ADCYAP1

Summary

ADCYAP1 (adenylate cyclase activating polypeptide 1, HGNC:241) is a protein-coding gene on chromosome 18p11.32, encoding Pituitary adenylate cyclase-activating polypeptide (P18509). PACAP is a neuropeptide involved in diverse array of physiological processes through activating the PACAP subfamily of class B1 G protein-coupled receptors: VIP receptor 1 (VIPR1), VIP receptor 2 (VIPR2), and PACAP type I receptor (ADCYAP1R1).

This gene encodes a secreted proprotein that is further processed into multiple mature peptides. These peptides stimulate adenylate cyclase and increase cyclic adenosine monophosphate (cAMP) levels, resulting in the transcriptional activation of target genes. The products of this gene are key mediators of neuroendocrine stress responses. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 116 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 131 total — 76 pathogenic, 2 likely-pathogenic
• MANE Select transcript: NM_001099733

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:241
Approved symbol	ADCYAP1
Name	adenylate cyclase activating polypeptide 1
Location	18p11.32
Locus type	gene with protein product
Status	Approved
Aliases	PACAP
Ensembl gene	ENSG00000141433
Ensembl biotype	protein_coding
OMIM	102980
Entrez	116

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 retained_intron

ENST00000269200, ENST00000450565, ENST00000579794, ENST00000581602, ENST00000961508

RefSeq mRNA: 2 — MANE Select: NM_001099733 NM_001099733, NM_001117

CCDS: CCDS11825

Canonical transcript exons

ENST00000450565 — 5 exons

Exon	Start	End
ENSE00000948525	907659	907790
ENSE00002234356	905386	905496
ENSE00002704276	904871	905060
ENSE00002715387	909446	912172
ENSE00003578951	908265	908363

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 94.81.

FANTOM5 (CAGE): breadth broad, TPM avg 2.9637 / max 310.0935, expressed in 367 samples.

FANTOM5 promoters (23 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169071	1.0585	205
169074	0.2333	84
169078	0.2208	75
169093	0.2060	116
169092	0.1482	48
169087	0.1322	30
169084	0.1276	50
169089	0.1146	45
169079	0.1103	47
169072	0.1062	46

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	94.81	gold quality
islet of Langerhans	UBERON:0000006	93.57	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.50	gold quality
hypothalamus	UBERON:0001898	81.14	gold quality
prefrontal cortex	UBERON:0000451	80.60	gold quality
Brodmann (1909) area 9	UBERON:0013540	78.54	gold quality
gall bladder	UBERON:0002110	77.99	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	77.78	gold quality
cingulate cortex	UBERON:0003027	77.45	gold quality
ganglionic eminence	UBERON:0004023	77.41	gold quality
anterior cingulate cortex	UBERON:0009835	77.21	gold quality
right frontal lobe	UBERON:0002810	76.59	gold quality
frontal cortex	UBERON:0001870	76.17	gold quality
neocortex	UBERON:0001950	75.91	gold quality
Brodmann (1909) area 10	UBERON:0013541	75.91	silver quality
pancreas	UBERON:0001264	75.31	gold quality
vermiform appendix	UBERON:0001154	75.04	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	74.27	silver quality
right coronary artery	UBERON:0001625	74.23	gold quality
right lung	UBERON:0002167	72.22	gold quality
cerebral cortex	UBERON:0000956	72.07	gold quality
primary visual cortex	UBERON:0002436	71.05	gold quality
caecum	UBERON:0001153	70.20	gold quality
Brodmann (1909) area 23	UBERON:0013554	69.69	silver quality
middle temporal gyrus	UBERON:0002771	68.97	silver quality
cortical plate	UBERON:0005343	68.91	gold quality
Brodmann (1909) area 46	UBERON:0006483	67.21	silver quality
body of pancreas	UBERON:0001150	67.10	gold quality
inferior olivary complex	UBERON:0002127	66.99	silver quality
pons	UBERON:0000988	66.66	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-ENAD-27	yes	1213.45
E-GEOD-83139	yes	799.58
E-GEOD-81608	yes	781.45
E-MTAB-5061	yes	199.97
E-HCAD-31	yes	19.92
E-GEOD-81547	yes	15.96
E-CURD-46	yes	6.08
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, ESR1, FOS, GATA2, GATA4, JUN, JUNB, KLF6, NFIC, NKX2-1, NR4A1, NR4A3, NR5A1, PGR, PLAGL1, REST, TTF1, USF1

miRNA regulators (miRDB)

139 targeting ADCYAP1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-103A-3P	99.98	69.14	1595

Literature-anchored findings (GeneRIF, showing 40)

• Besides their presence and functions in the gut and the brain VIP and PACAP have distinct physiological roles in the genital tract. (PMID:11713978)
• PACAP might play a role in the regulation of colon cancer growth and modulation of T lymphocyte anti-tumoral response via the Fas-R/Fas-L apoptotic pathway (PMID:12409223)
• PACAP-27 phosphorylates mitogen activated protein kinase and increases VEGF expression in lung cancer cells (PMID:12409225)
• possible role for PACAP in the regulation of expression of genes encoding catecholamine-synthesizing enzymes in intra-adrenal pheochromocytomas (PMID:12573802)
• PACAP has a role in downregulating interferon gamma in the inflammatory response in the central nervous system (PMID:12754213)
• The PACAP, through PAC1, is a potent mediator of adult neural stem cell proliferation. (PMID:15048918)
• PACAP is a direct activator of polymorphonuclear neutrophils (PMNs) as well as an effective PMN priming agent that requires phospholipase C, extracellular signal-regulated kinase ERK, and p38 MAP kinase activities. (PMID:15356166)
• PACAP, PACAP receptor and tyrosine hydroxylase (TH) mRNAs in neuroblastomas (PMID:15518890)
• the PACAP precursor gene underwent adaptive changes during human origin and may have contributed to the formation of human cognition (PMID:15834139)
• both extracellular and intracellular calcium play key roles in PACAP proinflammatory activities in neutrophils (PMID:16148159)
• Results show that the combination of different amino terminal and intracellular loop 3 splicing variants in the PAC1 receptor dictates the ability of agonists, including PACAP and VIP, to activate signaling pathways. (PMID:16226889)
• PACAP27 specifically activates human neutrophils by activating formyl peptide receptor-like 1 (FPRL1). (PMID:16493055)
• review of the functional role of PACAP on the biological timing system [review] (PMID:16687279)
• VIP and PACAP stimulate the synthesis and release of adrenomedullary catecholamines, and all three subtypes of PACAP/VIP Rs mediate this effect, PAC(1)-Rs being coupled to AC, VPAC(1)-Rs to both AC and PLC, and VPAC(2)-Rs only to PLC. (PMID:16697281)
• observations provide additional evidence for a role of PACAP and PAC1 R in the events determining the outcome of prostate cancer (PMID:16888207)
• we provide evidence that genetic variants of the genes encoding PACAP and its receptor, PAC1, are associated with schizophrenia. (PMID:17387318)
• In this review PACAP plays an integrative role in glucose and energy homeostasis of multiple processes in several tissues. (PMID:17430174)
• the increase of glial PACAP immunoreactivity may be interpreted as part of a complex endogenous neuroprotective response in the pericontusional regions (PMID:17431645)
• structure of the N-terminal EC domain of the hPAC1-RS receptor in complex with the PACAP (6’-38’) peptide antagonist; identified hormone residues that are critical for binding to the N-terminal EC domain of PAC1-RS (PMID:17470806)
• The ability of PBMC to produce and to respond to PACAP might influence neuroimmune interactions that regulate pain and inflammation in chronic pancreatitis. (PMID:17962362)
• No evidence of an association of the PACAP gene with bipolar disorder I was found in this group of patients. (PMID:18349695)
• Novel stable PACAP analogs with potent activity towards the PAC1 receptor are reported. (PMID:18353507)
• PACAP and vasoactive intestinal polypeptide appear to play a role in maintenance of follicle viability as a consequence of the antiapoptotic effect (PMID:18782879)
• In African Americans, a non-synonymous single nucleotide polymorphism (i.e. an aspartic acid/glycine coding variant, rs2856966) within exon 2 of PACAP was significantly associated with sudden infant death syndrome (p = 0.004). (PMID:19120039)
• a novel mechanism of calmodulin in regulating PACAP signaling by possible interaction with the inactive state of PAC1 and VPAC2 receptors. (PMID:19269029)
• These data indicate that PACAP functionally can stimulate 5-HT release and promote the growth of the BON neuroendocrine tumor cell line. (PMID:19701709)
• Results suggest for the first time a role of FOS in PACAP-induced VIP gene expression in human NB-1 neuroblastoma cells. (PMID:19712974)
• PACAP signaling might contribute to the pathogenesis of MDD. (PMID:19914336)
• LH causes a transient stimulation of PACAP & PAC(1)-R expression & PACAP stimulates progesterone production in human luteinized granulosa cells, suggesting possible role of PACAP as a local ovarian regulator in luteinization. (PMID:19926922)
• These results suggest that p53 plays a pivotal role in decreased integrin-mediated extracellular matrix component expression in cisplatin-induced tubule cell apoptosis, and reveal a novel aspect of PACAP-mediated renoprotection. (PMID:20034524)
• PACAP markedly reduces oxidative DNA stress and hippocampal CA1 neuronal death following transient global ischemia. (PMID:20133634)
• Data suggest that promoter activity of the 80-bp fragment might be involved in the testis-specific gene expression of PACAP. (PMID:20500521)
• PACAP38-LI levels show sensitive change during normal pregnancy and delivery. Our findings suggest that the fetal organs actively synthesize PACAP. (PMID:20671407)
• Data describe neurons and nerve fibers of intestinal plexuses containing vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide and neuropeptide Y in pathologically changed parts of the large intestine in intestinal cancer. (PMID:20675276)
• hypermethylation in the ADCYAP1 promoter is responsible for the transcriptional silencing of the ADCYAP1 gene in cervical cancer cells (PMID:21109983)
• Our MALDI TOF and MALDI TOF/TOF spectrometry results show that PACAP38 is present in all of the follicular fluid samples, and PACAP-like immunoreactivity was also measured by radioimmunoassay. (PMID:21259400)
• data suggest that perturbations in the PACAP-PAC1 pathway are involved in abnormal stress responses underlying post-traumatic stress disorder (PMID:21350482)
• Pituitary adenylate cyclase-activating polypeptide 38 ameliorated renal tubular injury, and reduced oxidative injury (PMID:21383633)
• Addition of PACAP to human lung cancer cells significantly increases tyrosine phosphorylation of focal adhesion kinase (FAK) or paxillin. (PMID:21898124)
• We hypothesized that PACAP plays a role in the activation of parasympathetic cranial outflow during migraine attacks (PMID:22108610)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	adcyap1a	ENSDARG00000004015
danio_rerio	adcyap1b	ENSDARG00000027740
mus_musculus	Adcyap1	ENSMUSG00000024256
rattus_norvegicus	Adcyap1	ENSRNOG00000049882

Paralogs (2): GHRH (ENSG00000118702), VIP (ENSG00000146469)

Protein

Protein identifiers

Pituitary adenylate cyclase-activating polypeptide — P18509 (reviewed: P18509)

All UniProt accessions (1): P18509

UniProt curated annotations — full annotation on UniProt →

Function. PACAP is a neuropeptide involved in diverse array of physiological processes through activating the PACAP subfamily of class B1 G protein-coupled receptors: VIP receptor 1 (VIPR1), VIP receptor 2 (VIPR2), and PACAP type I receptor (ADCYAP1R1). Exerts neuroprotective and general cytoprotective effects due to anti-apoptotic, anti-inflammatory, and antioxidant actions. Promotes neuron projection development through the RAPGEF2/Rap1/B-Raf/ERK pathway. In chromaffin cells, induces long-lasting increase of intracellular calcium concentrations and neuroendocrine secretion. Involved in the control of glucose homeostasis, induces insulin secretion by pancreatic beta cells. PACAP exists in two bioactive forms from proteolysis of the same precursor protein, PACAP27 and PACAP38, which differ by eleven amino acid residues in the C-terminus.

Subcellular location. Secreted.

Similarity. Belongs to the glucagon family.

RefSeq proteins (2): NP_001093203, NP_001108 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000532	Glucagon_GIP_secretin_VIP	Domain
IPR046963	VIP/GHRH-like	Family

Pfam: PF00123

UniProt features (19 total): mutagenesis site 6, peptide 3, propeptide 2, modified residue 2, region of interest 2, signal peptide 1, sequence variant 1, helix 1, compositionally biased region 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
8E3X	ELECTRON MICROSCOPY	2.3
8E3Y	ELECTRON MICROSCOPY	2.3
7VQX	ELECTRON MICROSCOPY	2.74
9P94	ELECTRON MICROSCOPY	3
6P9Y	ELECTRON MICROSCOPY	3.01
6VN7	ELECTRON MICROSCOPY	3.2
7WBJ	ELECTRON MICROSCOPY	3.42
6M1I	ELECTRON MICROSCOPY	3.5
6LPB	ELECTRON MICROSCOPY	3.9
1GEA	SOLUTION NMR
2D2P	SOLUTION NMR
2JOD	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P18509-F1	63.64	0.11

Antibody-complex structures (SAbDab): 9 — 6LPB, 6M1I, 6P9Y, 6VN7, 7VQX, 7WBJ, 8E3X, 8E3Y, 9P94

Functional residue map

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

Post-translational modifications (2): 169, 158

Mutagenesis-validated functional residues (6):

Position	Phenotype
150	strongly reduced affinity for adcyap1r1.
151	strongly reduced affinity for adcyap1r1.
152	strongly reduced affinity for adcyap1r1.
153	strongly reduced affinity for adcyap1r1.
157	strongly reduced affinity for adcyap1r1.
158	strongly reduced affinity for adcyap1r1.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-187024	NGF-independant TRKA activation
R-HSA-418555	G alpha (s) signalling events
R-HSA-420092	Glucagon-type ligand receptors

MSigDB gene sets: 320 (showing top): YAATNRNNNYNATT_UNKNOWN, TAATAAT_MIR126, REACTOME_GLUCAGON_TYPE_LIGAND_RECEPTORS, MORF_FLT1, CAR_TNFRSF25, BENPORATH_ES_WITH_H3K27ME3, GOBP_REGULATION_OF_PHOSPHORYLATION, RORA1_01, TTTGTAG_MIR520D, GOBP_INSULIN_SECRETION, AAGCCAT_MIR135A_MIR135B, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_POSITIVE_REGULATION_OF_LYASE_ACTIVITY

GO Biological Process (22): adenylate cyclase-modulating G protein-coupled receptor signaling pathway (GO:0007188), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), activation of adenylate cyclase activity (GO:0007190), positive regulation of cytosolic calcium ion concentration (GO:0007204), neuropeptide signaling pathway (GO:0007218), cell-cell signaling (GO:0007267), female pregnancy (GO:0007565), regulation of G protein-coupled receptor signaling pathway (GO:0008277), insulin secretion (GO:0030073), neuron projection development (GO:0031175), regulation of protein localization (GO:0032880), positive regulation of GTPase activity (GO:0043547), negative regulation of cell cycle (GO:0045786), positive regulation of protein kinase activity (GO:0045860), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of growth hormone secretion (GO:0060124), positive regulation of ERK1 and ERK2 cascade (GO:0070374), positive regulation of chemokine (C-C motif) ligand 5 production (GO:0071651), positive regulation of cold-induced thermogenesis (GO:0120162), positive regulation of cAMP/PKA signal transduction (GO:0141163), nervous system development (GO:0007399), positive regulation of gene expression (GO:0010628)

GO Molecular Function (8): signaling receptor binding (GO:0005102), neuropeptide hormone activity (GO:0005184), pituitary adenylate cyclase activating polypeptide activity (GO:0016521), type 1 vasoactive intestinal polypeptide receptor binding (GO:0031891), type 2 vasoactive intestinal polypeptide receptor binding (GO:0031892), peptide hormone receptor binding (GO:0051428), hormone activity (GO:0005179), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), neuron projection (GO:0043005), perikaryon (GO:0043204)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Activation of TRKA receptors	1
GPCR downstream signalling	1
Class B/2 (Secretin family receptors)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	3
hormone activity	2
vasoactive intestinal polypeptide receptor binding	2
cellular anatomical structure	2
adenylate cyclase activity	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
positive regulation of adenylate cyclase activity	1
regulation of biological quality	1
cell communication	1
signaling	1
multi-organism reproductive process	1
multi-multicellular organism process	1
regulation of signal transduction	1
protein secretion	1
peptide hormone secretion	1
neuron development	1
plasma membrane bounded cell projection organization	1
intracellular protein localization	1
regulation of localization	1
GTPase activity	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
cell cycle	1
negative regulation of cellular process	1
regulation of cell cycle	1
positive regulation of protein phosphorylation	1
protein kinase activity	1
positive regulation of kinase activity	1
regulation of protein kinase activity	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
growth hormone secretion	1
regulation of growth hormone secretion	1
positive regulation of peptide hormone secretion	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
positive regulation of chemokine production	1

Protein interactions and networks

STRING

1744 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADCYAP1	VIPR1	P32241	999
ADCYAP1	ADCYAP1R1	P41586	999
ADCYAP1	VIPR2	P41587	998
ADCYAP1	SCT	P09683	932
ADCYAP1	GHRH	P01286	843
ADCYAP1	SCTR	P47872	831
ADCYAP1	PPIP5K2	O43314	789
ADCYAP1	PLAGL1	Q9UM63	776
ADCYAP1	GCG	P01275	725
ADCYAP1	IER3	P46695	706
ADCYAP1	PPIP5K1	Q6PFW1	700
ADCYAP1	TAC1	P20366	696
ADCYAP1	GAL	P22466	675
ADCYAP1	NPY	P01303	673
ADCYAP1	CRHR1	P34998	647

IntAct

17 interactions, top by confidence:

A	B	Type	Score
ADCYAP1	ADCYAP1R1	psi-mi:“MI:0407”(direct interaction)	0.560
APP	ADCYAP1	psi-mi:“MI:0915”(physical association)	0.560
CLU	ADCYAP1	psi-mi:“MI:0915”(physical association)	0.540
CLU	ADCYAP1	psi-mi:“MI:0403”(colocalization)	0.540
ADCYAP1	GGPS1	psi-mi:“MI:0914”(association)	0.530
ADCYAP1	DPP4	psi-mi:“MI:0194”(cleavage reaction)	0.440
FAP	ADCYAP1	psi-mi:“MI:0194”(cleavage reaction)	0.440
CFTR	ADCYAP1	psi-mi:“MI:0915”(physical association)	0.370
ADCYAP1	CETN3	psi-mi:“MI:0914”(association)	0.350
ADCYAP1	CCDC85C	psi-mi:“MI:0914”(association)	0.350
Gnb1	ADCYAP1	psi-mi:“MI:0915”(physical association)	0.320

BioGRID (54): AMD1 (Affinity Capture-MS), MKLN1 (Affinity Capture-MS), CETN3 (Affinity Capture-MS), NUCB1 (Affinity Capture-MS), GID4 (Affinity Capture-MS), COPRS (Affinity Capture-MS), CLNS1A (Affinity Capture-MS), PXDN (Affinity Capture-MS), COPS8 (Affinity Capture-MS), GID8 (Affinity Capture-MS), STK3 (Affinity Capture-MS), STK4 (Affinity Capture-MS), YPEL5 (Affinity Capture-MS), PM20D2 (Affinity Capture-MS), PCSK1N (Affinity Capture-MS)

ESM2 similar proteins: A0JMK6, A5A6J6, B9WZ56, C0HKY1, C0HM54, E1ZXU8, O12956, O35314, O35417, O70176, P01165, P01282, P01362, P05060, P05408, P06300, P06308, P10362, P12285, P12961, P13521, P13589, P16014, P16613, P17685, P17686, P18509, P18844, P20616, P23389, P27682, P30945, P41534, P41535, P41585, P45644, P48143, P48144, P81401, P85799

Diamond homologs: C6EVG1, C6EVG2, O70176, P01282, P01283, P04203, P04204, P0DJ94, P0DJ95, P13589, P16613, P18509, P20394, P26349, P32648, P39089, P41535, P45644, P48143, P48144, P63289, P63290, P63291, P81039, P81401, P84488, P84771, P84772, Q29W19, P09684, P09685, P41534, P41585, P42692, P48142, P63292, P81016, Q09169, Q60549, P01284

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ADCYAP1	up-regulates	VIPR1	binding
ADCYAP1	up-regulates	ADCYAP1R1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	76
Likely pathogenic	2
Uncertain significance	46
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
146225	GRCh38/hg38 18p11.32(chr18:148963-2221286)x3	Pathogenic
146582	GRCh38/hg38 18p11.32-11.31(chr18:148963-6086668)x1	Pathogenic
146636	GRCh38/hg38 18p11.32-11.31(chr18:131500-4421014)x3	Pathogenic
147395	GRCh38/hg38 18p11.32(chr18:148963-2313458)x1	Pathogenic
147704	GRCh38/hg38 18p11.32-11.22(chr18:180229-10762632)x1	Pathogenic
148011	GRCh38/hg38 18p11.32-11.21(chr18:148963-10900517)x1	Pathogenic
148017	GRCh38/hg38 18p11.32(chr18:148963-1949961)x1	Pathogenic
148382	GRCh38/hg38 18p11.32-11.21(chr18:118760-14089410)x4	Pathogenic
148383	GRCh38/hg38 18p11.32-11.21(chr18:118760-14089410)x1	Pathogenic
149895	GRCh38/hg38 18p11.32(chr18:149089-1754473)x1	Pathogenic
150126	GRCh38/hg38 18p11.32-11.22(chr18:118760-8999132)x1	Pathogenic
150597	GRCh38/hg38 18p11.32-11.31(chr18:118760-6275718)x1	Pathogenic
150684	GRCh38/hg38 18p11.32-11.31(chr18:149089-5276567)x1	Pathogenic
151749	GRCh38/hg38 18p11.32-11.21(chr18:136226-15175006)	Pathogenic
151983	GRCh38/hg38 18p11.32-11.31(chr18:118760-4470508)x1	Pathogenic
152369	GRCh38/hg38 18p11.32-11.31(chr18:136226-2994136)x1	Pathogenic
152548	GRCh38/hg38 18p11.32-11.21(chr18:118760-15024003)x1	Pathogenic
1526590	GRCh37/hg19 18p11.32-11.31(chr18:136226-6103499)	Pathogenic
152926	GRCh38/hg38 18p11.32-11.21(chr18:14316-14206225)x3	Pathogenic
152927	GRCh38/hg38 18p11.32-11.31(chr18:85432-7094700)x1	Pathogenic
153128	GRCh38/hg38 18p11.32-11.21(chr18:48782-14978076)x1	Pathogenic
153999	GRCh38/hg38 18p11.32-11.31(chr18:136226-4002983)x1	Pathogenic
155367	GRCh38/hg38 18p11.32-11.21(chr18:136226-15198991)x4	Pathogenic
155410	GRCh38/hg38 18p11.32-11.21(chr18:136226-14337134)x3	Pathogenic
155594	GRCh38/hg38 18p11.32-11.31(chr18:136226-4802275)x1	Pathogenic
160884	GRCh38/hg38 18p11.32-11.21(chr18:148963-14081888)x1	Pathogenic
1703623	GRCh37/hg19 18p11.32-11.23(chr18:136226-7131132)	Pathogenic
1807753	GRCh37/hg19 18p11.32-11.21(chr18:136227-11283184)x1	Pathogenic
1807830	GRCh37/hg19 18p11.32-11.23(chr18:136227-7218594)x1	Pathogenic
2446821	GRCh37/hg19 18p11.32-11.1(chr18:1-15400035)	Pathogenic

SpliceAI

836 predictions. Top by Δscore:

Variant	Effect	Δscore
18:905059:GG:G	donor_gain	1.0000
18:905060:GG:G	donor_gain	1.0000
18:905375:A:AG	acceptor_gain	1.0000
18:905376:T:G	acceptor_gain	1.0000
18:905379:T:A	acceptor_gain	1.0000
18:905381:C:CA	acceptor_gain	1.0000
18:905384:A:AG	acceptor_gain	1.0000
18:905385:G:GG	acceptor_gain	1.0000
18:905385:GA:G	acceptor_gain	1.0000
18:905385:GAAT:G	acceptor_gain	1.0000
18:905493:TCAGG:T	donor_loss	1.0000
18:905497:G:GA	donor_loss	1.0000
18:905498:T:G	donor_loss	1.0000
18:907645:C:CA	acceptor_gain	1.0000
18:907658:GGCCA:G	acceptor_gain	1.0000
18:908264:GA:G	acceptor_gain	1.0000
18:905056:GAAGG:G	donor_gain	0.9900
18:905061:G:GA	donor_loss	0.9900
18:905061:G:GG	donor_gain	0.9900
18:905062:T:G	donor_loss	0.9900
18:905135:G:GT	donor_gain	0.9900
18:905135:G:T	donor_gain	0.9900
18:905273:G:GT	donor_gain	0.9900
18:905375:ATCCT:A	acceptor_gain	0.9900
18:905384:AGAA:A	acceptor_loss	0.9900
18:905384:AGAAT:A	acceptor_gain	0.9900
18:905385:G:T	acceptor_loss	0.9900
18:905385:GAA:G	acceptor_gain	0.9900
18:905385:GAATG:G	acceptor_gain	0.9900
18:905497:G:GG	donor_gain	0.9900

AlphaMissense

1124 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:909513:T:C	F137L	0.998
18:909514:T:G	F137C	0.998
18:909515:C:A	F137L	0.998
18:909515:C:G	F137L	0.998
18:909538:G:C	R145P	0.998
18:909514:T:C	F137S	0.997
18:909541:A:T	K146I	0.997
18:909565:T:C	L154S	0.997
18:909542:A:C	K146N	0.996
18:909542:A:T	K146N	0.996
18:909562:A:G	Y153C	0.996
18:909534:T:G	Y144D	0.994
18:909549:G:C	A149P	0.994
18:909550:C:A	A149D	0.994
18:909561:T:C	Y153H	0.994
18:909528:A:C	S142R	0.993
18:909530:C:A	S142R	0.993
18:909530:C:G	S142R	0.993
18:909561:T:G	Y153D	0.993
18:909494:G:C	K130N	0.992
18:909494:G:T	K130N	0.992
18:909525:T:G	Y141D	0.992
18:909562:A:C	Y153S	0.991
18:909570:G:C	A156P	0.991
18:909505:A:T	D134V	0.990
18:909525:T:C	Y141H	0.990
18:909537:C:G	R145G	0.990
18:909544:A:C	Q147P	0.990
18:909574:T:A	V157D	0.990
18:909522:A:C	S140R	0.989

dbSNP variants (sampled 300 via entrez): RS1000146897 (18:910513 A>G), RS1000270789 (18:903347 C>T), RS1000401843 (18:912235 A>T), RS1000621347 (18:903631 G>A,T), RS1000752992 (18:912429 A>G), RS1001203323 (18:911273 G>C), RS1001357318 (18:911129 C>T), RS1001525363 (18:903900 T>A), RS1001654675 (18:911093 T>G), RS1002629931 (18:905414 G>A,C), RS1002666693 (18:904947 A>G), RS1003276926 (18:909900 A>T), RS1003668740 (18:906070 G>A), RS1003719735 (18:905832 A>C,G), RS1003751440 (18:905054 T>C)

Disease associations

OMIM: gene MIM:102980 | disease phenotypes: MIM:146390

GenCC curated gene-disease

Mondo (2): chromosome 18p deletion syndrome (MONDO:0007800), neurodevelopmental disorder (MONDO:0700092)

Orphanet (2): Monosomy 18p syndrome (Orphanet:1598), Partial deletion of the short arm of chromosome 18 syndrome (Orphanet:261974)

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001762_521	Obesity-related traits	3.000000e-06
GCST002688_5	Very long-chain saturated fatty acid levels (fatty acid 22:0)	9.000000e-06
GCST006623_1	Midgestational cytokine/chemokine levels (fetal genetic effect)	1.000000e-08
GCST007576_254	Chronotype	4.000000e-11
GCST010989_278	Body size at age 10	3.000000e-14
GCST90016669_8	Pancreas volume	4.000000e-09

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0006796	very long-chain saturated fatty acid measurement
EFO:0004747	protein measurement
EFO:0007650	soluble interleukin-2 receptor subunit alpha measurement
EFO:0007959	fetal genotype effect measurement
EFO:0007964	gestational serum measurement
EFO:0008328	chronotype measurement
EFO:0009819	comparative body size at age 10, self-reported

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
C538309	Chromosome 18p deletion syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

Binding affinities (BindingDB)

22 measured of 22 human assays (22 total across all organisms); most potent 22 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
PACAP(6-38)	KI	1.5 nM
PACAP(4-38)	KI	5 nM
PACAP(5-38)	KI	5 nM
PACAP(7-38)	KI	8 nM
[Phe2]PACAP(1-38)	KI	10 nM
[AcHis1,Phe2]PACAP(1-38)	KI	10 nM
[D-Phe2]PACAP-38	KI	10 nM
[AcHis1,DPhe2]PACAP(1-38)	KI	10 nM
PACAP(3-38)	KI	29 nM
PACAP(8-38)	KI	30 nM
PACAP(9-38)	KI	50 nM
PACAP(6-27)	KI	100 nM
[AcHis1,Phe2]PACAP(1-27)	KI	100 nM
PACAP(5-27)	KI	150 nM
PACAP(3-27)	KI	200 nM
[Phe2]PACAP(1-27)	KI	200 nM
[Asn3]PACAP(1-27)	KI	200 nM
[D-Phe2]PACAP-27	KI	300 nM
PACAP(4-27)	KI	500 nM
[AcHis1,DPhe2]PACAP(1-27)	KI	1000 nM
PACAP(8-27)	KI	1300 nM

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	3
belinostat	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression, decreases expression	2
Panobinostat	affects cotreatment, increases expression	2
arsenite	increases methylation	1
sodium arsenite	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases methylation	1
Decitabine	increases expression	1
Cyclic AMP	increases abundance, affects binding	1
Arsenates	affects cotreatment, increases expression	1
Arsenic	affects methylation	1
Atrazine	affects cotreatment, increases expression	1
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	1
Carmustine	decreases expression	1
Lead	affects expression	1
Progesterone	increases abundance	1
Triclosan	increases expression	1
1-Methyl-4-phenylpyridinium	decreases reaction, increases response to substance	1
Cyclosporine	decreases methylation	1
Aflatoxin B1	increases expression	1
Okadaic Acid	increases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice