AIP

Summary

AIP (AHR interacting HSP90 co-chaperone, HGNC:358) is a protein-coding gene on chromosome 11q13.2, encoding AH receptor-interacting protein (O00170). May play a positive role in AHR-mediated (aromatic hydrocarbon receptor) signaling, possibly by influencing its receptivity for ligand and/or its nuclear targeting.

The protein encoded by this gene is a receptor for aryl hydrocarbons and a ligand-activated transcription factor. The encoded protein is found in the cytoplasm as part of a multiprotein complex, but upon binding of ligand is transported to the nucleus. This protein can regulate the expression of many xenobiotic metabolizing enzymes. Also, the encoded protein can bind specifically to and inhibit the activity of hepatitis B virus. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 9049 — RefSeq curated summary.

At a glance

• Gene–disease (curated): growth hormone secreting pituitary adenoma 1 (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 1,167 total — 55 pathogenic, 17 likely-pathogenic
• Phenotypes (HPO): 167
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003977

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:358
Approved symbol	AIP
Name	AHR interacting HSP90 co-chaperone
Location	11q13.2
Locus type	gene with protein product
Status	Approved
Aliases	XAP2, ARA9, FKBP16, FKBP37
Ensembl gene	ENSG00000110711
Ensembl biotype	protein_coding
OMIM	605555
Entrez	9049

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 14 protein_coding, 1 retained_intron

ENST00000279146, ENST00000525341, ENST00000528641, ENST00000529797, ENST00000682324, ENST00000682659, ENST00000682699, ENST00000683237, ENST00000683856, ENST00000684006, ENST00000684657, ENST00000872352, ENST00000872353, ENST00000934217, ENST00000934218

RefSeq mRNA: 3 — MANE Select: NM_003977 NM_001302959, NM_001302960, NM_003977

CCDS: CCDS8168, CCDS91515, CCDS91516

Canonical transcript exons

ENST00000279146 — 6 exons

Exon	Start	End
ENSE00000823991	67489267	67489455
ENSE00001185840	67490788	67491103
ENSE00001185842	67490316	67490457
ENSE00003703875	67490038	67490214
ENSE00003705911	67487006	67487185
ENSE00003842753	67483026	67483257

Expression profiles

Bgee: expression breadth ubiquitous, 241 present calls, max score 97.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.9039 / max 218.8286, expressed in 1818 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115480	21.2306	1815
115481	9.6487	1770
115483	0.0246	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	97.50	gold quality
popliteal artery	UBERON:0002250	96.80	gold quality
tibial artery	UBERON:0007610	96.79	gold quality
descending thoracic aorta	UBERON:0002345	96.75	gold quality
thoracic aorta	UBERON:0001515	96.64	gold quality
right coronary artery	UBERON:0001625	96.62	gold quality
ascending aorta	UBERON:0001496	96.61	gold quality
aorta	UBERON:0000947	96.58	gold quality
left coronary artery	UBERON:0001626	96.29	gold quality
endocervix	UBERON:0000458	96.22	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.14	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.05	gold quality
lower esophagus	UBERON:0013473	96.02	gold quality
body of uterus	UBERON:0009853	95.98	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.90	gold quality
left ovary	UBERON:0002119	95.83	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.75	gold quality
monocyte	CL:0000576	95.72	gold quality
tibial nerve	UBERON:0001323	95.67	gold quality
right ovary	UBERON:0002118	95.48	gold quality
leukocyte	CL:0000738	95.47	gold quality
right lung	UBERON:0002167	95.46	gold quality
mononuclear cell	CL:0000842	95.40	gold quality
left uterine tube	UBERON:0001303	95.37	gold quality
mucosa of stomach	UBERON:0001199	95.29	gold quality
apex of heart	UBERON:0002098	95.28	gold quality
right lobe of thyroid gland	UBERON:0001119	95.07	gold quality
ectocervix	UBERON:0012249	95.05	gold quality
coronary artery	UBERON:0001621	95.02	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.92	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.68
E-CURD-112	no	2.49

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
AHR	Activation
ESR1	Repression
GREB1	Repression
NFKB2	Repression
RSF1	Repression
TFF1	Repression

Upstream regulators (CollecTRI, top): AHR, ESR1

miRNA regulators (miRDB)

14 targeting AIP, 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-4789-5P	99.98	70.76	2721
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6768-3P	99.14	67.38	1319
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-1245B-5P	98.88	66.55	576
HSA-MIR-3142	98.88	66.09	529
HSA-MIR-4736	97.96	65.89	1287
HSA-MIR-194-3P	97.36	65.96	1027

Literature-anchored findings (GeneRIF, showing 40)

• Two distinct regions of the immunophilin-like protein XAP2 regulate dioxin receptor function and interaction with hsp90 (PMID:11805120)
• XAP2 has a role in stabilization of the dioxin receptor (PMID:12837759)
• identified germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene in individuals with pituitary adenoma predisposition; AIP is an example of a low-penetrance tumor susceptibility gene (PMID:16728643)
• survivin-AIP complex may influence the cellular xenobiotic response to environmental toxin(s) and contribute to subcellular chaperone trafficking during cell death regulation (PMID:16807248)
• Small inhibitory RNA-mediated knockdown of XAP2 affects the stability of TRbeta1 and abrogates specifically TRbeta1-mediated (but not TRbeta2) activation of hypothalamic TRH transcription. (PMID:16936638)
• AIP mutations, of which nine new mutations are described here, occur in approximately 15% of familial isolated pituitary adenoma families (PMID:17244780)
• AIP mutations do not appear to play a prominent role in sporadic pituitary tumorigenesis in this population of European subjects (PMID:17299063)
• identification of a novel AIP mutation in a family with acromegaly, which further validates the role of this gene in human pituitary tumor predisposition (PMID:17341560)
• AIP contributes to pituitary adenoma predisposition in patients from Europe and the United States (PMID:17360484)
• Role of AIP in pituitary tumorigenesis. (PMID:17609395)
• present study reviews the current state of knowledge regarding the genes associated to inherited pituitary neoplasia, with a particular focus on the novel pituitary adenoma predisposing genes, CDKN1B and AIP [review] (PMID:17613551)
• Comprehensive study of a large Brazilian FIPA kindred with an E174 frameshift (E174fs) AIP mutation to assess clinical, hormonal, and radiological features in mutation carriers. (PMID:17893251)
• Somatic AIP mutations are not common in pituitary adenomas and suggest that such mutations are rare in other endocrine tumors as well. (PMID:17914118)
• mutations in AIP are not identified in sporadic pituitary adenomas of Canadian patients (PMID:17916996)
• A tumor-suppressor role for AIP and its involvement in familial acromegaly. (PMID:18381572)
• Germline AIP mutations can be found in children and adolescents with GH-secreting tumours, even in the absence of family history. (PMID:18410548)
• AIP mutations are rare in sporadic pituitary adenomas in a German population and occur independently from hormone secreting adenomas. (PMID:18484068)
• Large genomic deletions in AIP in pituitary adenoma predisposition. (PMID:18628514)
• Mutations in the CDKN1B and AIP genes are relatively uncommon in MEN1 mutation-negative multiple endocrine neoplasia I syndrome patients. (PMID:18710468)
• AIP is involved in the development of pituitary tumors, especially involving the somatomammotroph lineage. (PMID:19188737)
• The identification of the AIP-RET complex represents a starting point to study key cellular processes involved in RET-induced apoptosis. (PMID:19366855)
• effect of XAP2 on glucocorticoid receptor requires its interaction with Hsp90 through the TPR motif (PMID:19375531)
• AHR signalling may be differentially affected according to pituitary adenoma phenotype. (PMID:19556287)
• This kindred exemplifies the aggressive features of pituitary adenomas associated with AIP mutations, while genetic analyses among three R271W FIPA families indicate that R271W represents a mutational hotspot. (PMID:19684062)
• Germline AIP mutations are rare or do not exist in familial non-medullary thyroid cancer. (PMID:19794292)
• mutations in AIP are involved in pituitary adenomas (PMID:19883897)
• Directly targeting the apoptotic protease activating factor-1 pathway by transgenic overexpression or protein delivery of AIP, a specific Apaf-1 inhibitor, confers robust neuroprotection in a neonatal hypoxic-ischemic brain injury model. (PMID:19910549)
• data provide strong evidence for a new founder effect of the AIPR304X mutation in central Italy and the observed variations in disease severity point out the role of additional genetic or environmental factors in such kindreds. (PMID:20354355)
• Exonic, promoter, splice-site, and large deletion mutations in AIP are implicated in 31% of families in the Familial isolated pituitary adenoma cohort. (PMID:20506337)
• Germ-line mutations in aryl hydrocarbon receptor interacting protein have been found in about 3% of sporadic acromegalic Italian patients without finding a causative nucleotide change. (PMID:20530095)
• Data show that the frequency of non-functioning adrenal lesions in acromegaly is not associated with aryl hydrocarbon receptor interacting protein gene mutations. (PMID:20595802)
• loss of MEN1 and AIP is likely to be pathogenetically essential for hibernoma development. (PMID:21078971)
• Four contemporary Northern Irish families who presented with gigantism, acromegaly, or prolactinoma have the same mutation and haplotype associated with the mutated gene as a patient from the 18th century. (PMID:21208107)
• Familial isolated pituitary neoplasms is a heterogeneous condition, which may be associated with AIP mutation. (PMID:21340155)
• Loss of heterozygoty at the AIP locus might be a late event in a potential progression from hyperplastic to adenomatous tissue. (PMID:21450940)
• eight exonic SNPs were identified at the AIP locus, including three novel SNPs: T48T, L212L, and V302V (PMID:21512261)
• mutated in 41 pediatric somatotropinoma cases (review) (PMID:21546764)
• pituitary adenomas were diagnosed in 2/21 AIPmut-screened carriers; both had asymptomatic microadenomas (PMID:21753072)
• XAP2 exerts a negative effect on ERalpha transcriptional activity and may thus prevent ERalpha-dependent events. (PMID:21984905)
• Data show that MEN1 gene is the main target for genetic analysis in Multiple endocrine neoplasia type 1 (MEN1) syndrome, and suggest that in patients without MEN1 gene mutation, CDKN1B or AIP genes should also be tested. (PMID:22026581)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	aip	ENSDARG00000104437
mus_musculus	Aip	ENSMUSG00000024847
rattus_norvegicus	Aip	ENSRNOG00000022289
drosophila_melanogaster	CG1847	FBGN0030345
caenorhabditis_elegans		WBGENE00016966

Paralogs (1): AIPL1 (ENSG00000129221)

Protein

Protein identifiers

AH receptor-interacting protein — O00170 (reviewed: O00170)

Alternative names: Aryl-hydrocarbon receptor-interacting protein, HBV X-associated protein 2, Immunophilin homolog ARA9

All UniProt accessions (10): O00170, A0A804HIX8, A0A804HJ38, A0A804HJ46, A0A804HKH9, A0A804HKK3, A0A804HKL7, A0A804HKP8, E9PMH2, V9GYQ3

UniProt curated annotations — full annotation on UniProt →

Function. May play a positive role in AHR-mediated (aromatic hydrocarbon receptor) signaling, possibly by influencing its receptivity for ligand and/or its nuclear targeting. Cellular negative regulator of the hepatitis B virus (HBV) X protein.

Subunit / interactions. Interacts with RET in the pituitary gland; this interaction prevents the formation of the AIP-survivin complex.

Subcellular location. Cytoplasm.

Tissue specificity. Widely expressed. Higher levels seen in the heart, placenta and skeletal muscle. Not expressed in the liver.

Disease relevance. Pituitary adenoma 1, multiple types (PITA1) [MIM:102200] A form of pituitary adenoma, a neoplasm of the pituitary gland and one of the most common neuroendocrine tumors. Pituitary adenomas are clinically classified as functional and non-functional tumors, and manifest with a variety of features, including local invasion of surrounding structures and excessive hormone secretion. Functional pituitary adenomas are further classified by the type of hormone they secrete: growth hormone (GH)-secreting, prolactin (PRL)-secreting, adrenocorticotropin (ACTH)-secreting, thyroid- stimulating hormone (TSH)-secreting, and plurihormonal (GH and TSH) tumors. Familial and sporadic forms have been reported. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (3): NP_001289888, NP_001289889, NP_003968* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001179	PPIase_FKBP_dom	Domain
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR039663	AIP/AIPL1/TTC9	Family
IPR046357	PPIase_dom_sf	Homologous_superfamily
IPR056277	PPIase_AIP	Domain

Pfam: PF23322

UniProt features (43 total): helix 16, sequence variant 8, strand 7, turn 6, repeat 3, chain 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4APO	X-RAY DIFFRACTION	1.9
4AIF	X-RAY DIFFRACTION	2.01
8QMO	ELECTRON MICROSCOPY	2.76
7ZUB	ELECTRON MICROSCOPY	2.85
2LKN	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00170-F1	91.09	0.78

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 (1): 43

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-8937144	Aryl hydrocarbon receptor signalling
R-HSA-8950505	Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1430728	Metabolism
R-HSA-168256	Immune System
R-HSA-211859	Biological oxidations
R-HSA-211945	Phase I - Functionalization of compounds
R-HSA-447115	Interleukin-12 family signaling
R-HSA-449147	Signaling by Interleukins
R-HSA-9020591	Interleukin-12 signaling

MSigDB gene sets: 473 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, REACTOME_BIOLOGICAL_OXIDATIONS, MODY_HIPPOCAMPUS_POSTNATAL, TGCGCANK_UNKNOWN, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_PROTEIN_TARGETING, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, chr11q13, GOBP_PROTEIN_MATURATION, YY1_02, GOTZMANN_EPITHELIAL_TO_MESENCHYMAL_TRANSITION_DN, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_AND_BRAIN_QTL_TRANS, NIKOLSKY_BREAST_CANCER_11Q12_Q14_AMPLICON, GOMF_SIGNALING_RECEPTOR_BINDING, GOBP_PROTEIN_TARGETING_TO_MITOCHONDRION

GO Biological Process (4): obsolete protein targeting to mitochondrion (GO:0006626), xenobiotic metabolic process (GO:0006805), protein maturation (GO:0051604), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (8): transcription coactivator activity (GO:0003713), peptidyl-prolyl cis-trans isomerase activity (GO:0003755), aryl hydrocarbon receptor binding (GO:0017162), GAF domain binding (GO:0036004), obsolete unfolded protein binding (GO:0051082), transcription coregulator activity (GO:0003712), protein binding (GO:0005515), isomerase activity (GO:0016853)

GO Cellular Component (6): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), aryl hydrocarbon receptor complex (GO:0034751), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Phase I - Functionalization of compounds	1
Interleukin-12 signaling	1
Immune System	1
Metabolism	1
Biological oxidations	1
Signaling by Interleukins	1
Cytokine Signaling in Immune system	1
Interleukin-12 family signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
metabolic process	1
cellular response to xenobiotic stimulus	1
gene expression	1
protein metabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
cis-trans isomerase activity	1
catalytic activity, acting on a protein	1
signaling receptor binding	1
RNA polymerase II-specific DNA-binding transcription factor binding	1
protein domain specific binding	1
transcription regulator activity	1
binding	1
catalytic activity	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
signaling receptor complex	1
intracellular protein-containing complex	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

850 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AIP	HSP90AA1	P07900	995
AIP	HSP90AB1	P08238	995
AIP	SRC	P12931	921
AIP	TOMM20	Q15388	826
AIP	MEN1	O00255	711
AIP	GPR101	Q96P66	684
AIP	PPARA	Q07869	678
AIP	AHR	P35869	663
AIP	GNAS	Q5JWF2	638
AIP	AHRR	A9YTQ3	602
AIP	RSF1	Q96T23	595
AIP	GUCY2D	Q02846	591
AIP	CYP1A1	P04798	585
AIP	ARNT	P27540	566
AIP	NUB1	Q9Y5A7	556

IntAct

161 interactions, top by confidence:

A	B	Type	Score
AIP	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.830
HSP90AB1	AIP	psi-mi:“MI:0407”(direct interaction)	0.830
CDK9	AIP	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PKN3	ARHGAP10	psi-mi:“MI:0914”(association)	0.680
CCDC120	AIP	psi-mi:“MI:0914”(association)	0.640
CRIPTO	AIP	psi-mi:“MI:0914”(association)	0.640
AIP	PDE2A	psi-mi:“MI:0915”(physical association)	0.600
PDE2A	AIP	psi-mi:“MI:0915”(physical association)	0.600
PDE2A	AIP	psi-mi:“MI:0403”(colocalization)	0.600

BioGRID (257): GNAQ (Reconstituted Complex), AIP (Two-hybrid), AIP (PCA), AIP (Affinity Capture-Western), RET (Affinity Capture-Western), AIP (Affinity Capture-Western), AIP (Affinity Capture-MS), AIP (Affinity Capture-MS), AIP (Affinity Capture-MS), AIP (Co-fractionation), PPA1 (Co-fractionation), PPA2 (Co-fractionation), AIP (Affinity Capture-Western), AIP (Reconstituted Complex), AIP (Reconstituted Complex)

ESM2 similar proteins: A0A0D1E2P6, A0A0D2XVZ5, A0A0P0VG31, A0AVF1, A2WYG9, A4III8, A4QP73, A8JA42, B5X0I6, C4NYP8, D3J162, F4JIN3, J9VKM5, O00170, O08915, O42668, O97628, P91240, Q0WT48, Q13217, Q17430, Q20255, Q27968, Q4R7Z9, Q54M21, Q5FWY5, Q5JJI4, Q5JNB5, Q5PR66, Q5U2N8, Q5ZI13, Q61LA1, Q6DKK2, Q7TT47, Q7XVN7, Q86DS1, Q8BS45, Q8CC21, Q8LQJ9, Q8S2A7

Diamond homologs: O00170, O08915, O35450, O97628, Q554J3, Q5FWY5, Q6MG81, Q7YRC1, Q924K1, Q95MN7, Q95MN8, Q95MN9, Q95MP0, Q95MP1, Q9JLG9, Q9NZN9, Q9QVC8, Q9UIM3, A4IFF3, K7TQE3, P15705, Q07617, Q28IV3, Q32PZ3, Q5RAP0, Q5U2X2, Q6NU95, Q6P5P3, Q80ZX8, Q810A3, Q8N5M4, Q99KD5, Q9BGT1, Q9C566, Q9H3U1, Q9LDC0, Q43207, Q9FJL3, Q9XSI2, O94826

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
AIP	“down-regulates quantity by repression”	TFF1	“transcriptional regulation”
AIP	“down-regulates activity”	ESR1	“transcriptional regulation”
AIP	“down-regulates quantity by repression”	GREB1	“transcriptional regulation”
CSNK2A1	unknown	AIP	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 133 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by ERBB2	6	23.3×	1e-04
FCGR3A-mediated IL10 synthesis	6	19.7×	2e-04
EPH-ephrin mediated repulsion of cells	5	12.3×	3e-03
Constitutive Signaling by Aberrant PI3K in Cancer	7	10.0×	8e-04
EPH-Ephrin signaling	5	9.3×	9e-03
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	8	8.7×	6e-04
PIP3 activates AKT signaling	9	6.8×	8e-04
G alpha (s) signalling events	8	6.6×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	9	31.9×	4e-09
cell surface receptor protein tyrosine kinase signaling pathway	12	17.5×	4e-09
ephrin receptor signaling pathway	5	14.4×	3e-03
protein autophosphorylation	11	13.4×	2e-07
determination of left/right symmetry	5	10.7×	8e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	13	8.6×	8e-07
protein phosphorylation	14	8.0×	6e-07
positive regulation of MAPK cascade	11	7.5×	4e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

1167 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	55
Likely pathogenic	17
Uncertain significance	603
Likely benign	374
Benign	16

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068574	NM_003977.4(AIP):c.504G>A (p.Trp168Ter)	Pathogenic
1076609	NM_003977.4(AIP):c.600del (p.Lys201fs)	Pathogenic
1076941	NM_003977.4(AIP):c.259C>T (p.Gln87Ter)	Pathogenic
1428442	NM_003977.4(AIP):c.343dup (p.Leu115fs)	Pathogenic
1437576	NM_003977.4(AIP):c.553G>T (p.Glu185Ter)	Pathogenic
1455922	NM_003977.4(AIP):c.673C>T (p.Gln225Ter)	Pathogenic
1457487	NC_000011.9:g.(?67250360)(67254666_?)del	Pathogenic
1751370	NM_003977.4(AIP):c.606C>G (p.Tyr202Ter)	Pathogenic
1760841	NM_003977.4(AIP):c.783C>G (p.Tyr261Ter)	Pathogenic
2023118	NM_003977.4(AIP):c.493C>T (p.Gln165Ter)	Pathogenic
2424799	NC_000011.9:g.(?67250360)(67258464_?)del	Pathogenic
2424800	NC_000011.9:g.(?67250360)(67250738_?)del	Pathogenic
2586854	NM_003977.4(AIP):c.361_362del (p.Cys121fs)	Pathogenic
2700398	NM_003977.4(AIP):c.874del (p.Leu292fs)	Pathogenic
2709292	NM_003977.4(AIP):c.252_253del (p.Glu84fs)	Pathogenic
2735673	NM_003977.4(AIP):c.427C>T (p.Gln143Ter)	Pathogenic
2735676	NM_003977.4(AIP):c.816del (p.Lys273fs)	Pathogenic
2870459	NM_003977.4(AIP):c.41_47del (p.Gln14fs)	Pathogenic
2874782	NM_003977.4(AIP):c.376C>T (p.Gln126Ter)	Pathogenic
3223609	NM_003977.4(AIP):c.338_341dup (p.Leu115fs)	Pathogenic
3223610	NM_003977.4(AIP):c.356_371del (p.Arg119fs)	Pathogenic
3223627	NM_003977.4(AIP):c.756_762dup (p.Ser255fs)	Pathogenic
3244751	NC_000011.9:g.(?67257767)(67258624_?)del	Pathogenic
3279548	NM_003977.4(AIP):c.200dup (p.Phe68fs)	Pathogenic
3649265	NM_003977.4(AIP):c.46del (p.Arg16fs)	Pathogenic
3650523	NM_003977.4(AIP):c.745G>T (p.Glu249Ter)	Pathogenic
3654758	NM_003977.4(AIP):c.107del (p.Phe36fs)	Pathogenic
3657603	NM_003977.4(AIP):c.792dup (p.Val265fs)	Pathogenic
41167	NM_003977.4(AIP):c.241C>T (p.Arg81Ter)	Pathogenic
41179	NM_003977.4(AIP):c.424C>T (p.Gln142Ter)	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

2175 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:67487108:T:C	F68L	0.999
11:67487110:C:A	F68L	0.999
11:67487110:C:G	F68L	0.999
11:67490071:T:A	W168R	0.999
11:67490071:T:C	W168R	0.999
11:67490073:G:C	W168C	0.999
11:67490073:G:T	W168C	0.999
11:67490173:T:C	Y202H	0.999
11:67490182:G:C	A205P	0.999
11:67490815:G:A	G272D	0.999
11:67487123:T:A	W73R	0.998
11:67487123:T:C	W73R	0.998
11:67490125:G:C	G186R	0.998
11:67490126:G:A	G186D	0.998
11:67490174:A:G	Y202C	0.998
11:67490195:T:C	L209P	0.998
11:67490374:T:C	L235P	0.998
11:67490378:C:A	N236K	0.998
11:67490378:C:G	N236K	0.998
11:67490382:T:C	C238R	0.998
11:67490384:C:G	C238W	0.998
11:67490390:C:G	C240W	0.998
11:67490798:G:C	K266N	0.998
11:67490798:G:T	K266N	0.998
11:67490810:G:C	K270N	0.998
11:67490810:G:T	K270N	0.998
11:67490812:G:C	R271P	0.998
11:67483257:G:C	K33N	0.997
11:67483257:G:T	K33N	0.997
11:67490094:G:C	K175N	0.997

dbSNP variants (sampled 300 via entrez): RS1000610865 (11:67485436 A>G), RS1001566683 (11:67481073 T>C), RS1001842367 (11:67489905 A>C), RS1002059452 (11:67484335 C>G,T), RS1002118256 (11:67485853 A>C,G), RS1002133683 (11:67491543 C>T), RS1002167294 (11:67490473 TGGGCTGCCGG>T), RS1002184809 (11:67487221 G>A,C), RS1002493875 (11:67483977 C>A), RS1002569334 (11:67482925 T>C), RS1002621976 (11:67482607 T>TC), RS1002718415 (11:67487330 C>T), RS1002780116 (11:67488704 C>T), RS1003526352 (11:67491174 G>A,T), RS1003759697 (11:67485500 T>A)

Disease associations

OMIM: gene MIM:605555 | disease phenotypes: MIM:102200, MIM:219090, MIM:617540, MIM:102000

GenCC curated gene-disease

Disease	Classification	Inheritance
growth hormone secreting pituitary adenoma 1	Definitive	Autosomal dominant
familial isolated pituitary adenoma	Supportive	Autosomal dominant
acromegaly	Supportive	Unknown
pituitary gigantism	Supportive	Autosomal dominant

Mondo (8): hereditary neoplastic syndrome (MONDO:0015356), growth hormone secreting pituitary adenoma 1 (MONDO:0007052), familial isolated pituitary adenoma (MONDO:0017824), Cushing disease due to pituitary adenoma (MONDO:0009050), pituitary adenoma 5, multiple types (MONDO:0054601), acroleukopathy, symmetric (MONDO:0007049), acromegaly (MONDO:0019933), pituitary gigantism (MONDO:0020479)

Orphanet (4): Inherited cancer-predisposing syndrome (Orphanet:140162), Familial isolated pituitary adenoma (Orphanet:314777), Acromegaly (Orphanet:963), Cushing disease (Orphanet:96253)

HPO phenotypes

167 total (30 of 167 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000026	Male hypogonadism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000098	Tall stature
HP:0000134	Female hypogonadism
HP:0000135	Hypogonadism
HP:0000140	Abnormality of the menstrual cycle
HP:0000141	Amenorrhea
HP:0000158	Macroglossia
HP:0000164	Abnormality of the dentition
HP:0000238	Hydrocephalus
HP:0000276	Long face
HP:0000280	Coarse facial features
HP:0000293	Full cheeks
HP:0000303	Mandibular prognathia
HP:0000336	Prominent supraorbital ridges
HP:0000337	Broad forehead
HP:0000400	Macrotia
HP:0000445	Wide nose
HP:0000508	Ptosis
HP:0000529	Progressive visual loss
HP:0000602	Ophthalmoplegia
HP:0000618	Blindness
HP:0000651	Diplopia
HP:0000664	Synophrys
HP:0000687	Widely spaced teeth
HP:0000689	Dental malocclusion
HP:0000712	Emotional lability
HP:0000716	Depression

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST008972_100	Urate levels	3.000000e-23
GCST008972_156	Urate levels	9.000000e-09
GCST010002_241	Refractive error	3.000000e-13
GCST010241_387	Apolipoprotein A1 levels	7.000000e-10
GCST90002390_35	Mean corpuscular hemoglobin	3.000000e-26
GCST90002396_470	Mean reticulocyte volume	2.000000e-31

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D049913	ACTH-Secreting Pituitary Adenoma	C04.557.470.035.012; C04.588.322.609.145; C10.228.140.617.738.675.149; C19.344.609.145; C19.700.734.145
D000172	Acromegaly	C05.116.132.082; C10.228.140.617.738.250.100; C19.700.355.179
D005877	Gigantism	C05.116.099.492; C05.116.132.479; C19.700.355.528
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
C566322	Acroleukopathy, Symmetric (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295645 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.36	Kd	43.75	nM	CHEMBL5653589
7.28	ED50	52.67	nM	CHEMBL5653589
5.22	IC50	6000	nM	CHEMBL5558644
5.16	IC50	7000	nM	CHEMBL5558181
5.00	IC50	1e+04	nM	CHEMBL5561795
5.00	IC50	1e+04	nM	MOLIBRESIB

PubChem BioAssay actives

5 with measured affinity, of 13 total; 5 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147827: Binding affinity to human AIP incubated for 45 mins by Kinobead based pull down assay	kd	0.0437	uM
methyl 2-[[2-[[5,6-bis(furan-2-yl)-1,2,4-triazin-3-yl]sulfanyl]acetyl]amino]-4,5-dimethylthiophene-3-carboxylate	2084027: Inhibition of GST-tagged human AIP expressed in Escherichia coli BL21 (DE3) using NH2-EDASRMEEVD-COOH peptide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by Alpha Screen assay	ic50	6.0000	uM
N,N’-bis(3-carbamoyl-4,5-dimethylthiophen-2-yl)pentanediamide	2084027: Inhibition of GST-tagged human AIP expressed in Escherichia coli BL21 (DE3) using NH2-EDASRMEEVD-COOH peptide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by Alpha Screen assay	ic50	7.0000	uM
N,N’-bis(3-carbamoyl-6-ethyl-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)pentanediamide	2084027: Inhibition of GST-tagged human AIP expressed in Escherichia coli BL21 (DE3) using NH2-EDASRMEEVD-COOH peptide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by Alpha Screen assay	ic50	10.0000	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178888: Inhibition of AIP (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	3
Tretinoin	decreases expression, increases expression	2
bisphenol F	affects cotreatment, increases expression	1
4-oxoretinoic acid	decreases expression	1
triphenyl phosphate	affects expression	1
1,12-benzoperylene	increases expression	1
trichostatin A	affects expression	1
sodium arsenite	increases expression	1
di-n-butylphosphoric acid	affects expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Alitretinoin	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	decreases phosphorylation	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	increases expression	1
Enzyme Inhibitors	increases O-linked glycosylation, decreases activity	1
Estradiol	decreases expression	1
Indomethacin	increases expression, affects cotreatment	1
Ivermectin	decreases expression	1
Methotrexate	increases expression	1
Rotenone	increases expression	1
Selenium	increases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tobacco Smoke Pollution	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Isotretinoin	decreases expression	1
Metribolone	decreases expression	1
Cyclosporine	increases expression	1
Sodium Selenite	increases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118745	Binding	Binding affinity to AIP in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1J9	Abcam HeLa AIP KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00068029	PHASE4	COMPLETED	Pegvisomant And Sandostatin LAR Combination Study
NCT00068042	PHASE4	COMPLETED	A Study To Compare The Efficacy And Safety Of Pegvisomant To That Of Sandostatin Lar Depot In Patients With Acromegaly
NCT00145405	PHASE4	COMPLETED	Comparable Effects of Lanreotide Autogel and Octreotide LAR on GH, IGF-I Levels and Patient Satisfaction
NCT00149188	PHASE4	COMPLETED	Somatuline Autogel: Acromegaly Self/Partner Injection Study
NCT00151437	PHASE4	COMPLETED	Canadian Pegvisomant Compassionate Study In Acromegalic Patients
NCT00171886	PHASE4	COMPLETED	Octreotide Efficacy and Safety in First-line Acromegalic Patients
NCT00216398	PHASE4	COMPLETED	Lanreotide Autogel in Patients With Acromegaly Previously Treated With Octreotide LAR
NCT00242541	PHASE4	TERMINATED	Study Assessing the Efficacy and Safety of Octreotide Acetate in Patients With Acromegaly, With Micro or Macroadenomas
NCT00376064	PHASE4	COMPLETED	Efficacy of Octreotide Acetate and Cabergoline in Patients With Acromegaly
NCT00461149	PHASE4	COMPLETED	Dose Escalation of Octreotide-LAR as First-Line Therapy in Resistant Acromegaly
NCT00521300	PHASE4	COMPLETED	Preoperative Octreotide Treatment of Acromegaly
NCT00552071	PHASE4	COMPLETED	Ultrasound Guided Octreotide LAR Injection in Acromegaly
NCT00552851	PHASE4	UNKNOWN	Changes of Left Ventricular Mass and Cardiac Function in Patients With Active Acromegaly During Treatment With the Growth Hormone Receptor Antagonist Pegvisomant
NCT00595140	PHASE4	COMPLETED	Acute Application of Pegvisomant and Octreotide in Acromegaly
NCT00627796	PHASE4	COMPLETED	Lanreotide Autogel-120 mg as First-Line Treatment of Acromegaly
NCT00642720	PHASE4	COMPLETED	Change in Quality of Life After Addition of Weekly 40 mg Pegvisomant/Placebo in Controlled Acromegalic Patients
NCT00701363	PHASE4	COMPLETED	Study to Assess the Efficacy of an Extended Injection Interval Schedule of Lanreotide Autogel in Acromegalic Subjects
NCT01278342	PHASE4	COMPLETED	Study to Evaluate the Efficacy and Safety of Sandostatin LAR at High Dose or in Combination Either With GH-receptor Antagonist or Dopamine-agonist in Acromegalic Patients
NCT01424241	PHASE4	COMPLETED	Effects of Sandostatin LAR® in Acromegaly
NCT01618513	PHASE4	COMPLETED	Treatment of Acromegaly With Somatostatin Analogs: GH vs. IGF-I as Primary Biochemical Target
NCT01794793	PHASE4	COMPLETED	Study to Allow Access to Pasireotide for Patients Benefiting From Pasireotide Treatment in Novartis-sponsored Studies
NCT01861717	PHASE4	TERMINATED	A Pilot Study of Pre- and Post-operative Use of Somatuline Depot.
NCT02060383	PHASE4	COMPLETED	Study of Management of Pasireotide-induced Hyperglycemia in Adult Patients With Cushing’s Disease or Acromegaly
NCT02427295	PHASE4	UNKNOWN	Hormonal Outcomes in Acromegalic Patients With Treated Surgery With or Without Long Acting Somatostatin Analogues
NCT02668172	PHASE4	UNKNOWN	Pasireotide LAR and Pegvisomant Study in Acromegaly
NCT03080181	PHASE4	COMPLETED	Adipokine Profile in Patients With Cushing’s Disease on Pasireotide Treatment
NCT00128232	PHASE3	COMPLETED	Safety and Efficacy of Octreotide Long Acting Release (LAR) in Treatment Naïve Acromegalic Patients
NCT00143416	PHASE3	COMPLETED	Long Term Study With B2036-PEG
NCT00210457	PHASE3	COMPLETED	Efficacy and Safety of Lanreotide Autogel (60, 90 or 120 mg) in Acromegalic Patients
NCT00225979	PHASE3	COMPLETED	Safety and Efficacy of Long-acting Repeatable Octreotide Acetate for Injectable Suspension vs. Surgery in Treatment-naïve Patients With Acromegaly
NCT00372697	PHASE3	COMPLETED	Efficacy/Safety of Octreotide Acetate in Patients With Uncontrolled Acromegaly
NCT00383708	PHASE3	COMPLETED	Lanreotide Autogel and Pegvisomant Combination Therapy in Acromegalic Patients
NCT00444873	PHASE3	COMPLETED	Effect of 120mg Somatuline Autogel at Different Dose Intervals (28, 42 or 56 Days) in Patients With Acromegaly
NCT00447499	PHASE3	COMPLETED	Assessment of the Ability of Subjects With Acromegaly or Their Partners to Administer Somatuline Autogel
NCT00499993	PHASE3	COMPLETED	Efficacy and Tolerability of Lanreotide (Autogel 120 mg) in Patients With Acromegaly
NCT00600886	PHASE3	COMPLETED	Safety and Efficacy of Pasireotide Long Acting Release (LAR) vs. Octreotide LAR in Patients With Active Acromegaly
NCT00616551	PHASE3	COMPLETED	Efficacy and Safety of C2L-OCT-01 PR in Acromegalic Patients
NCT00635765	PHASE3	COMPLETED	Open Label Extension Study Evaluating Safety and Biological Activity of C2L-OCT-01 PR in Acromegalic Patients
NCT00642421	PHASE3	TERMINATED	Safety and Biological Activity of C2L-OCT-01 PR in Acromegalic Patients
NCT00690898	PHASE3	COMPLETED	Lanreotide as Primary Treatment for Acromegalic Patients With Pituitary Gland Macroadenoma