CITED2

Summary

CITED2 (Cbp/p300 interacting transactivator with ED-rich tail 2, HGNC:1987) is a protein-coding gene on chromosome 6q24.1, encoding Cbp/p300-interacting transactivator 2 (Q99967). Transcriptional coactivator of the p300/CBP-mediated transcription complex.

The protein encoded by this gene inhibits transactivation of HIF1A-induced genes by competing with binding of hypoxia-inducible factor 1-alpha to p300-CH1. Mutations in this gene are a cause of cardiac septal defects. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 10370 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (Moderate, ClinGen) — +3 more curated relationships
• GWAS associations: 36
• Clinical variants (ClinVar): 100 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 60
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_006079

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1987
Approved symbol	CITED2
Name	Cbp/p300 interacting transactivator with ED-rich tail 2
Location	6q24.1
Locus type	gene with protein product
Status	Approved
Aliases	MRG1
Ensembl gene	ENSG00000164442
Ensembl biotype	protein_coding
OMIM	602937
Entrez	10370

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000367651, ENST00000536159, ENST00000537332, ENST00000935620

RefSeq mRNA: 3 — MANE Select: NM_006079 NM_001168388, NM_001168389, NM_006079

CCDS: CCDS5195, CCDS75530

Canonical transcript exons

ENST00000367651 — 2 exons

Exon	Start	End
ENSE00001445266	139374413	139374648
ENSE00003724332	139371807	139373952

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 99.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 234.1402 / max 4303.4301, expressed in 1824 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
75967	233.1024	1824
75965	0.4450	246
75966	0.3141	151
75964	0.2787	138

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.45	gold quality
type B pancreatic cell	CL:0000169	99.09	gold quality
mucosa of stomach	UBERON:0001199	98.83	gold quality
left ovary	UBERON:0002119	98.65	gold quality
right ovary	UBERON:0002118	98.58	gold quality
nipple	UBERON:0002030	98.55	gold quality
decidua	UBERON:0002450	98.34	gold quality
left uterine tube	UBERON:0001303	98.09	gold quality
right lung	UBERON:0002167	98.09	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.64	gold quality
thyroid gland	UBERON:0002046	97.61	gold quality
left lobe of thyroid gland	UBERON:0001120	97.60	gold quality
penis	UBERON:0000989	97.56	gold quality
bone marrow cell	CL:0002092	97.46	gold quality
renal medulla	UBERON:0000362	97.43	gold quality
tibial nerve	UBERON:0001323	97.42	gold quality
upper lobe of left lung	UBERON:0008952	97.41	gold quality
ovary	UBERON:0000992	97.34	gold quality
upper lobe of lung	UBERON:0008948	97.34	gold quality
amniotic fluid	UBERON:0000173	97.33	gold quality
lower lobe of lung	UBERON:0008949	97.33	gold quality
right lobe of thyroid gland	UBERON:0001119	97.06	gold quality
granulocyte	CL:0000094	96.91	gold quality
trachea	UBERON:0003126	96.68	gold quality
heart right ventricle	UBERON:0002080	96.54	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.50	gold quality
superficial temporal artery	UBERON:0001614	96.49	gold quality
skin of leg	UBERON:0001511	96.47	gold quality
skin of abdomen	UBERON:0001416	96.40	gold quality
lower esophagus mucosa	UBERON:0035834	96.32	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-GEOD-114530	yes	4035.41
E-HCAD-13	yes	1873.32
E-MTAB-10885	yes	1646.08
E-MTAB-10855	yes	754.34
E-GEOD-124472	yes	573.61
E-CURD-112	yes	46.70
E-MTAB-8410	yes	31.20
E-CURD-122	yes	27.88
E-ANND-3	yes	16.12
E-MTAB-9067	yes	11.11
E-MTAB-8271	yes	7.17
E-HCAD-1	yes	5.80
E-MTAB-8381	no	543.65
E-MTAB-7606	no	534.28
E-MTAB-6524	no	250.33

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
CEBPA	Repression
MMP1	Repression
MMP13	Repression
MMP9	Activation

