HEY2

Summary

HEY2 (hes related family bHLH transcription factor with YRPW motif 2, HGNC:4881) is a protein-coding gene on chromosome 6q22.31, encoding Hairy/enhancer-of-split related with YRPW motif protein 2 (Q9UBP5). Downstream effector of Notch signaling which may be required for cardiovascular development.

This gene encodes a member of the hairy and enhancer of split-related (HESR) family of basic helix-loop-helix (bHLH)-type transcription factors. The encoded protein forms homo- or hetero-dimers that localize to the nucleus and interact with a histone deacetylase complex to repress transcription. Expression of this gene is induced by the Notch signal transduction pathway. Two similar and redundant genes in mouse are required for embryonic cardiovascular development, and are also implicated in neurogenesis and somitogenesis. Alternatively spliced transcript variants have been found, but their biological validity has not been determined.

Source: NCBI Gene 23493 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial thoracic aortic aneurysm and aortic dissection (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 26
• Clinical variants (ClinVar): 68 total — 1 pathogenic
• Phenotypes (HPO): 42
• Transcription factor: yes — 22 downstream targets (CollecTRI)
• MANE Select transcript: NM_012259

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4881
Approved symbol	HEY2
Name	hes related family bHLH transcription factor with YRPW motif 2
Location	6q22.31
Locus type	gene with protein product
Status	Approved
Aliases	bHLHb32, HERP1, HESR2
Ensembl gene	ENSG00000135547
Ensembl biotype	protein_coding
OMIM	604674
Entrez	23493

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000368364, ENST00000368365

RefSeq mRNA: 1 — MANE Select: NM_012259 NM_012259

CCDS: CCDS5131

Canonical transcript exons

ENST00000368364 — 5 exons

Exon	Start	End
ENSE00000919127	125752007	125752090
ENSE00000919128	125754465	125754546
ENSE00001446976	125749632	125749859
ENSE00001446986	125759117	125761269
ENSE00003469226	125751801	125751879

Expression profiles

Bgee: expression breadth ubiquitous, 247 present calls, max score 95.80.

FANTOM5 (CAGE): breadth broad, TPM avg 4.2200 / max 199.1152, expressed in 654 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69667	3.4715	598
69666	0.7486	400

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
popliteal artery	UBERON:0002250	95.80	gold quality
tibial artery	UBERON:0007610	95.79	gold quality
heart right ventricle	UBERON:0002080	95.75	gold quality
left ventricle myocardium	UBERON:0006566	94.46	gold quality
blood vessel layer	UBERON:0004797	94.13	gold quality
right coronary artery	UBERON:0001625	93.10	gold quality
aorta	UBERON:0000947	92.94	gold quality
oocyte	CL:0000023	92.38	gold quality
descending thoracic aorta	UBERON:0002345	91.66	gold quality
secondary oocyte	CL:0000655	91.64	gold quality
cardiac ventricle	UBERON:0002082	90.48	gold quality
right uterine tube	UBERON:0001302	90.46	gold quality
heart left ventricle	UBERON:0002084	90.35	gold quality
corpus epididymis	UBERON:0004359	90.23	gold quality
apex of heart	UBERON:0002098	90.14	gold quality
coronary artery	UBERON:0001621	89.86	gold quality
left coronary artery	UBERON:0001626	89.69	gold quality
thoracic aorta	UBERON:0001515	89.27	gold quality
ascending aorta	UBERON:0001496	89.05	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	88.49	gold quality
biceps brachii	UBERON:0001507	86.47	gold quality
caput epididymis	UBERON:0004358	85.85	gold quality
saphenous vein	UBERON:0007318	85.44	gold quality
heart	UBERON:0000948	85.30	gold quality
myocardium	UBERON:0002349	84.85	gold quality
gastrocnemius	UBERON:0001388	84.50	gold quality
sperm	CL:0000019	83.86	gold quality
muscle of leg	UBERON:0001383	83.67	gold quality
medial globus pallidus	UBERON:0002477	83.53	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.52	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.17
E-CURD-112	no	432.85

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

22 targets.

Target	Regulation
ACTA2	Repression
CDKN1B
DDR1
DYM
EFNB2
GATA4	Repression
GATA6	Repression
HES1
HEY1	Activation
HEY2
KDR	Activation
MMP10
MYL2
MYL7
MYOCD
NOTCH1
NOTCH4
NPPA
RUNX2	Repression
SMTN	Repression
SPP1	Activation
TBX2	Repression

JASPAR motifs

Motif	Name	Family
MA0649.1	HEY2	Hairy-related factors
MA0649.2	HEY2	Hairy-related factors

JASPAR matrix evidence (PMIDs): PMID:22615585

Upstream regulators (CollecTRI, top): FOXC1, FOXC2, FOXO3, HEY2, HEYL, JAG1, NOTCH1, NOTCH3, NOTCH4, NR2F2, PDCD10, RBPJ, TAL1

miRNA regulators (miRDB)

126 targeting HEY2, 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-4262	100.00	73.26	3931
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
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-767-5P	99.95	70.85	993
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-1236-3P	99.94	68.04	1695

Literature-anchored findings (GeneRIF, showing 30)

• These results indicate that the molecular association between HES1-, HEY2- and SIRT1-related proteins is conserved among metazoans, from Drosophila to human, and suggest that the Sir2-bHLH interaction also plays important roles in human cells. (PMID:12535671)
• To clarify the role of HEY2 in human CHD and AGS, we screened by direct sequencing 23 children with CHD and 38 patients diagnosed with AGS. Mutation of HEY2 is not a major contributing factor. (PMID:15389319)
• A similar gene in mouse regulates cardiovascular development (PMID:15680351)
• HERP1 may play a role in promoting the phenotypic modulation of vascular smooth muscle cells during vascular injury and atherosclerotic process by interfering with SRF binding to CArG-box (PMID:16151017)
• CHF1/Hey2 may affect smooth-muscle cell phenotype through an important transcriptional mechanism (PMID:16293227)
• This result suggests a possible role of HEY2 in the regulation of ventricular septation in humans. (PMID:16329098)
• Present a novel mechanism by which a balance between Notch-1/-2/-4 signaling, via CBF-1, and HRT-1/-2 activity determines the expression of smooth muscle differentiation markers including actin. (PMID:18239137)
• The absence of mutations in NOTCH2 and Hey2 its downstream target in the heart does not exclude the possibility that other genes in this pathway might be implicated in the diverse phenotypes observed in Alagille syndrome (PMID:18266235)
• In this study, we analyzed the effects of HESR1, -2, and -3 on DAT1 expression in human neuroblastoma SH-SY5Y cells (PMID:21290414)
• Through activating the Dll4-Notch-Hey2 signaling pathway, HGF indirectly promotes the proliferation and migration ability of cells, so that offspring artery branches are formed. (PMID:21362320)
• Report down-regulation of Notch signaling components NOTCH3 and HEY2 in abdominal aortic aneurysms. (PMID:22310065)
• Hey2 and COUP-TFII have an important role in arteriovenous differentiation of human endothelial cells. (PMID:23744056)
• Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death (PMID:23872634)
• Data indicate that culture abrogated differential gene expression in part due to gradual loss of canonical Notch activity and HEY2 expression. (PMID:24108462)
• a new HRD1-associated membrane protein named HERP2, which is homologous to the previously identified HRD1 partner HERP1. Despite sequence homology, HERP2 is constitutively expressed in cells, whereas HERP1 is highly induced by ER stress. (PMID:24366871)
• Overexpression of HEY1 and HEY2 in esophageal squamous cell carcinoma (ESCC) is correlated to different indices of poor prognosis, and it is extrapolated that such overexpression is important in progression and development of ESCC tumorigenesis. (PMID:25361534)
• bone morphogenic proteins within the serum of cell culture medium are potent inducers of endothelial Hey1 and Hey2 gene expression within the first few hours after medium change (PMID:25799559)
• Individuals with HEY2 duplications should be screened for congenital heart defects. (PMID:25832314)
• HEY2 CC genotype may be a favorable prognostic marker for BrS, protectively acting to prevent ventricular fibrillation presumably by regulating the repolarization current. (PMID:26729854)
• HEY2 as a promising biomarker for unfavorable outcomes and a novel therapeutic target for the clinical management of HCC (PMID:27191260)
• Genetic variation of HEY2 is associated with Brugada syndrome through alteration of ion channel expression in the cardiac ventricular wall. (PMID:28637782)
• We also highlighted that Hey2 is involved in radiation-induced EndoMT and that Hey2 invalidation reduces EndoMT and tissue damage. (PMID:28694461)
• The findings identify HEY2 as a novel component of the NKX2-5 cardiac transcriptional network. (PMID:29636455)
• These results provide evidence that miR-146a and Hey2 form a mutual negative feedback regulatory loop to regulate the inflammatory response in chronic apical periodontitis. (PMID:30125982)
• we confirmed that lncRNA PRNCR1 upregulates HEY2 to promote tumor progression in non-small cell lung cancer by competitively binding miR-448. (PMID:30257372)
• Attenuation of PRRX2 and HEY2 enables efficient conversion of adult human skin fibroblasts to neurons. (PMID:31255287)
• microRNA-599 promotes apoptosis and represses proliferation and epithelial-mesenchymal transition of papillary thyroid carcinoma cells via downregulation of Hey2-depentent Notch signaling pathway. (PMID:31565805)
• TWIST1 correlates with Notch signaling pathway to develop esophageal squamous cell carcinoma. (PMID:32712748)
• Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms. (PMID:32820247)
• Notch-HEY2 signaling pathway contributes to the differentiation of CD34(+) hematopoietic-like stem cells from adult peripheral blood insulin-producing cells after the treatment with platelet-derived mitochondria. (PMID:32997309)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	hey2	ENSDARG00000013441
mus_musculus	Hey2	ENSMUSG00000019789
rattus_norvegicus	Hey2	ENSRNOG00000013364
drosophila_melanogaster	E(spl)m8-HLH	FBGN0000591
drosophila_melanogaster	E(spl)m3-HLH	FBGN0002609
drosophila_melanogaster	E(spl)m5-HLH	FBGN0002631
drosophila_melanogaster	E(spl)m7-HLH	FBGN0002633
drosophila_melanogaster	E(spl)mbeta-HLH	FBGN0002733
drosophila_melanogaster	E(spl)mdelta-HLH	FBGN0002734
drosophila_melanogaster	E(spl)mgamma-HLH	FBGN0002735
drosophila_melanogaster	Hesr	FBGN0030899
drosophila_melanogaster	cwo	FBGN0259938

Paralogs (12): HES2 (ENSG00000069812), HES1 (ENSG00000114315), BHLHE41 (ENSG00000123095), BHLHE40 (ENSG00000134107), HES6 (ENSG00000144485), HEYL (ENSG00000163909), HEY1 (ENSG00000164683), HES3 (ENSG00000173673), HES7 (ENSG00000179111), HELT (ENSG00000187821), HES4 (ENSG00000188290), HES5 (ENSG00000197921)

Protein

Protein identifiers

Hairy/enhancer-of-split related with YRPW motif protein 2 — Q9UBP5 (reviewed: Q9UBP5)

Alternative names: Cardiovascular helix-loop-helix factor 1, Class B basic helix-loop-helix protein 32, HES-related repressor protein 2, Hairy and enhancer of split-related protein 2, Hairy-related transcription factor 2, Protein gridlock homolog

All UniProt accessions (2): Q9UBP5, Q5TF93

UniProt curated annotations — full annotation on UniProt →

Function. Downstream effector of Notch signaling which may be required for cardiovascular development. Transcriptional repressor which binds preferentially to the canonical E box sequence 5’-CACGTG-3’. Represses transcription by the cardiac transcriptional activators GATA4 and GATA6.

Subunit / interactions. May self-associate. Interacts with GATA4, HES1 and HEYL. Interacts with HDAC1, NCOR1 and SIN3A. Interacts with ARNT and GATA6.

Subcellular location. Nucleus.

Similarity. Belongs to the HEY family.

RefSeq proteins (1): NP_036391* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003650	Orange_dom	Domain
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR050370	HES_HEY	Family

Pfam: PF00010, PF07527

UniProt features (15 total): sequence variant 4, region of interest 3, compositionally biased region 3, domain 2, chain 1, mutagenesis site 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBP5-F1	65.56	0.30

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 (1):

Position	Phenotype
54	impairs transcriptional repression.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-2122947	NOTCH1 Intracellular Domain Regulates Transcription
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-8940973	RUNX2 regulates osteoblast differentiation
R-HSA-9013508	NOTCH3 Intracellular Domain Regulates Transcription
R-HSA-9013695	NOTCH4 Intracellular Domain Regulates Transcription
R-HSA-9733709	Cardiogenesis

MSigDB gene sets: 453 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, REACTOME_SIGNALING_BY_NOTCH, GOBP_REGULATION_OF_VASCULOGENESIS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_AXIS_SPECIFICATION, GOBP_VENTRICULAR_SEPTUM_MORPHOGENESIS, GOBP_CORONARY_VASCULATURE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CARDIAC_LEFT_VENTRICLE_MORPHOGENESIS, GOBP_HEART_TRABECULA_MORPHOGENESIS, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS

GO Biological Process (67): negative regulation of transcription by RNA polymerase II (GO:0000122), vasculogenesis (GO:0001570), muscular septum morphogenesis (GO:0003150), outflow tract morphogenesis (GO:0003151), cardiac conduction system development (GO:0003161), aortic valve morphogenesis (GO:0003180), pulmonary valve morphogenesis (GO:0003184), tricuspid valve morphogenesis (GO:0003186), tricuspid valve formation (GO:0003195), epithelial to mesenchymal transition involved in endocardial cushion formation (GO:0003198), endocardial cushion to mesenchymal transition involved in heart valve formation (GO:0003199), cardiac ventricle morphogenesis (GO:0003208), cardiac left ventricle morphogenesis (GO:0003214), cardiac right ventricle morphogenesis (GO:0003215), ventricular trabecula myocardium morphogenesis (GO:0003222), regulation of transcription by RNA polymerase II (GO:0006357), Notch signaling pathway (GO:0007219), anterior/posterior axis specification (GO:0009948), anterior/posterior pattern specification (GO:0009952), positive regulation of heart rate (GO:0010460), negative regulation of gene expression (GO:0010629), cardiac muscle cell apoptotic process (GO:0010659), negative regulation of cardiac muscle cell apoptotic process (GO:0010667), mesenchymal cell development (GO:0014031), cardiac muscle hypertrophy in response to stress (GO:0014898), ascending aorta morphogenesis (GO:0035910), dorsal aorta morphogenesis (GO:0035912), umbilical cord morphogenesis (GO:0036304), cell fate commitment (GO:0045165), regulation of inner ear auditory receptor cell differentiation (GO:0045607), negative regulation of Notch signaling pathway (GO:0045746), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of neurogenesis (GO:0050767), smooth muscle cell differentiation (GO:0051145), negative regulation of smooth muscle cell differentiation (GO:0051151), ventricular cardiac muscle cell development (GO:0055015), cardiac muscle cell proliferation (GO:0060038), positive regulation of cardiac muscle cell proliferation (GO:0060045), cardiac epithelial to mesenchymal transition (GO:0060317)

GO Molecular Function (13): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription factor activity (GO:0003700), identical protein binding (GO:0042802), histone deacetylase binding (GO:0042826), sequence-specific DNA binding (GO:0043565), protein dimerization activity (GO:0046983), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), transcription repressor complex (GO:0017053)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Signaling by NOTCH1	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
RUNX2 regulates bone development	1
Signaling by NOTCH3	1
Signaling by NOTCH4	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
heart valve morphogenesis	2
cardiac ventricle morphogenesis	2
regulation of DNA-templated transcription	2
transcription cis-regulatory region binding	2
protein binding	2
negative regulation of DNA-templated transcription	1
cell differentiation	1
blood vessel morphogenesis	1
ventricular septum morphogenesis	1
muscle tissue morphogenesis	1
heart morphogenesis	1
anatomical structure morphogenesis	1
cardiac muscle tissue development	1
aortic valve development	1
pulmonary valve development	1
tricuspid valve development	1
atrioventricular valve morphogenesis	1
tricuspid valve morphogenesis	1
atrioventricular valve formation	1
endocardial cushion formation	1
cardiac epithelial to mesenchymal transition	1
heart valve formation	1
endocardial cushion to mesenchymal transition	1
cardiac chamber morphogenesis	1
cardiac ventricle development	1
ventricular cardiac muscle tissue morphogenesis	1
heart trabecula morphogenesis	1
cell surface receptor signaling pathway	1
axis specification	1
anterior/posterior pattern specification	1
regionalization	1
regulation of heart rate	1
positive regulation of heart contraction	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1

Protein interactions and networks

STRING

1428 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HEY2	JAG1	P78504	915
HEY2	NOTCH1	P46531	865
HEY2	NOTCH4	Q99466	819
HEY2	NOTCH2	Q04721	797
HEY2	GATA4	P43694	780
HEY2	EPHB4	P54760	752
HEY2	DLL4	Q9NR61	748
HEY2	RBPJ	Q06330	738
HEY2	EFNB2	P52799	738
HEY2	TBX5	Q99593	708
HEY2	NOTCH3	Q9UM47	705
HEY2	NKX2-5	P52952	704
HEY2	DLL1	O00548	677
HEY2	JAG2	Q9Y219	674
HEY2	SNRK	Q9NRH2	667

IntAct

77 interactions, top by confidence:

A	B	Type	Score
TRAF1	HEY2	psi-mi:“MI:0915”(physical association)	0.720
HEY2	TRAF1	psi-mi:“MI:0915”(physical association)	0.720
HEY2	HEY1	psi-mi:“MI:0915”(physical association)	0.670
HEY2	ARL10	psi-mi:“MI:0914”(association)	0.640
RBPMS	HEY2	psi-mi:“MI:0915”(physical association)	0.560
HEY2	RBPMS	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	HEY2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP4-4	HEY2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP1-1	HEY2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-9	HEY2	psi-mi:“MI:0915”(physical association)	0.560
HSF2BP	HEY2	psi-mi:“MI:0915”(physical association)	0.560
TRAF4	HEY2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-1	HEY2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP3-1	HEY2	psi-mi:“MI:0915”(physical association)	0.560
FHL5	HEY2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP8-1	HEY2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP11-1	HEY2	psi-mi:“MI:0915”(physical association)	0.560
PDLIM7	HEY2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-2	HEY2	psi-mi:“MI:0915”(physical association)	0.560
HOXA1	HEY2	psi-mi:“MI:0915”(physical association)	0.560
SIRT1	HEY2	psi-mi:“MI:0915”(physical association)	0.540
HEY2	SIRT1	psi-mi:“MI:0407”(direct interaction)	0.540
HEY2	HTT	psi-mi:“MI:0915”(physical association)	0.510
	HEY2	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (69): HEY2 (Two-hybrid), HEY2 (Two-hybrid), HEY1 (Affinity Capture-MS), CARM1 (Affinity Capture-MS), ARL10 (Affinity Capture-MS), IST1 (Affinity Capture-MS), HEY2 (Two-hybrid), FBXO45 (Affinity Capture-Western), HEY1 (Affinity Capture-MS), ARL10 (Affinity Capture-MS), CHMP1A (Affinity Capture-MS), IST1 (Affinity Capture-MS), CARM1 (Affinity Capture-MS), HEY2 (Reconstituted Complex), HEY2 (Reconstituted Complex)

ESM2 similar proteins: O57337, P09086, P13096, P13097, P14003, P29303, P31362, P31364, P35428, P42128, P42571, P49335, P54841, P54842, P62515, P62516, Q00196, Q00P32, Q01068, Q01069, Q01070, Q04666, Q07291, Q14469, Q26263, Q29013, Q2KIN4, Q3UCQ1, Q3ZBG4, Q5PPM5, Q5PRF9, Q66KK8, Q6IRB2, Q6PBD4, Q6PFG8, Q7KM13, Q812B1, Q8AVU4, Q8AXV5, Q8AXV6

Diamond homologs: A0MLS5, A6NFD8, O00327, O14503, O35779, O54792, O57337, O61734, O88529, P13097, P14003, P29303, P35428, P35429, P70120, Q00P32, Q01069, Q03062, Q04666, Q14469, Q26263, Q28HA8, Q2KIN4, Q2NL18, Q3ZBG4, Q5PPM5, Q5R4T2, Q5RAI7, Q5TA89, Q66KK8, Q6IRB2, Q6PBD4, Q6QB00, Q6YGZ5, Q7KM13, Q7TS99, Q8AVU4, Q8AXV5, Q8AXV6, Q8BKT2

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
HEY2	down-regulates	NOTCH1	binding
NOTCH	“up-regulates quantity by expression”	HEY2	“transcriptional regulation”
NOTCH4	“up-regulates quantity by expression”	HEY2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 30 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
Keratinization	8	22.3×	7e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	50
Likely benign	3
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3777042	NM_012259.3(HEY2):c.171G>C (p.Glu57Asp)	Pathogenic

SpliceAI

600 predictions. Top by Δscore:

Variant	Effect	Δscore
6:125749857:GGG:G	donor_gain	1.0000
6:125749858:GGG:G	donor_gain	1.0000
6:125749859:GGT:G	donor_loss	1.0000
6:125749860:GT:G	donor_loss	1.0000
6:125749861:T:G	donor_loss	1.0000
6:125751875:GAGGG:G	donor_gain	1.0000
6:125751877:GGG:G	donor_gain	1.0000
6:125751878:GGG:G	donor_gain	1.0000
6:125752000:T:A	acceptor_gain	1.0000
6:125752001:G:A	acceptor_gain	1.0000
6:125752005:A:AG	acceptor_gain	1.0000
6:125752006:G:GT	acceptor_gain	1.0000
6:125752006:GA:G	acceptor_gain	1.0000
6:125752006:GAT:G	acceptor_gain	1.0000
6:125752006:GATT:G	acceptor_gain	1.0000
6:125752091:G:GG	donor_gain	1.0000
6:125749855:TCGGG:T	donor_gain	0.9900
6:125749856:CGGG:C	donor_gain	0.9900
6:125749857:GGGG:G	donor_gain	0.9900
6:125749858:GG:G	donor_gain	0.9900
6:125749859:GG:G	donor_gain	0.9900
6:125749860:G:GG	donor_gain	0.9900
6:125751795:TCATA:T	acceptor_loss	0.9900
6:125751796:CATA:C	acceptor_loss	0.9900
6:125751798:TAGGC:T	acceptor_loss	0.9900
6:125751799:A:AG	acceptor_gain	0.9900
6:125751799:AGGC:A	acceptor_loss	0.9900
6:125751800:G:GG	acceptor_gain	0.9900
6:125751874:A:T	donor_gain	0.9900
6:125751876:AGGGG:A	donor_loss	0.9900

AlphaMissense

2181 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:125751876:A:C	R53S	1.000
6:125751876:A:T	R53S	1.000
6:125752011:T:A	I56K	1.000
6:125752013:G:A	E57K	1.000
6:125752014:A:T	E57V	1.000
6:125752015:G:C	E57D	1.000
6:125752015:G:T	E57D	1.000
6:125752016:A:G	K58E	1.000
6:125752017:A:T	K58I	1.000
6:125752018:A:C	K58N	1.000
6:125752018:A:T	K58N	1.000
6:125752021:G:C	R59S	1.000
6:125752021:G:T	R59S	1.000
6:125752022:C:A	R60S	1.000
6:125752022:C:G	R60G	1.000
6:125752022:C:T	R60C	1.000
6:125752023:G:C	R60P	1.000
6:125752026:G:C	R61P	1.000
6:125752032:G:C	R63P	1.000
6:125752035:T:A	I64K	1.000
6:125752035:T:C	I64T	1.000
6:125752035:T:G	I64R	1.000
6:125752037:A:G	N65D	1.000
6:125752039:T:A	N65K	1.000
6:125752039:T:G	N65K	1.000
6:125752043:A:C	S67R	1.000
6:125752045:T:A	S67R	1.000
6:125752045:T:G	S67R	1.000
6:125752047:T:C	L68S	1.000
6:125752056:T:C	L71S	1.000

dbSNP variants (sampled 300 via entrez): RS1000054095 (6:125749026 T>A), RS1000261176 (6:125756126 C>A,T), RS1000514239 (6:125753873 C>G), RS1000547136 (6:125753532 A>G,T), RS1000647912 (6:125757160 G>A), RS1000731219 (6:125760073 T>C), RS1000997409 (6:125757411 A>G,T), RS1001007674 (6:125747982 G>T), RS1001439482 (6:125752617 T>G), RS1001459786 (6:125747756 G>A), RS1001491360 (6:125752179 A>T), RS1001868056 (6:125748276 G>C), RS1001878157 (6:125754521 G>A), RS1001992606 (6:125754269 C>A,T), RS1002103793 (6:125761055 A>C)

Disease associations

OMIM: gene MIM:604674 | disease phenotypes: MIM:187500

GenCC curated gene-disease

Disease	Classification	Inheritance
familial thoracic aortic aneurysm and aortic dissection	Supportive	Autosomal dominant
congenital heart disease	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital heart disease	Limited	AD

Mondo (3): tetralogy of fallot (MONDO:0008542), congenital heart disease (MONDO:0005453), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625)

Orphanet (1): Tetralogy of Fallot (Orphanet:3303)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000023	Inguinal hernia
HP:0000098	Tall stature
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000525	Abnormality iris morphology
HP:0000766	Abnormal sternum morphology
HP:0000822	Hypertension
HP:0000965	Cutis marmorata
HP:0000978	Bruising susceptibility
HP:0001166	Arachnodactyly
HP:0001297	Stroke
HP:0001640	Cardiomegaly
HP:0001643	Patent ductus arteriosus
HP:0001647	Bicuspid aortic valve
HP:0001659	Aortic regurgitation
HP:0001677	Coronary artery atherosclerosis
HP:0001763	Pes planus
HP:0002105	Hemoptysis
HP:0002107	Pneumothorax
HP:0002138	Subarachnoid hemorrhage
HP:0002140	Ischemic stroke
HP:0002326	Transient ischemic attack
HP:0002616	Aortic root aneurysm
HP:0002647	Aortic dissection
HP:0002650	Scoliosis
HP:0002686	Pregnancy history
HP:0002705	High, narrow palate
HP:0002875	Exertional dyspnea
HP:0003549	Abnormality of connective tissue
HP:0004933	Ascending aortic dissection

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST002098_3	Brugada syndrome	5.000000e-17
GCST003524_2	Endometrial cancer	4.000000e-10
GCST003525_1	Endometrial endometrioid carcinoma	1.000000e-11
GCST003542_18	Night sleep phenotypes	6.000000e-06
GCST003720_42	Migraine	5.000000e-09
GCST004284_3	Midgestational circulating levels of PCBs (fetal genetic effect)	3.000000e-07
GCST006464_9	Endometrial cancer	3.000000e-10
GCST006465_17	Endometrial cancer (endometrioid histology)	4.000000e-10
GCST010346_42	TPE interval (resting)	2.000000e-08
GCST010702_89	Subcortical volume (MOSTest)	1.000000e-08
GCST010703_304	Brain morphology (MOSTest)	2.000000e-26
GCST010796_5251	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-09
GCST010796_5252	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-10
GCST010796_5253	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-09
GCST010796_5254	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-10
GCST010796_5255	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-09
GCST010796_5256	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-10
GCST010796_5298	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_5299	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_5300	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-09
GCST010988_377	Adult body size	3.000000e-08
GCST011054_3	Brugada syndrome	8.000000e-09
GCST012353_33	Serum metabolite concentrations in chronic kidney disease	1.000000e-10
GCST90000025_67	Appendicular lean mass	7.000000e-26
GCST90020027_1109	Waist-hip index	4.000000e-08
GCST90086158_10	Brugada syndrome	1.000000e-39

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:1001514	endometrial endometrioid carcinoma
EFO:0007042	polychlorinated biphenyls measurement
EFO:0007959	fetal genotype effect measurement
EFO:0007964	gestational serum measurement
EFO:0004644	TPE interval measurement
EFO:0004346	neuroimaging measurement
EFO:0004327	electrocardiography
EFO:0004980	appendicular lean mass
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D013771	Tetralogy of Fallot	C14.240.400.849; C14.280.400.849; C16.131.240.400.849

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases expression, affects cotreatment	8
Acetaminophen	increases expression	3
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Cadmium	decreases expression, increases expression	2
Estradiol	increases expression, decreases reaction	2
Nickel	decreases expression	2
methylmercuric chloride	decreases expression	1
baicalein	increases expression, decreases reaction	1
2-methyl-4-isothiazolin-3-one	increases expression	1
cypermethrin	decreases expression, decreases reaction	1
sodium arsenite	increases expression	1
baicalin	increases expression, decreases reaction	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
diallyl trisulfide	decreases expression	1
CGP 52608	increases reaction, affects binding	1
N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester	decreases reaction, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
MRK 003	decreases expression	1
Decitabine	affects expression	1
Arsenic Trioxide	decreases expression	1
Acetylcysteine	decreases expression, decreases reaction	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	affects expression	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression, affects response to substance, increases expression	1
Niclosamide	increases expression, decreases reaction	1

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A2P6	SEES3-1V human HEY2, clone1	Embryonic stem cell	Male
CVCL_A2P7	SEES3-1V human HEY2, clone2	Embryonic stem cell	Male
CVCL_A2P8	SEES3-1V human HEY2, clone3	Embryonic stem cell	Male
CVCL_D9G7	Ubigene HEK293 HEY2 KO	Transformed cell line	Female

Clinical trials (associated diseases)

369 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
NCT01971593	PHASE4	TERMINATED	The Effects of Eplerenone on Markers of Myocardial Fibrosis in Adult Congenital Heart Disease
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
NCT00564993	PHASE3	TERMINATED	Cardiac Function Under Stress for Early Detection of the Right Ventricular Insufficiency After Repair of Tetralogy of Fallot
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