ID2

Summary

ID2 (inhibitor of DNA binding 2, HGNC:5361) is a protein-coding gene on chromosome 2p25.1, encoding DNA-binding protein inhibitor ID-2 (Q02363). Transcriptional regulator (lacking a basic DNA binding domain) which negatively regulates the basic helix-loop-helix (bHLH) transcription factors by forming heterodimers and inhibiting their DNA binding and transcriptional activity.

The protein encoded by this gene belongs to the inhibitor of DNA binding family, members of which are transcriptional regulators that contain a helix-loop-helix (HLH) domain but not a basic domain. Members of the inhibitor of DNA binding family inhibit the functions of basic helix-loop-helix transcription factors in a dominant-negative manner by suppressing their heterodimerization partners through the HLH domains. This protein may play a role in negatively regulating cell differentiation. A pseudogene of this gene is located on chromosome 3.

Source: NCBI Gene 3398 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (Disputed, ClinGen)
• GWAS associations: 56
• Clinical variants (ClinVar): 30 total
• Transcription factor: yes — 71 downstream targets (CollecTRI)
• MANE Select transcript: NM_002166

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5361
Approved symbol	ID2
Name	inhibitor of DNA binding 2
Location	2p25.1
Locus type	gene with protein product
Status	Approved
Aliases	GIG8, bHLHb26
Ensembl gene	ENSG00000115738
Ensembl biotype	protein_coding
OMIM	600386
Entrez	3398

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 retained_intron

ENST00000234091, ENST00000331129, ENST00000396290, ENST00000472142, ENST00000855860, ENST00000929710

RefSeq mRNA: 1 — MANE Select: NM_002166 NM_002166

CCDS: CCDS1659

Canonical transcript exons

ENST00000396290 — 3 exons

Exon	Start	End
ENSE00001524495	8683685	8684461
ENSE00003892949	8682056	8682513
ENSE00003894825	8682843	8682906

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 255.8660 / max 5209.7775, expressed in 1803 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
18732	255.5610	1803
202068	0.3050	159

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
popliteal artery	UBERON:0002250	99.66	gold quality
tibial artery	UBERON:0007610	99.66	gold quality
saphenous vein	UBERON:0007318	99.62	gold quality
cortical plate	UBERON:0005343	99.57	gold quality
pericardium	UBERON:0002407	99.51	gold quality
right lobe of liver	UBERON:0001114	99.44	gold quality
aorta	UBERON:0000947	99.36	gold quality
granulocyte	CL:0000094	99.34	gold quality
trachea	UBERON:0003126	99.29	gold quality
lower lobe of lung	UBERON:0008949	99.28	gold quality
renal medulla	UBERON:0000362	99.27	gold quality
seminal vesicle	UBERON:0000998	99.17	gold quality
right ovary	UBERON:0002118	99.15	gold quality
vena cava	UBERON:0004087	99.06	gold quality
urethra	UBERON:0000057	99.04	gold quality
pylorus	UBERON:0001166	98.99	gold quality
ascending aorta	UBERON:0001496	98.99	gold quality
left ovary	UBERON:0002119	98.98	gold quality
thoracic aorta	UBERON:0001515	98.97	gold quality
nipple	UBERON:0002030	98.97	gold quality
gall bladder	UBERON:0002110	98.95	gold quality
descending thoracic aorta	UBERON:0002345	98.92	gold quality
left uterine tube	UBERON:0001303	98.84	gold quality
calcaneal tendon	UBERON:0003701	98.83	gold quality
cartilage tissue	UBERON:0002418	98.82	gold quality
liver	UBERON:0002107	98.76	gold quality
blood vessel layer	UBERON:0004797	98.75	gold quality
peritoneum	UBERON:0002358	98.74	gold quality
omental fat pad	UBERON:0010414	98.74	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.68	gold quality

Single-cell (SCXA)

Detected in 41 experiment(s), a significant marker in 34.

Experiment	Marker?	Max mean expression
E-CURD-46	yes	3760.66
E-MTAB-8142	yes	3656.67
E-GEOD-89232	yes	2621.92
E-HCAD-1	yes	2401.78
E-CURD-6	yes	1894.22
E-CURD-88	yes	1529.37
E-MTAB-7052	yes	1527.88
E-GEOD-139324	yes	1521.84
E-GEOD-75140	yes	1444.87
E-HCAD-5	yes	1222.08
E-GEOD-81608	yes	1203.18
E-MTAB-10018	yes	493.54
E-MTAB-8271	yes	419.40
E-MTAB-6701	yes	130.56
E-HCAD-4	yes	114.50

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

71 targets.

Target	Regulation
AICDA	Repression
ALPL
BCL2L1
BGLAP	Repression
BMAL1
BMP4
CAV3
CCNA2	Repression
CCND1	Activation
CD74
CD79A
CD8A	Repression
CDH1	Repression
CDH5	Unknown
CDKN1A	Activation
CDKN1B
CDKN1C	Unknown
CDKN2A	Activation
CDKN2B
CEL
CLOCK
COL1A2	Repression
CREBBP
CSH1	Repression
DKK1
DPPA4
ERVW-4
FAS	Repression
FGFR1
FSHR	Repression

Upstream regulators (CollecTRI, top): ACVRL1, BMP2, CEBPB, CTNNB1, DDIT3, EGR1, EGR2, EWSR1, FLI1, FOXC1, FOXO1, FOXO3, GATA4, GDF2, GDNF, GFI1, HIF1A, HNF4A, HOXA10, HOXA9, ID1, ID2, ID3, JUN, MAX, MXD1, MXD4, MYC, MYCN, MYOG, NHLH1, NKX2-5, OVOL1, PAX7, POU2AF1, POU2F2, POU5F1, RFX1, SMAD1, SMAD4

miRNA regulators (miRDB)

78 targeting ID2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-199A-3P	99.75	70.48	929
HSA-MIR-199B-3P	99.75	70.48	929

Literature-anchored findings (GeneRIF, showing 40)

• Id2 is critical for cellular proliferation and is the oncogenic effector of N-myc in human neuroblastoma. (PMID:11782392)
• determination as a novel target of transcriptional activation by EWS-ETS fusion proteins in Ewing family tumors (PMID:12447693)
• upregulation is mediated by the chimeric EWS/ets protein in Ewing sarcoma (PMID:12527902)
• We found no correlation between MYCN and ID2 expression in neuroblastoma cell lines or tumor specimens. However, we did find a significant positive correlation between MYC and ID2 expressions in both MYCN-amplified and single-copy tumor specimens (PMID:12545167)
• Id2 is up-regulated during dendritic cells development in vitro and crucial for the development of distinct dendritic cells subsets in vivo (PMID:12598895)
• Transcriptional regulation of ID2 by the MycN oncoprotein is unlikely to be a seminal molecular event resulting in a highly malignant neuroblastoma phenotype. (PMID:12670915)
• Mad expression and Id2 down-regulation are important events during the TGF-beta cytostatic program in epithelial cells. (PMID:12824180)
• The decreased level of Id2 was associated with growth suppression and does support the prevalent conception of the action of Id2 as a stimulator of cell growth (PMID:14582708)
• ID-2 appears to act as an important protein for the maintenance of a differentiated and noninvasive phenotype in normal and transformed breast cells. (PMID:14612502)
• Id2 developmental regulator degradation is targeted via N-terminal ubiquitination (PMID:14733935)
• Id-1 and Id-2 proteins control prostate cancer cell phenotypes and could serve as molecular markers of aggressive human prostate cancer. (PMID:15041724)
• Hypoxia-induced ID2 expression could play a significant role in the previously observed dedifferentiation of hypoxic neuroblastoma cells, which in a clinical setting could lead to less mature and more aggressive tumors. (PMID:15252039)
• Id1, 2 and 3 might play a role in the early stages of hepatocarcinogenesis, but not in the development of advanced carcinoma, and might consequently be related to HCC dedifferentiation (PMID:15645115)
• reenters the cell cycle after radiation-induced cell cycle arrest to permit the recovery of keratinocytes (PMID:15691830)
• Constitutive Id2 expression accelerates final maturation of both eosinophils and neutrophils, whereas inhibition of Id2 expression blocks differentiation of both lineages (PMID:15701714)
• These results indicate ID1 and ID2 are important retinoic acid responsive genes in acute promyelocytic leukemia [APL], and suggest that inhibition of specific bHLH transcription factor complexes may play a role in the therapeutic effect of ATRA in APL (PMID:15744343)
• PU.1 and Id2 modulate lineage options of langerhans cell precursors, downstream of TGF-beta1. (PMID:16223775)
• PKD2 regulates the cell cycle through direct interaction with Id2; Id2 expression suppresses the induction of a cdk inhibitor, p21, by either PKD1 or PDK2. The PDK2-Id2 interaction is regulated by PDK1-dependent phosphorylation of PDK2. (PMID:16311606)
• enigma homolog enigma-like LIM domain protein is a restraining factor of the oncogenic activity of Id proteins in neural tumors (PMID:16549780)
• ID proteins (ID1, ID2, ID3 and ID4) were significantly increased in Mecp2-deficient Rett syndrome brain; ID genes are ideal targets for MeCP2 regulation of neuronal maturation that may explain the molecular pathogenesis of Rett syndrome (PMID:16682435)
• Global gene expression analysis in neuroblastoma cells engineered to acutely express the E protein E47 and Id2, showed that p57Kip2 is a target of E47. (PMID:16705184)
• findings indicate that deregulated Id activity might be useful to reprogramme quiescent neurons into the axonal growth mode (PMID:16810178)
• ID2, which can inactivate E2A and perhaps PAX5, is not detectable in normal B cells but is strongly and uniformly expressed in Hodgkin-Reed/Sternberg (HRS) cells of all cases of classical Hodgkin’s lymphoma (HL). (PMID:16877363)
• OLIG2 expression was predominant over ID2 expression in oligodendroglial tumors, while ID2 expression was predominant over OLIG2 expression in astrocytic tumors. (PMID:17431671)
• RFX1 mediates the immediate early response of the Id2 gene by serum stimulation and suggest that the function of RFX1 is regulated intramolecularly in its suppression in growth-arrested cells. (PMID:17630394)
• Our data demonstrate that IL-1beta-induced Id2 expression in VSMC is mediated by the transcription factor Egr-1 in VSMC. (PMID:17631285)
• The high levels of Id-2 expression in both cytoplasmic and nuclear regions predicted longer patient survival, and Id-2 may be used for prognostication for oesophageal squamous cell carcinoma (ESCC) patients. (PMID:18000500)
• Id2 commonly is overexpressed in highly proliferative T-cell lymphomas, and its expression may result from transcriptional activation of myc in these tumors. (PMID:18085637)
• ID2 plays a significant role in the metastatic process during progression of HCC. This action might be explained, at least in part, by altered cell mobility due to decreased secretion of VEGF. (PMID:18281534)
• The integration of signals at the level of Id gene expression may contribute to the pathogenesis of familial pulmonary arterial hypertension (PMID:18436795)
• activation of protein kinase A elicits an immediate response through induction of genes such as ID2 and FosB, followed by sustained secretion of bone-related cytokines such as BMP-2, IGF-1, and IL-11 (PMID:18490653)
• Id2 is upregulated in CRC, and is important in promoting cell survival. (PMID:18806828)
• Results suggest that in lymphoma cells overexpressing growth hormone, there is an upregulation of Id2 protein that appears to involve STAT protein activity. (PMID:19010462)
• ID2 protein was expressed in 83.3% of this group of classical Hodgkin lymphoma, staining strongly in both cytoplasm and nucleus of the Hodgkin and Reed-Sternberg (HRS) cells, and was positively correlated with EBV-LMP1 (PMID:19099554)
• the relationship between the expression of ID2 in non-small cell lung cancer (NSCLC) patients and the clinicopathological features and prognosis of these patients (PMID:19129913)
• VEGF165 may partially inhibit TGF-beta1-induced epithelial-mesenchymal transition by upregulating the expressions of BMP-7 and Id2. (PMID:19180920)
• Overexpression of Id2 in ERalpha-positive epithelial tumor cells indeed increases the cells’ invasive potential through a mechanism independent of dimerization to basic helix-loop-helix factors. (PMID:19257909)
• association between Id2 and lymphangiogenesis is suggested by co-localization of Id2, VEGFR-3 and lymphatic vascular endothelial hyaluronan receptor-1 (PMID:19260835)
• Id2-deficient mice display increased CD8+ T cell apoptosis resulting in fewer effector and memory T cells (PMID:19269192)
• Genes for Fra2, Id2, and CSF1-receptor are deregulated, regardless of whether the in anaplastic large cell lymphoma contains the t(2;5). (PMID:19321746)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	id2b	ENSDARG00000029544
danio_rerio	id2a	ENSDARG00000055283
mus_musculus	Id2	ENSMUSG00000020644
rattus_norvegicus	Id2	ENSRNOG00000007237
drosophila_melanogaster	emc	FBGN0000575

Paralogs (3): ID3 (ENSG00000117318), ID1 (ENSG00000125968), ID4 (ENSG00000172201)

Protein

Protein identifiers

DNA-binding protein inhibitor ID-2 — Q02363 (reviewed: Q02363)

Alternative names: Class B basic helix-loop-helix protein 26, Inhibitor of DNA binding 2, Inhibitor of differentiation 2

All UniProt accessions (2): Q02363, Q53T66

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator (lacking a basic DNA binding domain) which negatively regulates the basic helix-loop-helix (bHLH) transcription factors by forming heterodimers and inhibiting their DNA binding and transcriptional activity. Implicated in regulating a variety of cellular processes, including cellular growth, senescence, differentiation, apoptosis, angiogenesis, and neoplastic transformation. Inhibits skeletal muscle and cardiac myocyte differentiation. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer. Restricts the CLOCK and BMAL1 localization to the cytoplasm. Plays a role in both the input and output pathways of the circadian clock: in the input component, is involved in modulating the magnitude of photic entrainment and in the output component, contributes to the regulation of a variety of liver clock-controlled genes involved in lipid metabolism.

Subunit / interactions. Interacts with GATA4 and NKX2-5. Interacts with NR0B2. Interacts with CLOCK and BMAL1. Interacts with IFI204. Interacts with NEDD9/HEF1. Interacts with ASB4; this interaction promotes ID2 proteasomal degradation.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Highly expressed in early fetal tissues, including those of the central nervous system.

Post-translational modifications. Ubiquitinated in a ASB4-depedent manner, leading to proteasomal degradation. Phosphorylated in vitro by CDK1, PKA and PKC.

Domain organisation. The bHLH domain is essential for its repressor activity towards the CLOCK-BMAL1 heterodimer.

RefSeq proteins (1): NP_002157* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR026052	DNA-bd_prot-inh	Family
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00010

UniProt features (10 total): modified residue 2, sequence conflict 2, helix 2, chain 1, domain 1, short sequence motif 1, strand 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4AYA	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q02363-F1	69.21	0.32

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): 14, 25

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9031628	NGF-stimulated transcription

MSigDB gene sets: 801 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_CIRCADIAN_RHYTHM, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_EPITHELIUM_DEVELOPMENT, chr2p25, KOBAYASHI_EGFR_SIGNALING_24HR_UP, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, FREAC2_01, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_NATURAL_KILLER_CELL_DIFFERENTIATION

GO Biological Process (61): negative regulation of transcription by RNA polymerase II (GO:0000122), metanephros development (GO:0001656), natural killer cell differentiation (GO:0001779), thigmotaxis (GO:0001966), membranous septum morphogenesis (GO:0003149), bundle of His development (GO:0003166), regulation of transcription by RNA polymerase II (GO:0006357), heart development (GO:0007507), circadian rhythm (GO:0007623), adult locomotory behavior (GO:0008344), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), oligodendrocyte development (GO:0014003), regulation of lipid metabolic process (GO:0019216), olfactory bulb development (GO:0021772), neuron differentiation (GO:0030182), B cell differentiation (GO:0030183), circadian regulation of gene expression (GO:0032922), mammary gland epithelial cell proliferation (GO:0033598), regulation of circadian rhythm (GO:0042752), entrainment of circadian clock by photoperiod (GO:0043153), enucleate erythrocyte differentiation (GO:0043353), obsolete negative regulation of DNA-binding transcription factor activity (GO:0043433), locomotor rhythm (GO:0045475), negative regulation of B cell differentiation (GO:0045578), positive regulation of fat cell differentiation (GO:0045600), positive regulation of erythrocyte differentiation (GO:0045648), positive regulation of macrophage differentiation (GO:0045651), regulation of neuron differentiation (GO:0045664), negative regulation of osteoblast differentiation (GO:0045668), positive regulation of blood pressure (GO:0045777), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), cell maturation (GO:0048469), Peyer’s patch development (GO:0048541), embryonic digestive tract morphogenesis (GO:0048557), positive regulation of smooth muscle cell proliferation (GO:0048661), neuron fate commitment (GO:0048663), cell morphogenesis involved in neuron differentiation (GO:0048667), astrocyte differentiation (GO:0048708)

GO Molecular Function (6): transcription corepressor activity (GO:0003714), transmembrane transporter binding (GO:0044325), protein dimerization activity (GO:0046983), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), transcription regulator inhibitor activity (GO:0140416), protein binding (GO:0005515)

GO Cellular Component (6): euchromatin (GO:0000791), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Nuclear Events (kinase and transcription factor activation)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of gene expression	4
cellular anatomical structure	3
transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
lymphocyte differentiation	2
gene expression	2
circadian rhythm	2
protein binding	2
regulation of transcription by RNA polymerase II	1
kidney development	1
natural killer cell activation	1
behavior	1
anatomical structure morphogenesis	1
ventricular septum morphogenesis	1
His-Purkinje system development	1
ventricular cardiac muscle tissue development	1
regulation of DNA-templated transcription	1
animal organ development	1
circulatory system development	1
rhythmic process	1
locomotory behavior	1
adult behavior	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
glial cell development	1
oligodendrocyte differentiation	1
lipid metabolic process	1
regulation of primary metabolic process	1
olfactory lobe development	1
anatomical structure development	1
cell differentiation	1
generation of neurons	1
B cell activation	1
epithelial cell proliferation	1
mammary gland epithelium development	1
regulation of biological process	1
transcription coregulator activity	1
DNA-binding transcription factor binding	1
transcription regulator activity	1
molecular function inhibitor activity	1

Protein interactions and networks

STRING

2066 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ID2	TCF3	P15883	870
ID2	OLIG1	Q8TAK6	868
ID2	OLIG2	Q13516	855
ID2	NKX2-5	P52952	854
ID2	TCF4	P15884	761
ID2	IL7R	P16871	749
ID2	ZBTB18	Q99592	724
ID2	NFIL3	Q16649	706
ID2	SPI1	P17947	704
ID2	KLF17	Q5JT82	702
ID2	GATA4	P43694	683
ID2	EOMES	O95936	675
ID2	TBX5	Q99593	662
ID2	PTPRC	P08575	661
ID2	TBX21	Q9UL17	659

IntAct

125 interactions, top by confidence:

A	B	Type	Score
ID2	TCF4	psi-mi:“MI:0915”(physical association)	0.800
ID2	TCF4	psi-mi:“MI:0914”(association)	0.800
ID2	TCF12	psi-mi:“MI:0915”(physical association)	0.750
ID2	TCF3	psi-mi:“MI:0915”(physical association)	0.670
ID2	ASCL4	psi-mi:“MI:0915”(physical association)	0.670
PDLIM5	ID2	psi-mi:“MI:0915”(physical association)	0.630
ID2	PDLIM5	psi-mi:“MI:0915”(physical association)	0.630
PDLIM5	ID2	psi-mi:“MI:0407”(direct interaction)	0.630
PKD2	ID2	psi-mi:“MI:0915”(physical association)	0.600
ID2	PKD2	psi-mi:“MI:0915”(physical association)	0.600
ID2	PKD2	psi-mi:“MI:0403”(colocalization)	0.600
ID2	TCF3	psi-mi:“MI:0915”(physical association)	0.580
TCF3	ID2	psi-mi:“MI:0915”(physical association)	0.580
ID2		psi-mi:“MI:0915”(physical association)	0.560
	ID2	psi-mi:“MI:0915”(physical association)	0.560
ID2	PICK1	psi-mi:“MI:0915”(physical association)	0.560
ID2	TCHP	psi-mi:“MI:0915”(physical association)	0.560
ID2	FANCL	psi-mi:“MI:0915”(physical association)	0.560
ID2	ENKD1	psi-mi:“MI:0915”(physical association)	0.560
FRS3	ID2	psi-mi:“MI:0915”(physical association)	0.560
ID2	C22orf39	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (149): ID2 (Two-hybrid), ID2 (Two-hybrid), ID2 (Reconstituted Complex), ID2 (Affinity Capture-Western), ID2 (Two-hybrid), ID2 (Two-hybrid), ID2 (Reconstituted Complex), ID2 (Affinity Capture-MS), ID2 (Biochemical Activity), DYRK1A (Affinity Capture-Western), DYRK1B (Affinity Capture-Western), ID2 (Biochemical Activity), TCF3 (Affinity Capture-MS), TCF12 (Affinity Capture-MS), RNF113A (Affinity Capture-MS)

ESM2 similar proteins: A0A3Q7H216, A2XS50, A4D998, A8E5T6, B8ASH8, F1B281, F4I274, F4IQQ9, F4JFR7, O49608, O81791, O81900, P0CJ65, P13902, P40923, P41136, P41137, P81393, Q02363, Q0WNR2, Q18053, Q18277, Q2HIV9, Q2QQ32, Q38851, Q3E7L7, Q3ZC46, Q42379, Q4PSR7, Q4PSU4, Q4R5J7, Q5RCH7, Q6PBD7, Q6R0H0, Q700E3, Q700E4, Q7SZ28, Q7XJU1, Q7XJU2, Q7XKS9

Diamond homologs: P18491, P20067, P41133, P41134, P41135, P41136, P41137, P41138, P41139, P47928, Q02363, Q02535, Q06AV5, Q2VIU1, Q3ZC46, Q4R5J7, Q5E981, Q5RCH7, Q66J78, Q688C4, Q6GL62, Q6PBD7, Q712G9, Q7SZ28, Q7ZXF3, Q91399, Q9PWJ5, O73823, O93507, P17542, P22091, P24899, Q6QHK4, O73615, O96004, P57100, P97832, Q0VCE2, Q28555, Q64279

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
CyclinE/CDK2	down-regulates	ID2	phosphorylation
CyclinA2/CDK2	down-regulates	ID2	phosphorylation
POU5F1	“down-regulates quantity by repression”	ID2	“transcriptional regulation”
PML-RARalpha	“up-regulates quantity by expression”	ID2	“transcriptional regulation”
ASB4	“down-regulates quantity by destabilization”	ID2	polyubiquitination
DYRK1B	“down-regulates activity”	ID2	phosphorylation
CDK2	down-regulates	ID2	phosphorylation
ID2	“down-regulates activity”	MYOD1	binding
ID2	“down-regulates activity”	TCF12	binding
ID2	“down-regulates activity”	TCF3	binding
ID2	“down-regulates activity”	MYOD/HEB	binding
ID2	“down-regulates activity”	MYOD/E2-2	binding
ID2	“down-regulates activity”	MYOD/E12E47	binding
ID2	“down-regulates activity”	TCF4	binding
GDNF	“up-regulates quantity by expression”	ID2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 47 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
Negative Regulation of CDH1 Gene Transcription	5	17.2×	6e-04
MITF-M-regulated melanocyte development	5	16.3×	7e-04
Chromatin organization	6	14.0×	6e-04
Chromatin modifying enzymes	6	12.4×	6e-04
RHO GTPase Effectors	5	9.7×	3e-03
PIP3 activates AKT signaling	5	9.5×	3e-03
RAF/MAP kinase cascade	5	8.7×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to glucose starvation	5	37.5×	1e-04
protein phosphorylation	7	10.6×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	24
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

900 predictions. Top by Δscore:

Variant	Effect	Δscore
2:8682837:TTCCA:T	acceptor_loss	1.0000
2:8682838:TCCA:T	acceptor_loss	1.0000
2:8682839:CCA:C	acceptor_loss	1.0000
2:8682840:CAG:C	acceptor_loss	1.0000
2:8679080:GCT:G	donor_gain	0.9900
2:8679140:G:GT	donor_gain	0.9900
2:8679141:G:T	donor_gain	0.9900
2:8679309:GCGGA:G	donor_gain	0.9900
2:8679311:GGA:G	donor_gain	0.9900
2:8679312:GAG:G	donor_gain	0.9900
2:8679314:GTGA:G	donor_gain	0.9900
2:8679318:G:GG	donor_gain	0.9900
2:8682511:CAGGT:C	donor_loss	0.9900
2:8682514:G:GC	donor_loss	0.9900
2:8682515:T:A	donor_loss	0.9900
2:8682841:A:AG	acceptor_gain	0.9900
2:8682841:AG:A	acceptor_gain	0.9900
2:8682842:G:GG	acceptor_gain	0.9900
2:8682842:GG:G	acceptor_gain	0.9900
2:8682842:GGCTT:G	acceptor_gain	0.9900
2:8682904:GCG:G	donor_gain	0.9900
2:8679101:A:T	donor_gain	0.9800
2:8679312:GA:G	donor_gain	0.9800
2:8681852:AGCTG:A	acceptor_gain	0.9800
2:8681853:GCT:G	acceptor_gain	0.9800
2:8681853:GCTGG:G	acceptor_gain	0.9800
2:8682842:GGC:G	acceptor_gain	0.9800
2:8682842:GGCT:G	acceptor_gain	0.9800
2:8679316:GA:G	donor_gain	0.9700
2:8681850:CCAG:C	acceptor_loss	0.9700

AlphaMissense

892 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:8682289:T:C	C42R	1.000
2:8682291:C:G	C42W	1.000
2:8682292:T:C	Y43H	1.000
2:8682292:T:G	Y43D	1.000
2:8682301:C:T	L46F	1.000
2:8682302:T:A	L46H	1.000
2:8682302:T:C	L46P	1.000
2:8682302:T:G	L46R	1.000
2:8682311:T:C	L49P	1.000
2:8682313:G:A	V50M	1.000
2:8682314:T:A	V50E	1.000
2:8682356:T:G	I64S	1.000
2:8682359:T:A	L65Q	1.000
2:8682359:T:C	L65P	1.000
2:8682359:T:G	L65R	1.000
2:8682362:A:C	Q66P	1.000
2:8682367:G:C	V68L	1.000
2:8682368:T:A	V68D	1.000
2:8682371:T:A	I69N	1.000
2:8682371:T:G	I69S	1.000
2:8682374:A:T	D70V	1.000
2:8682376:T:C	Y71H	1.000
2:8682380:T:A	I72N	1.000
2:8682380:T:C	I72T	1.000
2:8682380:T:G	I72S	1.000
2:8682389:T:A	L75Q	1.000
2:8682389:T:C	L75P	1.000
2:8682392:A:C	Q76P	1.000
2:8682401:T:A	L79Q	1.000
2:8682401:T:C	L79P	1.000

dbSNP variants (sampled 300 via entrez): RS1000021926 (2:8684237 C>T), RS1000098881 (2:8680330 G>T), RS1000154781 (2:8680184 A>G), RS1000553136 (2:8683470 G>T), RS1000903246 (2:8683709 T>C), RS1000993532 (2:8683217 CTA>C), RS1001197004 (2:8684724 G>C), RS1001647958 (2:8684538 C>A,G,T), RS1001774942 (2:8681414 A>G), RS1002227209 (2:8681179 G>C), RS1002636224 (2:8684813 G>C), RS1002988001 (2:8681832 T>A,C,G), RS1002999301 (2:8681449 GCTTT>G), RS1003495392 (2:8682143 T>C,G), RS1003849397 (2:8682295 T>G)

Disease associations

OMIM: gene MIM:600386 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart disease	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital heart disease	Disputed	AD

Mondo (1): congenital heart disease (MONDO:0005453)

Orphanet (0):

HPO phenotypes

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

GWAS associations

56 associations (top):

Study	Trait	p-value
GCST001316_9	IgE levels	2.000000e-07
GCST002083_11	Self-reported allergy	1.000000e-07
GCST003075_106	Cognitive decline rate in late mild cognitive impairment	4.000000e-08
GCST003075_74	Cognitive decline rate in late mild cognitive impairment	1.000000e-07
GCST003987_21	Asthma	1.000000e-08
GCST003990_10	Allergy	2.000000e-11
GCST004004_12	Mean corpuscular volume	9.000000e-06
GCST004004_9	Mean corpuscular volume	1.000000e-11
GCST004860_70	Alcoholic chronic pancreatitis	7.000000e-06
GCST004861_37	Itch intensity from mosquito bite	9.000000e-11
GCST005080_3	PR interval	3.000000e-08
GCST006409_42	Allergic rhinitis	1.000000e-14
GCST007045_16	PR interval	1.000000e-26
GCST007994_16	Asthma (age of onset)	2.000000e-06
GCST007995_13	Asthma (childhood onset)	2.000000e-13
GCST008042_19	PR interval	1.000000e-10
GCST008042_29	PR interval	7.000000e-08
GCST009798_27	Asthma	9.000000e-15
GCST010321_103	PR interval	6.000000e-68
GCST010321_163	PR interval	3.000000e-07
GCST010796_177	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-10
GCST010796_1771	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-23
GCST010796_1772	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-14
GCST010796_1773	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-13
GCST010796_1774	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-12
GCST010796_1775	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-12
GCST010796_1801	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-11
GCST010796_1802	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-11
GCST010796_1803	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-11
GCST010796_1805	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0004462	PR interval
EFO:0004327	electrocardiography

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

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	affects expression, affects cotreatment, increases expression, decreases expression	9
sodium arsenite	increases abundance, increases expression, affects cotreatment, decreases expression	7
Estradiol	increases expression, affects cotreatment, decreases expression, decreases reaction, affects binding	7
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	5
Arsenic Trioxide	affects expression, decreases expression, increases expression, affects cotreatment	4
Benzo(a)pyrene	affects methylation, decreases expression	4
Tetrachlorodibenzodioxin	increases expression	4
Cadmium Chloride	decreases expression, increases abundance, increases expression, affects cotreatment	4
Particulate Matter	decreases expression, increases abundance	4
bisphenol A	decreases expression, increases expression	3
Arsenic	decreases expression, increases abundance, affects cotreatment	3
Dexamethasone	decreases expression, affects cotreatment, increases expression	3
Formaldehyde	increases expression	3
Dronabinol	decreases expression, increases expression	3
methylmercuric chloride	decreases expression, increases expression	2
sodium arsenate	decreases expression, increases abundance	2
manganese chloride	increases expression, affects cotreatment, decreases expression, increases abundance	2
cupric chloride	affects expression, decreases expression	2
nickel sulfate	increases expression	2
(+)-JQ1 compound	decreases expression, increases expression	2
Decitabine	affects cotreatment, affects expression, increases expression	2
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Calcitriol	decreases expression	2
Cisplatin	increases expression	2
Doxorubicin	increases expression, affects response to substance	2
Fluorouracil	increases reaction, decreases expression, increases expression, affects response to substance	2
Hydrogen Peroxide	affects expression, increases expression	2
Manganese	increases expression, affects cotreatment, decreases expression, increases abundance	2
Progesterone	affects cotreatment, decreases expression, increases expression	2

Cellosaurus cell lines

33 cell lines: 30 transformed cell line, 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7TU	e-hChon-1	Transformed cell line	Female
CVCL_B7TV	e-hChon-2	Transformed cell line	Female
CVCL_B7TW	e-hChon-3	Transformed cell line	Female
CVCL_B7U0	e-hDFib3	Transformed cell line	Male
CVCL_B7U4	e-hLEC-1	Transformed cell line
CVCL_B7U5	e-hLEC-2	Transformed cell line
CVCL_B7U6	e-hMEC-1	Transformed cell line
CVCL_B7U7	e-hMEC-2	Transformed cell line
CVCL_B7U8	e-hMEC-3	Transformed cell line
CVCL_B7U9	e-hOB-1	Transformed cell line	Female

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