Upstream regulators (CollecTRI, top): AR, E2F3, ELK1, EPAS1, FOXA2, FOXO1, FOXO3, HDAC9, HIF1A, HNF4A, MYC, NFKB, NR5A1, PPARG, STAT5A, STAT5B, TFAP2A, TFAP2C, VEZF1

miRNA regulators (miRDB)

94 targeting CITED2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-182-5P	99.87	74.03	2589

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Both TGFbeta and flow shear stimulated expression of CITED2 and also association of CIT-ED2 with p300 by dissociating Ets-1 from p300. Thus, CITED2 plays a major role in shear-induced down-regulation of MMP-1 and MMP-13 via a TGFbeta-dependent pathway. (PMID:12960175)
• CIT-ED2 is a coactivator of PPARalpha and both proteins may participate in signaling cascades of hypoxic response and angiogenesis (PMID:15051727)
• CITED2 mutations have a causative impact in the development of CHD in humans. (PMID:16287139)
• TGF-beta-mediated down-regulation of Cited2 is post-transcriptional, through the Smad pathway, and requires the presence of its coding sequence (PMID:16675452)
• Cited2, a coactivator of HNF4alpha, is essential for liver development (PMID:17932483)
• CITED2 regulates colon cancer invasion and might be a target for histone deacetylase inhibitor-based intervention of colon cancer. (PMID:18054336)
• CITED2 and PBX1 are likely to be important mediators of adrenal development and function in humans, but mutations in these genes are not common causes of adrenal failure. (PMID:18984668)
• The effects of endothelial-cell-conditioned medium (ECCM), as produced during the incubation of human umbilical vein endothelial cells for 24 h, on the promoter activity and mRNA and protein expression of CITED2 in adrenocortical cells, was examined. (PMID:19319572)
• Reducing CITED2 expression in a mammary tumor cell line inhibits the establishment of bone metastasis and osteolysis in vivo. (PMID:19642106)
• Both NCOR2 and CITED2 mRNA levels were associated with MFS, that is, tumour aggressiveness, independently of traditional prognostic factors (PMID:19904269)
• CITED2 may act as a mechanosensitive molecular switch regulating cartilage matrix breakdown. (PMID:20392269)
• CITED2 is a novel regulator of NF-kappaB in the nucleus, which reveals a negative feedback mechanism for NF-kappaB signaling. (PMID:21098220)
• CITED2 activation may induce mucosal apoptosis and erosion by activating p53 and thus play a critical role in linking enteric bacteria with mucosal inflammation in ulcerative colitis. (PMID:21165656)
• A combination of cisplatin and CITED2 shRNA may represent an effective treatment against p53-sensitive cancer cells. (PMID:21660965)
• We conclude that mutations in CITED2 may be involved in premature ovarian failure pathogenesis. (PMID:22709740)
• CITED2 variants decreased its ability to mediate the expression of vascular endothelial growth factor (VEGF) and the expression of the paired-like homeodomain transcription factor 2-gamma (PITX2C), both of which are closely related to cardiac development. (PMID:22735262)
• CITED2 functions as a molecular switch of TGF-alpha and TGF-beta-induced growth control, and MYC-CITED2 signaling axis provides a new index for predicting clinical outcome. (PMID:22814619)
• CITED2 is phosphorylated by MAPK1 in vitro at T166, and that MAPK1 activation enhances the coactivation function of CITED2 but not of CITED2-T166N. (PMID:23082118)
• CITED2 is a direct effector of PPARgamma for tumor suppression. (PMID:23212831)
• data indicate that CITED2 functions as a transcriptional co-activator of ER in breast cancer cells and that its increased expression in tumors may result in estrogen-independent ER activation (PMID:23811274)
• Our study suggests that CITED2 gene mutations and methylation may play an important role in the development of pediatric congenital heart disease. (PMID:24456003)
• CITED2 has a potential causative impact on congenital heart disease (PMID:24848765)
• The increased CITED2 expression in acute myeloid leukemia results in better hematopoietic stem cell survival, lower PU.1 levels, and perturbed myeloid differentiation program that contributes to leukemia persistence. (PMID:25184385)
• FBXL5-mediated degradation of CITED2 leads to the activation of HIF-1 alpha. (PMID:25956243)
• High Cited2 level in cumulus cells was associated with low embryo quality and pregnancy outcome in in vitro fertilization patients. (PMID:26812245)
• Intrinsic protein disorder plays a prominent role in the function and interactions of the transcriptional co-activators CBP and p300. (Review) (PMID:26851278)
• CITED2 plays important roles in the progression and chemoresistance of breast carcinoma and that CITED2 status is a potent prognostic factor in breast cancer patients. (PMID:27627783)
• down-regulation of Cited2 was associated with high glucose-induced apoptosis in cardiomyocytes in vitro (PMID:27680315)
• CITED2 regulates primary breast tumor growth, likely by influencing tumor vasculature via TGF-beta-dependent regulation of VEGFA. (PMID:28008154)
• the downregulation of CITED2 contributes to TGFbeta-mediated senescence. (PMID:28084522)
• Through allosteric enhancement of HIF-1alpha release, CITED2 activates a highly responsive negative feedback circuit that rapidly and efficiently attenuates the hypoxic response, even at modest CITED2 concentrations. (PMID:28273070)
• The results suggest that CITED2 mutations in conserved regions lead to disease-causing biological and functional changes and may contribute to the occurrence of conotruncal heart defects in Chinese children. (PMID:28436679)
• CITED2 supports gastric cancer cell colony formation and proliferation while inhibiting apoptosis making it a potential gene therapy target for gastric cancer. (PMID:28501104)
• CITED2 gene mutation may play a significant role in the development of pediatric congenital heart disease. (PMID:28687891)
• Knockdown of CITED2 led to a decreased interaction of p53 with its inhibitor MDM2, which results in increased amounts of total p53 protein. Data indicate that CITED2 functions in pathways regulating p53 activity. (PMID:29072699)
• Observations identify CITED2 as a novel negative regulator of macrophage proinflammatory activation that protects the host from inflammatory insults. (PMID:29203644)
• GINS2 plays an important role in cell proliferation and apoptosis of thyroid cancer by regulating the expressions of CITED2 and LOXL2, which may be a potential biomarker for diagnosis or prognosis and a drug target for therapy. (PMID:30177819)
• CITED2 acts as a molecular chaperone to guide PRMT5 and p300 to nucleolin, thereby activating nucleolin. Informatics and experimental data suggest that the CITED2-nucleolin axis is involved in prostate cancer metastasis. (PMID:30291252)
• The results showed that the core promoter area of MUC5AC was located within the 935/+48 region and that P300 reduced the expression of MUC5AC in A549 cells. (PMID:30628655)
• tested the hypothesis that CITED2 mediates cross-talk between IL-4 signaling and mechanical loading-induced pathways that result in chondroprotection, at least in part, by downregulating MMP13 (PMID:30891766)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cited2	ENSDARG00000030905
mus_musculus	Cited2	ENSMUSG00000039910
rattus_norvegicus	Cited2	ENSRNOG00000056940

Paralogs (2): CITED1 (ENSG00000125931), CITED4 (ENSG00000179862)

Protein

Protein identifiers

Cbp/p300-interacting transactivator 2 — Q99967 (reviewed: Q99967)

Alternative names: MSG-related protein 1, P35srj

All UniProt accessions (3): Q99967, A0A0A0MTM3, D9ZGF1

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional coactivator of the p300/CBP-mediated transcription complex. Acts as a bridge, linking TFAP2 transcription factors and the p300/CBP transcriptional coactivator complex in order to stimulate TFAP2-mediated transcriptional activation. Positively regulates TGF-beta signaling through its association with the SMAD/p300/CBP-mediated transcriptional coactivator complex. Stimulates the peroxisome proliferator-activated receptors PPARA transcriptional activity. Enhances estrogen-dependent transactivation mediated by estrogen receptors. Also acts as a transcriptional corepressor; interferes with the binding of the transcription factors HIF1A or STAT2 and the p300/CBP transcriptional coactivator complex. Participates in sex determination and early gonad development by stimulating transcription activation of SRY. Plays a role in controlling left-right patterning during embryogenesis; potentiates transcriptional activation of NODAL-mediated gene transcription in the left lateral plate mesoderm (LPM). Plays an essential role in differentiation of the adrenal cortex from the adrenogonadal primordium (AGP); stimulates WT1-mediated transcription activation thereby up-regulating the nuclear hormone receptor NR5A1 promoter activity. Associates with chromatin to the PITX2 P1 promoter region.

Subunit / interactions. Interacts (via C-terminus) with SMAD2. Interacts (via C-terminus) with SMAD3 (via MH2 domain). Interacts with LHX2 (via LIM domains). Interacts with WT1. Interacts (via C-terminus) with EP300 (via CH1 domain); the interaction is stimulated in response to hypoxia. Interacts with PPARA. Interacts (via C-terminus) with TFAP2A, TFAP2B and TFAP2C.

Subcellular location. Nucleus.

Disease relevance. Ventricular septal defect 2 (VSD2) [MIM:614431] A common form of congenital cardiovascular anomaly that may occur alone or in combination with other cardiac malformations. It can affect any portion of the ventricular septum, resulting in abnormal communications between the two lower chambers of the heart. Classification is based on location of the communication, such as perimembranous, inlet, outlet (infundibular), central muscular, marginal muscular, or apical muscular defect. Large defects that go unrepaired may give rise to cardiac enlargement, congestive heart failure, pulmonary hypertension, Eisenmenger’s syndrome, delayed fetal brain development, arrhythmias, and even sudden cardiac death. The disease is caused by variants affecting the gene represented in this entry. Atrial septal defect 8 (ASD8) [MIM:614433] A congenital heart malformation characterized by incomplete closure of the wall between the atria resulting in blood flow from the left to the right atria. The disease is caused by variants affecting the gene represented in this entry.

Induction. By hypoxia and deferoxamine.

Similarity. Belongs to the CITED family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q99967-1	1	yes
Q99967-2	2

RefSeq proteins (3): NP_001161860, NP_001161861, NP_006070* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007576	CITED	Family

Pfam: PF04487

UniProt features (17 total): helix 4, sequence variant 4, mutagenesis site 3, chain 1, region of interest 1, strand 1, turn 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7QGS	X-RAY DIFFRACTION	2
7LVS	X-RAY DIFFRACTION	2.02
1P4Q	SOLUTION NMR
1R8U	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99967-F1	52.07	0.00

Functional residue map

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

Mutagenesis-validated functional residues (3):

Position	Phenotype
246	inhibits transactivation activity; when associated with e-243.
243–246	inhibits transactivation activity.
243	inhibits transactivation activity; when associated with e-246.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1234158	Regulation of gene expression by Hypoxia-inducible Factor
R-HSA-8866906	TFAP2 (AP-2) family regulates transcription of other transcription factors
R-HSA-8866907	Activation of the TFAP2 (AP-2) family of transcription factors
R-HSA-9614657	FOXO-mediated transcription of cell death genes

MSigDB gene sets: 822 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RNGTGGGC_UNKNOWN, FXR_IR1_Q6, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, MODULE_52, E2F_Q4_01, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, FREAC2_01, GOBP_MUSCLE_TISSUE_DEVELOPMENT

GO Biological Process (71): negative regulation of transcription by RNA polymerase II (GO:0000122), vasculogenesis (GO:0001570), response to hypoxia (GO:0001666), trophectodermal cell differentiation (GO:0001829), neural tube closure (GO:0001843), liver development (GO:0001889), embryonic placenta development (GO:0001892), heart looping (GO:0001947), lens morphogenesis in camera-type eye (GO:0002089), hematopoietic progenitor cell differentiation (GO:0002244), determination of left/right asymmetry in lateral mesoderm (GO:0003140), outflow tract morphogenesis (GO:0003151), regulation of animal organ formation (GO:0003156), endocardial cushion development (GO:0003197), transforming growth factor beta receptor signaling pathway (GO:0007179), determination of left/right symmetry (GO:0007368), central nervous system development (GO:0007417), peripheral nervous system development (GO:0007422), heart development (GO:0007507), sex determination (GO:0007530), cell population proliferation (GO:0008283), male gonad development (GO:0008584), response to mechanical stimulus (GO:0009612), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), cranial nerve morphogenesis (GO:0021602), positive regulation of cell-cell adhesion (GO:0022409), negative regulation of cell migration (GO:0030336), positive regulation of transforming growth factor beta receptor signaling pathway (GO:0030511), granulocyte differentiation (GO:0030851), response to fluid shear stress (GO:0034405), positive regulation of peroxisome proliferator activated receptor signaling pathway (GO:0035360), adrenal cortex formation (GO:0035802), skeletal muscle cell differentiation (GO:0035914), nodal signaling pathway (GO:0038092), negative regulation of apoptotic process (GO:0043066), response to estrogen (GO:0043627), positive regulation of cell cycle (GO:0045787), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (10): chromatin binding (GO:0003682), transcription coactivator activity (GO:0003713), transcription corepressor activity (GO:0003714), protein domain specific binding (GO:0019904), histone acetyltransferase binding (GO:0035035), SMAD binding (GO:0046332), LBD domain binding (GO:0050693), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), molecular function activator activity (GO:0140677), protein binding (GO:0005515)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	2
Cellular response to hypoxia	1
FOXO-mediated transcription	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cell differentiation	3
negative regulation of DNA-templated transcription	2
anatomical structure morphogenesis	2
nervous system development	2
system development	2
binding	2
transcription coregulator activity	2
protein binding	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
blood vessel morphogenesis	1
response to stress	1
response to decreased oxygen levels	1
blastocyst formation	1
primary neural tube formation	1
tube closure	1
gland development	1
hepaticobiliary system development	1
in utero embryonic development	1
placenta development	1
embryonic organ development	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
lens development in camera-type eye	1
camera-type eye morphogenesis	1
hemopoiesis	1
determination of left/right symmetry	1
lateral mesoderm development	1
heart morphogenesis	1
animal organ formation	1
regulation of animal organ morphogenesis	1
heart development	1
mesenchyme development	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
determination of bilateral symmetry	1
left/right pattern formation	1
animal organ development	1
circulatory system development	1

Protein interactions and networks

STRING

1156 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CITED2	EP300	Q09472	993
CITED2	TFAP2A	P05549	935
CITED2	CREBBP	Q92793	888
CITED2	HIF1A	Q16665	864
CITED2	LHX2	P50458	858
CITED2	PCGF2	P35227	741
CITED2	TP53	P04637	722
CITED2	WT1	P19544	711
CITED2	TFAP2C	Q92754	675
CITED2	EPAS1	Q99814	658
CITED2	BMI1	P35226	646
CITED2	R4GMX3	R4GMX3	646
CITED2	FOXP2	O15409	632
CITED2	LEFTY2	O00292	604
CITED2	NCOA2	Q15596	598

IntAct

23 interactions, top by confidence:

A	B	Type	Score
GRN	CITED2	psi-mi:“MI:0915”(physical association)	0.560
CITED2	PRPS1	psi-mi:“MI:0915”(physical association)	0.560
WFS1	CITED2	psi-mi:“MI:0915”(physical association)	0.560
CITED2	HNF4A	psi-mi:“MI:0915”(physical association)	0.540
HNF4A	CITED2	psi-mi:“MI:0915”(physical association)	0.540
CITED2	HNF4A	psi-mi:“MI:0403”(colocalization)	0.540
EP300	CITED2	psi-mi:“MI:0915”(physical association)	0.510
CITED2	TFAP2C	psi-mi:“MI:0915”(physical association)	0.510
TFAP2C	CITED2	psi-mi:“MI:0915”(physical association)	0.510
EP300	TFAP2A	psi-mi:“MI:0915”(physical association)	0.510
CITED2	TFAP2A	psi-mi:“MI:0915”(physical association)	0.400
CITED2	TFAP2B	psi-mi:“MI:0915”(physical association)	0.400
TPST2	NDC80	psi-mi:“MI:0914”(association)	0.350
CITED2		psi-mi:“MI:0915”(physical association)	0.000
	CITED2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (36): TFAP2A (Two-hybrid), CITED2 (Affinity Capture-MS), CITED2 (Biochemical Activity), FBXL5 (Two-hybrid), FBXL5 (Reconstituted Complex), FBXL5 (PCA), EP300 (PCA), TFAP2C (Two-hybrid), CITED2 (Affinity Capture-MS), CITED2 (Affinity Capture-MS), CITED2 (Two-hybrid), CITED2 (Two-hybrid), EP300 (Two-hybrid), CITED2 (Two-hybrid), CITED2 (Affinity Capture-Western)

ESM2 similar proteins: A1YFU7, A8WL06, O14770, O35740, O42368, O46250, O76971, O77215, P07548, P09077, P09081, P20482, P20822, P23023, P25822, P31264, P40657, P40791, P43699, P54231, P54269, P56672, P83949, P83950, P91607, P91613, P91686, P91697, P91698, P91705, P91716, P92203, P97367, Q05201, Q0VCT9, Q24248, Q24255, Q24573, Q2Z1R2, Q5XGW7

Diamond homologs: A1YFU7, O35740, P97769, Q0VCT9, Q2HJ78, Q5XGW7, Q6NX30, Q96RK1, Q99966, Q99967, Q99MA0, Q9BDI3, Q9I8K7, Q9WUL8

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
FOXO3	“up-regulates quantity by expression”	CITED2	“transcriptional regulation”
FOXO	“up-regulates quantity by expression”	CITED2	“transcriptional regulation”
CITED2	“down-regulates quantity by repression”	MMP13	“transcriptional regulation”
CITED2	“down-regulates quantity by repression”	MMP1	“transcriptional regulation”
MAPK1	“up-regulates activity”	CITED2	phosphorylation
VEZF1	“down-regulates quantity by repression”	CITED2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	71
Likely benign	9
Benign	9

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
6722	CITED2, 27-BP INS, NT534	Pathogenic
804240	NM_006079.5(CITED2):c.701A>C (p.Glu234Ala)	Likely pathogenic

SpliceAI

98 predictions. Top by Δscore:

Variant	Effect	Δscore
6:139373948:CAGTC:C	acceptor_gain	1.0000
6:139373949:AGTC:A	acceptor_gain	1.0000
6:139373950:GTC:G	acceptor_gain	1.0000
6:139373951:TC:T	acceptor_gain	1.0000
6:139373951:TCCTG:T	acceptor_loss	1.0000
6:139373952:CC:C	acceptor_gain	1.0000
6:139373953:C:CC	acceptor_gain	1.0000
6:139373959:G:C	acceptor_gain	1.0000
6:139373959:G:GC	acceptor_gain	1.0000
6:139374408:CTTA:C	donor_loss	1.0000
6:139374409:TTAC:T	donor_loss	1.0000
6:139374410:TACCT:T	donor_loss	1.0000
6:139374411:A:AC	donor_gain	1.0000
6:139374411:ACC:A	donor_loss	1.0000
6:139374411:ACCTT:A	donor_gain	1.0000
6:139374412:C:CC	donor_gain	1.0000
6:139374412:CCTT:C	donor_gain	1.0000
6:139374412:CCTTC:C	donor_gain	1.0000
6:139374415:T:A	donor_gain	1.0000
6:139373953:C:T	acceptor_gain	0.9900
6:139374411:AC:A	donor_gain	0.9900
6:139374412:CC:C	donor_gain	0.9900
6:139373953:C:A	acceptor_gain	0.9800
6:139374412:CCT:C	donor_gain	0.9800
6:139373949:AGTCC:A	acceptor_gain	0.9700
6:139373950:GTCCT:G	acceptor_gain	0.9700
6:139373951:TCCT:T	acceptor_gain	0.9700
6:139373954:T:A	acceptor_gain	0.9700
6:139373954:T:C	acceptor_loss	0.9600
6:139373952:CCTGG:C	acceptor_gain	0.9500

AlphaMissense

1854 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:139373186:A:C	F253L	1.000
6:139373186:A:T	F253L	1.000
6:139373188:A:G	F253L	1.000
6:139373202:A:G	L248P	1.000
6:139373206:A:G	W247R	1.000
6:139373206:A:T	W247R	1.000
6:139373208:A:G	L246P	1.000
6:139373208:A:T	L246H	1.000
6:139373214:G:A	P244L	1.000
6:139373214:G:T	P244H	1.000
6:139373215:G:A	P244S	1.000
6:139373215:G:T	P244T	1.000
6:139373217:A:G	L243P	1.000
6:139373217:A:T	L243Q	1.000
6:139373229:C:G	R239P	1.000
6:139373232:T:A	D238V	1.000
6:139373235:A:G	L237S	1.000
6:139373238:C:A	G236V	1.000
6:139373239:C:A	G236C	1.000
6:139373239:C:G	G236R	1.000
6:139373244:T:A	E234V	1.000
6:139373253:A:C	L231W	1.000
6:139373253:A:G	L231S	1.000
6:139373257:A:G	S230P	1.000
6:139373262:A:G	L228P	1.000
6:139373262:A:T	L228H	1.000
6:139373271:T:A	E225V	1.000
6:139373274:T:A	D224V	1.000
6:139373277:A:T	I223N	1.000
6:139373172:T:A	D258V	0.999

dbSNP variants (sampled 300 via entrez): RS1000375923 (6:139376004 A>C), RS1000475052 (6:139374833 A>C,G), RS1001122499 (6:139374817 G>A,C), RS1001751673 (6:139373461 C>G,T), RS1002085174 (6:139374275 A>C,G,T), RS1002388253 (6:139375783 G>T), RS1003219346 (6:139374034 C>A,T), RS1003769447 (6:139374902 C>G), RS1003802349 (6:139374789 C>T), RS1004159120 (6:139373837 G>A,C), RS1004530630 (6:139373997 C>T), RS1005105795 (6:139371480 G>A), RS1005120152 (6:139373039 G>A,T), RS1005268036 (6:139372839 T>G), RS1005280274 (6:139376234 C>T)

Disease associations

OMIM: gene MIM:602937 | disease phenotypes: MIM:614433, MIM:614431

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart defects, multiple types	Moderate	Autosomal dominant
congenital heart disease	Moderate	Autosomal dominant
atrial septal defect 8	Moderate	Autosomal dominant
ventricular septal defect 2	Limited	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
congenital heart disease	Moderate	AD

Mondo (4): atrial septal defect 8 (MONDO:0013750), ventricular septal defect 2 (MONDO:0013748), congenital heart defects, multiple types (MONDO:0000119), congenital heart disease (MONDO:0005453)

Orphanet (1): Interatrial communication (Orphanet:1478)

HPO phenotypes

60 total (30 of 60 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000233	Thin vermilion border
HP:0000268	Dolichocephaly
HP:0000337	Broad forehead
HP:0000520	Proptosis
HP:0000961	Cyanosis
HP:0001156	Brachydactyly
HP:0001279	Syncope
HP:0001297	Stroke
HP:0001511	Intrauterine growth retardation
HP:0001631	Atrial septal defect
HP:0001633	Abnormal mitral valve morphology
HP:0001635	Congestive heart failure
HP:0001636	Tetralogy of Fallot
HP:0001653	Mitral regurgitation
HP:0001692	Atrial arrhythmia
HP:0001708	Right ventricular failure
HP:0001907	Thromboembolism
HP:0001962	Palpitations
HP:0002090	Pneumonia
HP:0002092	Pulmonary arterial hypertension
HP:0002094	Dyspnea
HP:0002326	Transient ischemic attack
HP:0002718	Recurrent bacterial infections
HP:0002875	Exertional dyspnea
HP:0003546	Exercise intolerance
HP:0003577	Congenital onset
HP:0004209	Clinodactyly of the 5th finger
HP:0004467	Preauricular pit

GWAS associations

36 associations (top):

Study	Trait	p-value
GCST000503_8	Mean corpuscular volume	5.000000e-25
GCST000504_2	Mean corpuscular hemoglobin	1.000000e-17
GCST000585_7	Mean corpuscular volume	1.000000e-09
GCST000587_5	Mean corpuscular hemoglobin	1.000000e-09
GCST000755_16	HDL cholesterol	3.000000e-08
GCST001762_1	Obesity-related traits	9.000000e-06
GCST001765_3	Red blood cell traits	5.000000e-36
GCST001780_2	Mean corpuscular hemoglobin	9.000000e-09
GCST001781_7	Mean corpuscular volume	4.000000e-08
GCST002039_4	Blood trace element (Se levels)	3.000000e-06
GCST002223_22	HDL cholesterol	3.000000e-08
GCST002830_29	Urate levels in lean individuals	9.000000e-06
GCST002897_27	Triglycerides	7.000000e-11
GCST003807_4	Systolic blood pressure response to hydrochlorothiazide in hypertension	7.000000e-06
GCST004004_17	Mean corpuscular volume	8.000000e-09
GCST004006_7	Mean corpuscular hemoglobin	1.000000e-10
GCST004232_59	HDL cholesterol levels	5.000000e-11
GCST004334_10	Mean corpuscular hemoglobin	2.000000e-09
GCST004335_12	Mean corpuscular volume	2.000000e-10
GCST005240_1	Caudate volume in trauma-exposed individuals	2.000000e-07
GCST005987_41	Albumin-globulin ratio	8.000000e-11
GCST005990_57	Non-albumin protein levels	2.000000e-10
GCST006624_72	Systolic blood pressure	7.000000e-12
GCST006630_6	Diastolic blood pressure	1.000000e-15
GCST007692_105	Chronic obstructive pulmonary disease	5.000000e-11
GCST007954_18	Glycated hemoglobin levels	4.000000e-08
GCST008568_6	IgA levels	7.000000e-07
GCST010241_74	Apolipoprotein A1 levels	7.000000e-14
GCST010242_413	HDL cholesterol levels	2.000000e-23
GCST010243_140	Apolipoprotein B levels	7.000000e-09

EFO canonical traits (15, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0004509	hemoglobin measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004531	urate measurement
EFO:0004530	triglyceride measurement
EFO:0006944	systolic blood pressure change measurement
EFO:0004830	caudate nucleus volume
EFO:0008483	response to trauma exposure
EFO:0005128	albumin:globulin ratio measurement
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0004541	HbA1c measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004615	apolipoprotein B measurement
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects expression, affects cotreatment, increases expression, decreases expression, decreases reaction	10
Cadmium Chloride	increases expression, decreases expression, increases abundance	4
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	4
methylmercuric chloride	increases expression, affects cotreatment	3
arsenite	increases reaction, decreases expression, increases abundance, increases expression, affects binding	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Tobacco Smoke Pollution	decreases expression	3
Tretinoin	decreases expression, increases expression	3
Cyclosporine	decreases expression	3
bisphenol A	affects expression, increases expression	2
cobaltous chloride	increases expression, decreases reaction	2
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Arsenic	increases abundance, affects methylation, affects cotreatment, decreases expression	2
Vehicle Emissions	increases abundance, increases expression	2
Cadmium	decreases expression, increases abundance, increases expression	2
Cisplatin	decreases expression, increases reaction, decreases response to substance, decreases activity, decreases acetylation (+8 more)	2
Formaldehyde	increases expression	2
Progesterone	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, affects expression, decreases expression	2
Valproic Acid	increases expression	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
lead acetate	decreases expression	1
sodium arsenate	increases abundance, increases expression	1
titanium dioxide	decreases methylation	1
decabromobiphenyl ether	affects expression	1
beta-lapachone	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7WN	Abcam Raji CITED2 KO	Cancer cell line	Male
CVCL_B9X7	Abcam THP-1 CITED2 KO	Cancer cell line	Male
CVCL_C6Z4	Abcam PC-3 CITED2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function
NCT01827059	PHASE2	UNKNOWN	Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE