ADCY6

Summary

ADCY6 (adenylate cyclase 6, HGNC:237) is a protein-coding gene on chromosome 12q13.12, encoding Adenylate cyclase type 6 (O43306). Catalyzes the formation of the signaling molecule cAMP downstream of G protein-coupled receptors.

This gene encodes a member of the adenylyl cyclase family of proteins, which are required for the synthesis of cyclic AMP. All members of this family have an intracellular N-terminus, a tandem repeat of six transmembrane domains separated by a cytoplasmic loop, and a C-terminal cytoplasmic domain. The two cytoplasmic regions bind ATP and form the catalytic core of the protein. Adenylyl cyclases are important effectors of transmembrane signaling pathways and are regulated by the activity of G protein coupled receptor signaling. This protein belongs to a small subclass of adenylyl cyclase proteins that are functionally related and are inhibited by protein kinase A, calcium ions and nitric oxide. A mutation in this gene is associated with arthrogryposis multiplex congenita.

Source: NCBI Gene 112 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lethal congenital contracture syndrome 8 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 223 total — 3 pathogenic
• Phenotypes (HPO): 24
• Druggable target: yes
• MANE Select transcript: NM_015270

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:237
Approved symbol	ADCY6
Name	adenylate cyclase 6
Location	12q13.12
Locus type	gene with protein product
Status	Approved
Aliases	AC6
Ensembl gene	ENSG00000174233
Ensembl biotype	protein_coding
OMIM	600294
Entrez	112

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 22 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000307885, ENST00000357869, ENST00000547260, ENST00000548351, ENST00000548820, ENST00000550422, ENST00000551435, ENST00000552090, ENST00000552099, ENST00000873895, ENST00000873896, ENST00000911287, ENST00000960695, ENST00000960696, ENST00000960697, ENST00000960698, ENST00000960699, ENST00000960700, ENST00000960701, ENST00000960702, ENST00000960703, ENST00000960704, ENST00000960705, ENST00000960706, ENST00000960707, ENST00000960708, ENST00000960709

RefSeq mRNA: 7 — MANE Select: NM_015270 NM_001390830, NM_001390831, NM_001412819, NM_001412820, NM_001412821, NM_001412822, NM_015270

CCDS: CCDS8767, CCDS8768

Canonical transcript exons

ENST00000357869 — 22 exons

Exon	Start	End
ENSE00000939500	48777104	48777231
ENSE00001272260	48773940	48774098
ENSE00001272273	48770766	48770970
ENSE00001272320	48774691	48774778
ENSE00001272373	48777410	48777521
ENSE00001272393	48778108	48778257
ENSE00001632940	48771710	48771973
ENSE00002349591	48782571	48783438
ENSE00003474356	48772295	48772424
ENSE00003482892	48777615	48777736
ENSE00003491346	48774402	48774518
ENSE00003498776	48772508	48772543
ENSE00003532472	48768937	48769061
ENSE00003552281	48776209	48776350
ENSE00003572552	48776428	48776586
ENSE00003579249	48775963	48776091
ENSE00003641807	48773469	48773647
ENSE00003643706	48775673	48775698
ENSE00003645168	48774957	48775054
ENSE00003689116	48775303	48775450
ENSE00003911001	48766194	48768716
ENSE00003911042	48788906	48789089

Expression profiles

Bgee: expression breadth ubiquitous, 212 present calls, max score 97.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.4371 / max 63.0455, expressed in 1407 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
130741	4.4371	1407

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	97.98	gold quality
heart left ventricle	UBERON:0002084	96.27	gold quality
right atrium auricular region	UBERON:0006631	96.12	gold quality
cardiac ventricle	UBERON:0002082	95.95	gold quality
mucosa of transverse colon	UBERON:0004991	95.71	gold quality
cardiac atrium	UBERON:0002081	95.40	gold quality
right coronary artery	UBERON:0001625	95.00	gold quality
heart	UBERON:0000948	94.90	gold quality
transverse colon	UBERON:0001157	94.88	gold quality
ascending aorta	UBERON:0001496	94.45	gold quality
stromal cell of endometrium	CL:0002255	94.42	gold quality
thoracic aorta	UBERON:0001515	94.38	gold quality
metanephros cortex	UBERON:0010533	94.14	gold quality
sural nerve	UBERON:0015488	94.07	gold quality
right ovary	UBERON:0002118	93.99	gold quality
body of stomach	UBERON:0001161	93.96	gold quality
left coronary artery	UBERON:0001626	93.71	gold quality
descending thoracic aorta	UBERON:0002345	93.67	gold quality
body of uterus	UBERON:0009853	93.57	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.53	gold quality
left ovary	UBERON:0002119	93.36	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.34	gold quality
aorta	UBERON:0000947	93.31	gold quality
body of pancreas	UBERON:0001150	93.15	gold quality
coronary artery	UBERON:0001621	93.07	gold quality
tibial nerve	UBERON:0001323	93.02	gold quality
rectum	UBERON:0001052	92.82	gold quality
omental fat pad	UBERON:0010414	92.76	gold quality
peritoneum	UBERON:0002358	92.71	gold quality
popliteal artery	UBERON:0002250	92.65	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-GEOD-36552	no	18.89
E-ANND-3	no	4.63

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 24)

• expression of nodular ADCY6, but not ADCY3, was lower than the expression of both in perinodular tissue, which may be part of the mechanisms occurring in the hyperfunctioning nodules (PMID:12782409)
• identified a single nucleotide polymorphism that may play a role in developing left ventricular hypertrophy (PMID:14871025)
• Raf1 potentiates drug-stimulated cyclic AMP accumulation in cells expressing adenyl cyclcase 6 after activation of multiple signaling pathways. (PMID:15470083)
• A2bR signals through adenylate cyclase (AC) 6 isoform in intestinal epithelial cells (PMID:16631311)
• AC6 overexpression in endothelial cells may have use as a means to enhance prostacyclin function and reduce endothelial barrier permeability. (PMID:16885208)
• Adenylyl cyclase V and adenylyl cyclase VI interacts with A-kinase anchoring protein 79 (AKAP79) in a complex that associates with protein kinase A forming a negative feedback loop that termporally regulates cAMP production. (PMID:16973443)
• These data show that, in an animal model that mimics key aspects of clinical congestive heart failure, cardiac gene transfer of ACVI increases function of the failing heart. (PMID:17007567)
• G protein betagamma subunits stimulate type V and VI adenylyl cyclases (PMID:17110384)
• Expression of a novel, relatively common variant of ADCY6 parallels an increase in adenylyl cyclase activity and adenylyl cyclase-mediated function in humans. (PMID:17916776)
• Parathyroid hormone communicates with IP(3)R via “cAMP junctions” that allow local delivery of a supramaximal concentration of cAMP to IP(3)R, directly increasing their sensitivity to IP(3). (PMID:18936250)
• The catalytic domains (C1 and C2) of adenylate cyclase 6 play a role in targeting adenylate cyclase 6 to lipid rafts. (PMID:19007881)
• Instead the knock down of the predominant subtype AC6 in HUVECs provided the first direct evidence that the Ca(2+)-mediated inhibition of AC6 accounts for the thrombin-induced decrease in cAMP levels. (PMID:19546162)
• In addition to its direct effect on renin gene transcription, PPARgamma “sensitizes” renin gene to cAMP via trans-activation of AC6 gene. (PMID:20861226)
• AC6 localizes in lipid raft fractions of bronchial airway smooth muscle where it is stimulated by beta2 adrenergic- and prostacyclin receptors and inhibited by divalent calcium ions. (PMID:21228062)
• Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects (PMID:24319099)
• LRs are essential not only for the proper membrane distribution and maintenance of AC5/6 activity but also for the regulation of D1R- and D5R-mediated AC signaling. (PMID:25049074)
• Sickle cell anemia patients carrying at least one allele of adcy6 rs3730070-G exhibited lower hemolytic rate than non-carriers in univariate analysis (p=0.006). (PMID:27067484)
• PDE8 is expressed in lipid rafts of human airway smooth muscle cells(HASM), where it specifically regulates beta2-adrenergic receptor/ AC6 signaling to modulate HASM responsiveness and airway remodeling in asthma. (PMID:29262264)
• model suggests Cys1004 in AC6 (subunit C2) and Cys174 in Galphas present at the AC-Galphas interface as the possible residues that might undergo reversible nitrosylation. Docking analysis predicted novel ligands of AC6 that include forskolin-based compounds and its derivatives. (PMID:29327289)
• rs3730071G/T and rs77913913G/T of ADCY6 were non-polymorphic with respect to HAPE. (PMID:29443612)
• Effect of Adenylyl Cyclase Type 6 on Localized Production of cAMP by beta-2 Adrenoceptors in Human Airway Smooth-Muscle Cells (PMID:31068382)
• Data found that direct binding of 4.1G to the N-terminus of AC6 (AC6-N) contributes to the plasma membrane association of AC6-N and the resulting suppression of AC6 cyclase activity. (PMID:31383768)
• Expanding the clinical and molecular spectrum of lethal congenital contracture syndrome 8 associated with biallelic variants of ADCY6. (PMID:31846058)
• Gene expression and DNA methylation analyses suggest that immune process-related ADCY6 is a prognostic factor of luminal-like breast cancer. (PMID:31886586)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	adcy6b	ENSDARG00000027797
danio_rerio	adcy6a	ENSDARG00000061445
mus_musculus	Adcy6	ENSMUSG00000022994
rattus_norvegicus	Adcy6	ENSRNOG00000054757

Paralogs (17): GUCY1B1 (ENSG00000061918), GUCY2C (ENSG00000070019), ADCY2 (ENSG00000078295), GUCY2F (ENSG00000101890), NPR3 (ENSG00000113389), ADCY7 (ENSG00000121281), ADCY4 (ENSG00000129467), GUCY2D (ENSG00000132518), ADCY3 (ENSG00000138031), GUCY1A2 (ENSG00000152402), ADCY8 (ENSG00000155897), NPR2 (ENSG00000159899), ADCY9 (ENSG00000162104), GUCY1A1 (ENSG00000164116), ADCY1 (ENSG00000164742), NPR1 (ENSG00000169418), ADCY5 (ENSG00000173175)

Protein

Protein identifiers

Adenylate cyclase type 6 — O43306 (reviewed: O43306)

Alternative names: ATP pyrophosphate-lyase 6, Adenylate cyclase type VI, Adenylyl cyclase 6, Ca(2+)-inhibitable adenylyl cyclase

All UniProt accessions (2): F8VZJ5, O43306

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the formation of the signaling molecule cAMP downstream of G protein-coupled receptors. Functions in signaling cascades downstream of beta-adrenergic receptors in the heart and in vascular smooth muscle cells. Functions in signaling cascades downstream of the vasopressin receptor in the kidney and has a role in renal water reabsorption. Functions in signaling cascades downstream of PTH1R and plays a role in regulating renal phosphate excretion. Functions in signaling cascades downstream of the VIP and SCT receptors in pancreas and contributes to the regulation of pancreatic amylase and fluid secretion. Signaling mediates cAMP-dependent activation of protein kinase PKA. This promotes increased phosphorylation of various proteins, including AKT. Plays a role in regulating cardiac sarcoplasmic reticulum Ca(2+) uptake and storage, and is required for normal heart ventricular contractibility. May contribute to normal heart function. Mediates vasodilatation after activation of beta-adrenergic receptors by isoproterenol. Contributes to bone cell responses to mechanical stimuli.

Subunit / interactions. Part of a complex containing AKAP5, ADCY5, PDE4C and PKD2. Interacts with RAF1. Interacts (via cytoplasmic N-terminus) with GNAS, GNB1 and GNG2.

Subcellular location. Cell membrane. Cell projection. Cilium. Stereocilium.

Tissue specificity. Detected in peripheral blood mononuclear leukocytes (at protein level). Detected in thyroid.

Post-translational modifications. Phosphorylation by RAF1 increases enzyme activity. Phosphorylation by PKA at Ser-662 inhibits the GNAS-mediated increase in catalytic activity. Phosphorylation by PKC at Ser-556, Ser-662 and Thr-919 inhibits catalytic activity.

Disease relevance. Lethal congenital contracture syndrome 8 (LCCS8) [MIM:616287] A form of lethal congenital contracture syndrome, an autosomal recessive disorder characterized by degeneration of anterior horn neurons, extreme skeletal muscle atrophy and congenital non-progressive joint contractures. The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth. LCCS8 is an axoglial form of arthrogryposis multiplex congenita, characterized by congenital distal joint contractures, reduced fetal movements, and severe motor paralysis leading to death early in the neonatal period. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by G(s) G alpha protein GNAS. Inhibited by G(i) G alpha protein GNAI1. Is further activated by the complex formed by GNB1 and GNG2. Activated by forskolin. Inhibited by calcium ions, already at micromolar concentrations. Inhibited by adenosine, AMP and their analogs. Phosphorylation by RAF1 results in its activation.

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.

Isoforms (2)

UniProt ID	Names	Canonical?
O43306-1	1	yes
O43306-2	2

RefSeq proteins (7): NP_001377759, NP_001377760, NP_001399748, NP_001399749, NP_001399750, NP_001399751, NP_056085* (*=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

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (38 total): transmembrane region 12, binding site 12, modified residue 5, topological domain 4, sequence variant 2, chain 1, glycosylation site 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43306-F1	76.33	0.31

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): 384–389; 384; 384; 385; 426–428; 428; 428; 472; 1031; 1105–1107; 1112–1116; 1152

Post-translational modifications (5): 54, 556, 576, 662, 919

Glycosylation sites (1): 793

Function

Pathways and Gene Ontology

Reactome pathways

49 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-381676	Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
R-HSA-400042	Adrenaline,noradrenaline inhibits insulin secretion
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

MSigDB gene sets: 455 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_RESPONSE_TO_PROSTAGLANDIN_E, GOBP_CELLULAR_RESPONSE_TO_LIPID, REACTOME_ADRENALINE_NORADRENALINE_INHIBITS_INSULIN_SECRETION, FISCHER_G1_S_CELL_CYCLE, GOBP_RESPONSE_TO_FLUID_SHEAR_STRESS, REACTOME_G_ALPHA_Z_SIGNALLING_EVENTS, GCANCTGNY_MYOD_Q6, GOBP_CELLULAR_RESPONSE_TO_FLUID_SHEAR_STRESS, GOBP_CELLULAR_RESPONSE_TO_PROSTAGLANDIN_STIMULUS, GOBP_CAMP_BIOSYNTHETIC_PROCESS, GOBP_NEUROGENESIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (18): renal water homeostasis (GO:0003091), cAMP biosynthetic process (GO:0006171), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), adenylate cyclase-activating dopamine receptor signaling pathway (GO:0007191), adenylate cyclase-activating serotonin receptor signaling pathway (GO:0007192), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), adenylate cyclase-inhibiting serotonin receptor signaling pathway (GO:0007198), negative regulation of neuron projection development (GO:0010977), intracellular signal transduction (GO:0035556), negative regulation of urine volume (GO:0035811), cellular response to glucagon stimulus (GO:0071377), cellular response to prostaglandin E stimulus (GO:0071380), cellular response to catecholamine stimulus (GO:0071870), vascular endothelial cell response to laminar fluid shear stress (GO:0097700), blood vessel diameter maintenance (GO:0097746), cellular response to vasopressin (GO:1904117), cellular response to forskolin (GO:1904322), cyclic nucleotide biosynthetic process (GO:0009190)

GO Molecular Function (9): adenylate cyclase activity (GO:0004016), protein kinase C binding (GO:0005080), ATP binding (GO:0005524), protein kinase binding (GO:0019901), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein binding (GO:0005515), lyase activity (GO:0016829), phosphorus-oxygen lyase activity (GO:0016849)

GO Cellular Component (5): plasma membrane (GO:0005886), cilium (GO:0005929), membrane (GO:0016020), stereocilium (GO:0032420), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
GPCR downstream signalling	3
G-protein mediated events	2
Regulation of insulin secretion	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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	2
adenylate cyclase-activating G protein-coupled receptor signaling pathway	2
cellular response to peptide hormone stimulus	2
cellular response to alcohol	2
cellular response to ketone	2
cellular anatomical structure	2
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 activator activity	1
G protein-coupled dopamine receptor signaling pathway	1
serotonin receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
Gi/o-coupled serotonin receptor activity	1
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1
G protein-coupled serotonin receptor signaling pathway	1
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
intracellular anatomical structure	1
signal transduction	1
regulation of urine volume	1
response to glucagon	1
response to prostaglandin E	1
cellular response to prostaglandin stimulus	1
cellular response to monoamine stimulus	1
response to catecholamine	1
cellular response to oxygen-containing compound	1
cellular response to laminar fluid shear stress	1
vascular endothelial cell response to fluid shear stress	1
vascular process in circulatory system	1
blood circulation	1
regulation of tube diameter	1
response to vasopressin	1
cellular response to lipid	1
response to forskolin	1
nucleotide biosynthetic process	1
cyclic nucleotide metabolic process	1

Protein interactions and networks

STRING

1240 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADCY6	AKAP5	P24588	826
ADCY6	STIM1	Q13586	790
ADCY6	PAIP2B	Q9ULR5	763
ADCY6	ATP1B3	P54709	763
ADCY6	ITPR2	Q14571	730
ADCY6	RAPGEF4	Q8WZA2	706
ADCY6	SLC1A1	P43005	703
ADCY6	AVPR2	P30518	662
ADCY6	CAV3	P56539	617
ADCY6	ADCY5	O95622	602
ADCY6	PRKACB	P22694	599
ADCY6	PRKACA	P17612	596
ADCY6	PRKACG	P22612	596
ADCY6	ADCY9	O60503	545
ADCY6	POLR1D	P0DPB6	542

IntAct

53 interactions, top by confidence:

A	B	Type	Score
NEUROG3	GXYLT2	psi-mi:“MI:0914”(association)	0.640
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
YIPF3	TMEM120B	psi-mi:“MI:0914”(association)	0.530
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.530
B4GAT1	ADCY6	psi-mi:“MI:0914”(association)	0.530
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
ADCY6	VAPA	psi-mi:“MI:0915”(physical association)	0.400
	ESYT2	psi-mi:“MI:0914”(association)	0.350
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
	SNAP23	psi-mi:“MI:0914”(association)	0.350
	HAX1	psi-mi:“MI:0914”(association)	0.350
SPAG16	ADCY6	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
TTMP	TMEM223	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
TSPAN15	TMEM223	psi-mi:“MI:0914”(association)	0.350
CHRNA4	TMEM223	psi-mi:“MI:0914”(association)	0.350
LGALS8	SLC22A23	psi-mi:“MI:0914”(association)	0.350
CHRNB2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
TMEM74	KLRG2	psi-mi:“MI:0914”(association)	0.350
EXTL3	CCDC85C	psi-mi:“MI:0914”(association)	0.350

BioGRID (86): ADCY6 (Affinity Capture-MS), ADCY6 (Affinity Capture-MS), ADCY6 (Affinity Capture-MS), ADCY6 (Affinity Capture-MS), ADCY6 (Affinity Capture-Western), ADCY6 (Affinity Capture-MS), ADCY6 (Affinity Capture-MS), ADCY6 (Affinity Capture-MS), ADCY6 (Affinity Capture-MS), ADCY6 (Affinity Capture-MS), ADCY6 (Affinity Capture-MS), ADCY6 (Affinity Capture-MS), ADCY6 (Affinity Capture-MS), ADCY6 (Affinity Capture-MS), ADCY6 (Affinity Capture-MS)

ESM2 similar proteins: A0A125YQS6, A0A125YY03, A0A7J6K338, A1Z7R6, A4IHK6, A5K9W3, G4SDH4, J9UD11, O43306, O60266, O75387, O76269, O76343, P14773, P30804, P48768, Q01341, Q03343, Q04400, Q0C8L9, Q0VCM6, Q41706, Q4D3E8, Q4X251, Q57VW6, Q5B0V6, Q5BKX6, Q5RF58, Q5ZMT9, Q6C520, Q6CGU8, Q7Z8U2, Q8BIV7, Q8BSM7, Q8CGA3, Q8K4S3, Q8K596, Q8N370, Q93380, Q93Z75

Diamond homologs: A0A078BQP2, A0A0U1RPR8, A8WPG9, A8XQC7, B1Q257, E7EAU8, G5EEE9, G5EFQ0, H2L002, N1NVB7, O02298, O02740, O16544, O16715, O19179, O43306, O54865, O62026, O62179, O75343, O95622, P0A4Y1, P11528, P16065, P16066, P16067, P16068, P18293, P18910, P19686, P19687, P20594, P20595, P22717, P23897, P25092, P30803, P30804, P33402, P40144

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
NF1	up-regulates	ADCY6
ADCY6	“up-regulates quantity”	“3’,5’-cyclic AMP”	“chemical modification”
GNB/GNG	“down-regulates activity”	ADCY6	binding
GNAI1	“down-regulates activity”	ADCY6	binding
GNAI2	“down-regulates activity”	ADCY6	binding
GNAI3	“down-regulates activity”	ADCY6	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 70 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
monoatomic ion transport	6	15.6×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	139
Likely benign	28
Benign	29

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
189260	NM_015270.5(ADCY6):c.3346C>T (p.Arg1116Cys)	Pathogenic
995839	NM_015270.5(ADCY6):c.1535+1G>A	Pathogenic
995840	NM_015270.5(ADCY6):c.3007G>A (p.Glu1003Lys)	Pathogenic

SpliceAI

3671 predictions. Top by Δscore:

Variant	Effect	Δscore
12:48768931:CCTCA:C	donor_loss	1.0000
12:48768932:CTCAC:C	donor_loss	1.0000
12:48768933:TCACC:T	donor_loss	1.0000
12:48768934:CA:C	donor_loss	1.0000
12:48769060:CC:C	acceptor_gain	1.0000
12:48769060:CCCT:C	acceptor_loss	1.0000
12:48769061:CC:C	acceptor_gain	1.0000
12:48769062:C:CC	acceptor_gain	1.0000
12:48769062:C:CG	acceptor_loss	1.0000
12:48769063:T:A	acceptor_loss	1.0000
12:48769067:G:GC	acceptor_gain	1.0000
12:48770762:TTACC:T	donor_loss	1.0000
12:48770763:TACCA:T	donor_loss	1.0000
12:48770764:A:AC	donor_gain	1.0000
12:48770764:A:T	donor_loss	1.0000
12:48770765:C:CT	donor_gain	1.0000
12:48770765:CCA:C	donor_gain	1.0000
12:48770765:CCAA:C	donor_gain	1.0000
12:48770765:CCAAT:C	donor_gain	1.0000
12:48770769:T:C	donor_gain	1.0000
12:48770966:ATAAT:A	acceptor_gain	1.0000
12:48770967:TAAT:T	acceptor_gain	1.0000
12:48770968:AAT:A	acceptor_gain	1.0000
12:48770969:AT:A	acceptor_gain	1.0000
12:48770971:C:CC	acceptor_gain	1.0000
12:48770972:T:A	acceptor_loss	1.0000
12:48770976:C:CT	acceptor_gain	1.0000
12:48770977:A:T	acceptor_gain	1.0000
12:48770979:C:CT	acceptor_gain	1.0000
12:48771705:AGTAC:A	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000211136 (12:48791130 C>T), RS1000467833 (12:48784097 A>G), RS1000590465 (12:48790778 G>A), RS1000717051 (12:48779425 CTACTGAG>C), RS1000914085 (12:48779591 G>A), RS1000937427 (12:48771860 A>G), RS1000968505 (12:48772116 G>A,C,T), RS1001019762 (12:48785758 C>A,T), RS1001101997 (12:48778821 G>A), RS1001255961 (12:48790811 C>T), RS1001328454 (12:48785919 T>C), RS1001969055 (12:48773811 C>T), RS1002014062 (12:48787626 C>T), RS1002500520 (12:48780324 C>T), RS1002574368 (12:48768369 TAAGA>T)

Disease associations

OMIM: gene MIM:600294 | disease phenotypes: MIM:616287, MIM:147920

GenCC curated gene-disease

Disease	Classification	Inheritance
lethal congenital contracture syndrome 8	Strong	Autosomal recessive
hypomyelination neuropathy-arthrogryposis syndrome	Supportive	Autosomal recessive

Mondo (3): lethal congenital contracture syndrome 8 (MONDO:0014570), Kabuki syndrome (MONDO:0016512), (MONDO:0017049)

Orphanet (1): Kabuki syndrome (Orphanet:2322)

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001252	Hypotonia
HP:0001284	Areflexia
HP:0001315	Reduced tendon reflexes
HP:0001349	Facial diplegia
HP:0001371	Flexion contracture
HP:0001376	Limitation of joint mobility
HP:0001522	Death in infancy
HP:0001558	Decreased fetal movement
HP:0001561	Polyhydramnios
HP:0001605	Vocal cord paralysis
HP:0001761	Pes cavus
HP:0001765	Hammertoe
HP:0002098	Respiratory distress
HP:0002936	Distal sensory impairment
HP:0003457	EMG abnormality
HP:0003577	Congenital onset
HP:0003693	Distal amyotrophy
HP:0003811	Neonatal death
HP:0005684	Distal arthrogryposis
HP:0007182	Peripheral hypomyelination
HP:0011968	Feeding difficulties
HP:0034197	Third trimester onset
HP:0200136	Oral-pharyngeal dysphagia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002595_10	Clozapine-induced agranulocytosis	1.000000e-06
GCST008163_120	Height	7.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537705	Kabuki 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)

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

Ligand	Action	Affinity	Parameter
NKY80	Inhibition	4.8	pIC50

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

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, affects cotreatment, affects expression, increases abundance	3
Valproic Acid	increases methylation, decreases expression	3
Nickel	decreases expression	2
Particulate Matter	increases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects cotreatment, affects expression	1
ginger extract	affects cotreatment, affects expression, increases abundance	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
sodium arsenite	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
perfluorooctanoic acid	affects cotreatment, affects expression	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	affects expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
perfluorobutanesulfonic acid	affects expression, affects cotreatment	1
bisphenol S	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Leflunomide	decreases expression	1
Arsenic	affects methylation	1
Ascorbic Acid	decreases expression	1
Benzo(a)pyrene	decreases methylation, affects methylation	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1
Cannabinoids	affects methylation, increases abundance	1
Carbamazepine	affects expression	1
Chelating Agents	affects binding, increases expression	1
Copper	affects binding, increases expression	1
Dexamethasone	affects cotreatment, decreases 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

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SB68	HAP1 ADCY6 (-) 1	Cancer cell line	Male
CVCL_XL05	HAP1 ADCY6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04722315	EARLY_PHASE1	COMPLETED	Study of Modified Atkins Diet in Kabuki Syndrome
NCT01314534	Not specified	COMPLETED	French Kabuki Syndrome Network. Epidemiology, Management of Patients and Research by Array-CGH
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT03547609	Not specified	COMPLETED	Assessment of Memory in Children With Kabuki Syndrom