38 16q12.1(chr16:49740807-51876620)x1	Pathogenic

SpliceAI

4827 predictions. Top by Δscore:

Variant	Effect	Δscore
16:50288347:GGGG:G	donor_gain	1.0000
16:50288348:G:GT	donor_gain	1.0000
16:50288348:GGG:G	donor_gain	1.0000
16:50288349:GG:G	donor_gain	1.0000
16:50288349:GGG:G	donor_gain	1.0000
16:50288350:GG:G	donor_gain	1.0000
16:50288351:G:T	donor_loss	1.0000
16:50288352:T:G	donor_loss	1.0000
16:50288353:GAGT:G	donor_loss	1.0000
16:50290658:CAG:C	donor_loss	1.0000
16:50290659:AGGTA:A	donor_loss	1.0000
16:50290660:GG:G	donor_loss	1.0000
16:50290661:G:GA	donor_loss	1.0000
16:50290662:T:G	donor_loss	1.0000
16:50292668:A:AG	acceptor_gain	1.0000
16:50292669:C:G	acceptor_gain	1.0000
16:50292673:CA:C	acceptor_loss	1.0000
16:50292674:A:AG	acceptor_gain	1.0000
16:50292674:A:G	acceptor_loss	1.0000
16:50292674:AGCT:A	acceptor_gain	1.0000
16:50292675:G:GC	acceptor_gain	1.0000
16:50292675:GC:G	acceptor_gain	1.0000
16:50292675:GCT:G	acceptor_gain	1.0000
16:50292675:GCTG:G	acceptor_gain	1.0000
16:50292675:GCTGC:G	acceptor_gain	1.0000
16:50292821:AGCAG:A	donor_loss	1.0000
16:50292822:GCAG:G	donor_gain	1.0000
16:50292822:GCAGG:G	donor_loss	1.0000
16:50292823:CAGG:C	donor_loss	1.0000
16:50292824:AGG:A	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000025031 (16:50254565 G>A,C), RS1000048117 (16:50294012 C>A), RS1000121288 (16:50312450 C>G,T), RS1000164472 (16:50277426 G>A), RS1000183954 (16:50316571 C>T), RS1000278725 (16:50276235 C>T), RS1000311696 (16:50248481 C>T), RS1000314822 (16:50288338 C>T), RS1000323166 (16:50270996 C>G), RS1000340364 (16:50317054 G>A), RS1000358711 (16:50283473 C>T), RS1000360639 (16:50243144 C>T), RS1000378136 (16:50316783 C>CTTTT), RS1000391375 (16:50242942 G>A), RS1000463528 (16:50242800 G>A)

Disease associations

OMIM: gene MIM:600385 | disease phenotypes: MIM:107480, MIM:614844

GenCC curated gene-disease

Mondo (3): breast ductal adenocarcinoma (MONDO:0005590), Townes-Brocks syndrome (MONDO:0007142), nephronophthisis 14 (MONDO:0013916)

Orphanet (3): Syndromic anorectal malformation (Orphanet:117573), Joubert syndrome with oculorenal defect (Orphanet:2318), Townes-Brocks syndrome (Orphanet:857)

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001729_21	Crohn’s disease	6.000000e-209
GCST003097_44	Pediatric autoimmune diseases	6.000000e-09
GCST004131_82	Inflammatory bowel disease	2.000000e-12
GCST004133_49	Ulcerative colitis	3.000000e-13
GCST008658_1	Ulcerative colitis	1.000000e-14
GCST010571_64	Autoimmune thyroid disease	1.000000e-14
GCST90002381_88	Eosinophil count	1.000000e-11
GCST90002382_439	Eosinophil percentage of white cells	9.000000e-17

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
C536974	Townes-Brocks syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2097167 (PROTEIN FAMILY)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Adenylyl cyclases (ACs)

ChEMBL bioactivities

24 potent at pChembl≥5 of 24 total, top 24 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.06	Ki	0.88	nM	CHEMBL3142312
8.77	Ki	1.7	nM	CHEMBL3142318
8.77	Ki	1.7	nM	CHEMBL3142332
8.72	Ki	1.9	nM	CHEMBL3142329
8.60	Ki	2.5	nM	CHEMBL3142331
8.59	Ki	2.6	nM	CHEMBL2369777
8.41	Ki	3.9	nM	CHEMBL2369525
8.38	Ki	4.2	nM	CHEMBL2369778
8.11	Ki	7.8	nM	CHEMBL3142313
7.85	Ki	14	nM	CHEMBL66087
7.77	Ki	17	nM	CHEMBL418135
7.70	Ki	20	nM	CHEMBL293907
7.54	Ki	29	nM	CHEMBL305151
7.48	Ki	33	nM	CHEMBL62123
7.16	Ki	69	nM	CHEMBL305151
7.15	EC50	71	nM	(R)-SKF-38393
6.96	Ki	110	nM	CHEMBL62412
6.84	Ki	144	nM	CHEMBL64475
6.59	Ki	254	nM	CHEMBL62444
6.52	Ki	300	nM	CHEMBL62892
6.50	Ki	317	nM	CHEMBL64646
6.21	Ki	610	nM	CHEMBL418468
6.00	Ki	1000	nM	CHEMBL64955
5.28	EC50	5200	nM	CHEMBL57873

PubChem BioAssay actives

24 with measured affinity, of 52 total; 23 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
(4R,7S,10S,13S,16S)-N-[(2R)-1-[[(2R)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0009	uM
(4R,7S,10S,13S,16S)-N-[(2S)-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0017	uM
(4R,7S,10S,13S,16S)-N-[(2S)-1-[[(2R)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0017	uM
(4R,7S,10S,13S,16S)-N-[(2R)-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0019	uM
(4R,7S,10S,13S,16S)-N-[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34312: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0025	uM
(4R,7S,10S,13S,16R)-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-N-[(2S)-5-(diaminomethylideneamino)-1-[[(2S)-1,6-diamino-1-oxohexan-2-yl]amino]-1-oxopentan-2-yl]-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0026	uM
(2S)-N-[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-1-[(4R,7S,10S,13S,16R)-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]pyrrolidine-2-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0039	uM
(4R,7S,10S,13S,16R)-N-[(2S)-6-amino-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0042	uM
(2S)-2-[[(2S)-2-[[(4R,7S,10S,13S,16S)-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0078	uM
3-[[4-[1-[4-(2,4-dichlorophenyl)anilino]-1-oxooctan-2-yl]oxybenzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.0140	uM
3-[[4-[1-[4-(1-benzofuran-2-yl)anilino]-1-oxooctan-2-yl]oxybenzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.0170	uM
3-[[4-[2-[[4-(1-benzofuran-2-yl)phenyl]carbamoyl]octyl]benzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.0200	uM
3-[[4-[3-[4-(1-benzofuran-2-yl)anilino]-2-(4-tert-butylphenyl)-3-oxopropyl]benzoyl]amino]propanoic acid	34296: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.0290	uM
3-[[4-[2-(4-tert-butylphenyl)-3-[4-(2,4-dichlorophenyl)anilino]-3-oxopropyl]benzoyl]amino]propanoic acid	34296: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.0330	uM
(5R)-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol	34592: Compound was tested for the adenylate cyclase stimulation	ec50	0.0710	uM
3-[[4-[2-(4-tert-butylphenyl)-3-oxo-3-[4-(trifluoromethoxy)anilino]propyl]benzoyl]amino]propanoic acid	34296: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.1100	uM
3-[[4-[1-(4-tert-butylphenyl)-2-oxo-2-(4-phenylanilino)ethoxy]benzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.1440	uM
3-[[4-[[(4-tert-butylcyclohexyl)-[[4-(trifluoromethoxy)phenyl]carbamoyl]amino]methyl]benzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.2540	uM
3-[[4-[2-(4-tert-butylphenyl)-3-oxo-3-(4-phenylanilino)propyl]benzoyl]amino]propanoic acid	34296: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.3000	uM
4-[1-(4-tert-butylphenyl)-2-oxo-2-(4-phenylanilino)ethoxy]-N-(2H-tetrazol-5-yl)benzamide	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.3170	uM
3-[[4-[2-(4-tert-butylphenyl)-3-oxo-3-(quinolin-3-ylamino)propyl]benzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.6100	uM
3-[[4-[2-(4-tert-butylphenyl)-3-[4-(hydroxymethyl)anilino]-3-oxopropyl]benzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	1.0000	uM
2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol	34592: Compound was tested for the adenylate cyclase stimulation	ec50	5.2000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects expression, increases expression	4
(+)-JQ1 compound	decreases expression	3
Benzo(a)pyrene	affects methylation, increases expression	3
Air Pollutants	increases expression, affects cotreatment, decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cyclosporine	increases expression	2
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects expression, affects cotreatment	1
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
perfluorooctanoic acid	affects cotreatment, affects expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	decreases methylation	1
nickel sulfate	decreases expression	1
methacrylaldehyde	decreases expression, increases abundance, affects cotreatment	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	affects expression, affects cotreatment	1
CGP 52608	increases reaction, affects binding	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
perfluorobutanesulfonic acid	affects cotreatment, affects expression	1

ChEMBL screening assays

16 unique, capped per target: 14 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3284336	Binding	Agonist activity at adenylyl cyclase (unknown origin) at 1.35 x 10’-4 M	Synthesis of a fragment of human parathyroid hormore, hPTH-(44-68). — J Med Chem
CHEMBL645298	Functional	In vitro antagonist activity was measured by inhibition of vasopressin-stimulated adenylate cyclase in renal medullary preparation in pig	Dicarbavasopressin antagonist analogues exhibit reduced in vivo agonist activity. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1J4	Abcam HeLa ADCY7 KO	Cancer cell line	Female
CVCL_SB69	HAP1 ADCY7 (-) 1	Cancer cell line	Male
CVCL_XL06	HAP1 ADCY7 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery