HAND2

Summary

HAND2 (heart and neural crest derivatives expressed 2, HGNC:4808) is a protein-coding gene on chromosome 4q34.1, encoding Heart- and neural crest derivatives-expressed protein 2 (P61296). Essential for cardiac morphogenesis, particularly for the formation of the right ventricle and of the aortic arch arteries.

The protein encoded by this gene belongs to the basic helix-loop-helix family of transcription factors. This gene product is one of two closely related family members, the HAND proteins, which are asymmetrically expressed in the developing ventricular chambers and play an essential role in cardiac morphogenesis. Working in a complementary fashion, they function in the formation of the right ventricle and aortic arch arteries, implicating them as mediators of congenital heart disease. In addition, this transcription factor plays an important role in limb and branchial arch development.

Source: NCBI Gene 9464 — RefSeq curated summary.

At a glance

• Gene–disease (curated): HAND2 related congenital heart defect (Moderate, ClinGen) — +3 more curated relationships
• GWAS associations: 20
• Clinical variants (ClinVar): 78 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 13
• Transcription factor: yes — 91 downstream targets (CollecTRI)
• MANE Select transcript: NM_021973

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4808
Approved symbol	HAND2
Name	heart and neural crest derivatives expressed 2
Location	4q34.1
Locus type	gene with protein product
Status	Approved
Aliases	dHand, Thing2, Hed, bHLHa26
Ensembl gene	ENSG00000164107
Ensembl biotype	protein_coding
OMIM	602407
Entrez	9464

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 1 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000359562, ENST00000503024, ENST00000505300

RefSeq mRNA: 1 — MANE Select: NM_021973 NM_021973

CCDS: CCDS3819

Canonical transcript exons

ENST00000359562 — 2 exons

Exon	Start	End
ENSE00001516248	173528735	173530229
ENSE00002030798	173526091	173527375

Expression profiles

Bgee: expression breadth ubiquitous, 147 present calls, max score 97.12.

FANTOM5 (CAGE): breadth broad, TPM avg 13.1919 / max 1715.3858, expressed in 682 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
54878	9.5267	632
54876	2.0756	424
54877	1.5897	331

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
muscle layer of sigmoid colon	UBERON:0035805	97.12	gold quality
apex of heart	UBERON:0002098	96.50	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.98	gold quality
body of uterus	UBERON:0009853	95.88	gold quality
lower esophagus	UBERON:0013473	95.88	gold quality
right atrium auricular region	UBERON:0006631	95.31	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.44	gold quality
endocervix	UBERON:0000458	93.90	gold quality
ascending aorta	UBERON:0001496	93.28	gold quality
thoracic aorta	UBERON:0001515	93.19	gold quality
descending thoracic aorta	UBERON:0002345	92.50	gold quality
heart left ventricle	UBERON:0002084	92.41	gold quality
left coronary artery	UBERON:0001626	92.23	gold quality
stromal cell of endometrium	CL:0002255	91.87	gold quality
right coronary artery	UBERON:0001625	91.80	gold quality
left uterine tube	UBERON:0001303	91.71	gold quality
gall bladder	UBERON:0002110	91.68	gold quality
cardiac atrium	UBERON:0002081	91.48	gold quality
cardiac ventricle	UBERON:0002082	91.22	gold quality
left ovary	UBERON:0002119	90.95	gold quality
aorta	UBERON:0000947	90.76	gold quality
heart	UBERON:0000948	90.07	gold quality
ectocervix	UBERON:0012249	89.78	gold quality
coronary artery	UBERON:0001621	89.40	gold quality
popliteal artery	UBERON:0002250	89.35	gold quality
mucosa of stomach	UBERON:0001199	89.34	gold quality
tibial artery	UBERON:0007610	89.32	gold quality
right ovary	UBERON:0002118	88.89	gold quality
calcaneal tendon	UBERON:0003701	88.01	gold quality
smooth muscle tissue	UBERON:0001135	86.58	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	781.34
E-MTAB-9906	yes	329.35
E-MTAB-6678	yes	27.35
E-MTAB-8410	yes	17.17
E-CURD-46	yes	9.48
E-ANND-3	yes	6.75
E-MTAB-9543	no	1.22

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

91 targets.

Target	Regulation
ABL1
ABRA	Activation
ACAN	Repression
BMP2
BMP4
BMP7	Repression
CARD11
CAT
CCL26
CCL7
CD28
CD3E
CD44
CHAT	Repression
CHST2
CIITA
CLEC6A
COL2A1	Repression
COPS5
CXCL14
CXCR3
DBH	Activation
DEF6
DUOX2
DUOXA2
DUSP16
EIF2S3	Repression
EMX2
FBN1
FN1

JASPAR motifs

Motif	Name	Family
MA1638.1	HAND2	Tal-related
MA1638.2	HAND2	Tal-related

JASPAR matrix evidence (PMIDs): PMID:11812799

Upstream regulators (CollecTRI, top): BCL6, BMP4, FOXO3, GATA3, GLI3, HAND1, HAND2, HOXD13, JUN, MAF, MEF2C, NEUROD1, NFATC1, NFATC2, PHOX2B, PPP3CA, SATB1, SMARCA1, SOX9, STAT1, STAT6, TBX21

miRNA regulators (miRDB)

65 targeting HAND2, 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-5193	100.00	67.26	1744
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-371A-3P	99.99	66.77	91
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
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-3682-5P	99.93	67.97	1163
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-3618	99.69	68.57	1012
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-4261	99.59	70.30	3415

Literature-anchored findings (GeneRIF, showing 37)

• effects of gene mutations on ventricular development (PMID:12858532)
• dHAND/E-protein (E2A, ME2, and ALF1) heterodimers have distinct DNA binding specificities (PMID:15351717)
• These results demonstrate the direct interactions of the Phox2a and b and dHAND transcription factors within a noradrenergic cell type (PMID:16280598)
• demonstrate evolutionarily conserved functions of HAND transcription factors in Drosophila and mammalian cardiogenesis, and reveal a previously unrecognized requirement of Hand genes in hematopoiesis (PMID:16467358)
• Hand2 plays a pivotal role in regulating both cell-autonomous and -nonautonomous functions of the cardiac neural crest. (PMID:19008477)
• Expression of HAND2 and DEIN genes in neuroblastoma is co-regulated by asymmetrical activity of this promoter and modulated by the activity of two cis-regulatory elements acting as weak repressors (PMID:19348682)
• HAND2 may be a potential candidate gene of stenosis of the right ventricle, outflow tract. (PMID:20819618)
• These data suggest that cytokines can inhibit norepinephrine transporter expression through downregulation of Hand2 or Gata3 in cultured sympathetic neurons, but axotomy in adult animals selectively suppresses Hand2 expression. (PMID:21241805)
• Hand2 performs an essential role during transgenic epicardialization, directly impacting epicardial cell differentiation and formation of the coronary vasculature. (PMID:21350214)
• No evidence of linkage between HAND2 and CL/P was obtained. Levelss of exclusion were obtained with different inheritance models. results did not support HAND2 in CL/P (PMID:21431856)
• Data suggest Hand2 plays an important role in decidualization; expression of Hand2 is significantly increased in response to prostaglandin E2. (PMID:21527398)
• Expression analyses on both Hand2 conditionally null and hypomorphic backgrounds demonstrate that Hand2 is required for reporter activation in a gene dosage-dependent manner during sympathetic neurogenesis. (PMID:22323723)
• Overdosage of Hand2 causes limb and heart defects in the human chromosomal disorder partial trisomy distal 4q. (PMID:23449628)
• Reduced protein expression of HAND2 in the myenteric plexus of the aganglionic segment would suggest that HAND2 was involved in the pathogenesis of Hirschsprung disease. (PMID:24210200)
• Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. (PMID:24265601)
• suggest that HAND2 plays a key role in the regulation of progestin-induced decidualization of human endometrial stromal cells. (PMID:24745730)
• HAND2-mediated proteolysis negatively regulates the function of estrogen receptor alpha. (PMID:26166202)
• this study is the first to report the association of a HAND2 loss-of-function mutation with an increased vulnerability to tetralogy of Fallot in humans, which provides novel insight into the molecular mechanism underpinning congenital heart disease (PMID:26676105)
• These findings indicate that HAND2 loss-of-function mutation contributes to human CHD, perhaps via its interaction with GATA4 and NKX2.5. (PMID:26865696)
• The results identify HAND2 loci associated with susceptibility to early onset atrial fibrillation in a Korean population. (PMID:28460022)
• Study showed that thalidomide inhibited the TBX5/HAND2 physical interaction, and the in silico docking revealed that the same amino acids involved in the interaction of TBX5 with DNA are also involved in its binding to HAND2. Results establish a HAND2/TBX5 pathway implicated in heart development and diseases. (PMID:28469241)
• HAND2 and microRNA-1 facilitated the early progress of human induced cardiomyocyte-like cells reprogramming. (PMID:28796841)
• HAND2 mRNA and protein low expressed in endometrial carcinoma (EC) tissues, which suggested the degree of endometrial malignancy. (PMID:29767873)
• HAND2 loss-of-function mutation co-segregated with familial dilated cardiomyopathy in the carrier family. (PMID:30217752)
• FGF1, FGF2, and FGF9 are downstream effectors of HAND2 in endometriosis, enhancing invasive capacity of endometrial fibroblasts. (PMID:30270745)
• Hand2 cardiac subtype diversity (CSD) domain through biochemical analysis of the N terminus. By integrating our RNA-seq and ATAC-seq datasets, we highlight desmosome organization as a hallmark feature of iPM formation. Collectively, our results illuminate Hand2-dependent mechanisms that may guide future efforts to rationally improve iPM formation. (PMID:31116981)
• Haploinsufficiency of the basic helix-loop-helix transcription factor HAND2 causes congenital heart defects. (PMID:32134193)
• The transcription factor HAND2 up-regulates transcription of the IL15 gene in human endometrial stromal cells. (PMID:32444497)
• HAND2 is a novel obesity-linked adipogenic transcription factor regulated by glucocorticoid signalling. (PMID:34014371)
• Expression dynamics of HAND1/2 in in vitro human cardiomyocyte differentiation. (PMID:34297940)
• Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma. (PMID:35354817)
• Genetic evaluation of HAND2 gene and its effects on thalidomide embryopathy. (PMID:36177858)
• NONO enhances mRNA processing of super-enhancer-associated GATA2 and HAND2 genes in neuroblastoma. (PMID:36416237)
• HAND2 Assists MYCN Enhancer Invasion to Regulate a Noradrenergic Neuroblastoma Phenotype. (PMID:36598365)
• [Association of ventricular septal defect with rare variations of the HAND2 gene]. (PMID:37073844)
• Molecular Genetic Study on HAND2 Gene Promoter in Ventricular Septal Defect. (PMID:38030295)
• HAND2 suppresses favipiravir efficacy in treatment of Borna disease virus infection. (PMID:38262560)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	hand2	ENSDARG00000008305
mus_musculus	Hand2	ENSMUSG00000038193
rattus_norvegicus	Hand2	ENSRNOG00000060448
drosophila_melanogaster	twi	FBGN0003900
drosophila_melanogaster	HLH54F	FBGN0022740
drosophila_melanogaster	Hand	FBGN0032209
drosophila_melanogaster	CG33557	FBGN0053557
caenorhabditis_elegans		WBGENE00001953

Paralogs (13): HAND1 (ENSG00000113196), TCF21 (ENSG00000118526), TWIST1 (ENSG00000122691), TCF15 (ENSG00000125878), FERD3L (ENSG00000146618), TCF23 (ENSG00000163792), PTF1A (ENSG00000168267), MSC (ENSG00000178860), FIGLA (ENSG00000183733), BHLHA9 (ENSG00000205899), TWIST2 (ENSG00000233608), SCX (ENSG00000260428), TCF24 (ENSG00000261787)

Protein

Protein identifiers

Heart- and neural crest derivatives-expressed protein 2 — P61296 (reviewed: P61296)

Alternative names: Class A basic helix-loop-helix protein 26, Deciduum, heart, autonomic nervous system and neural crest derivatives-expressed protein 2

All UniProt accessions (2): P61296, H0YAH1

UniProt curated annotations — full annotation on UniProt →

Function. Essential for cardiac morphogenesis, particularly for the formation of the right ventricle and of the aortic arch arteries. Required for vascular development and regulation of angiogenesis, possibly through a VEGF signaling pathway. Also plays an important role in limb development, particularly in the establishment of anterior-posterior polarization, acting as an upstream regulator of sonic hedgehog (SHH) induction in the limb bud. Is involved in the development of branchial arches, which give rise to unique structures in the head and neck. Binds DNA on E-box consensus sequence 5’-CANNTG-3'.

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein. Forms homodimers and heterodimers with TCF3 gene products E12 and E47, HAND1 and HEY1, HEY2 and HEYL (hairy-related transcription factors).

Subcellular location. Nucleus.

Tissue specificity. Heart.

Isoforms (2)

UniProt ID	Names	Canonical?
P61296-1	1	yes
P61296-2	2

RefSeq proteins (1): NP_068808* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR050283	E-box_TF_Regulators	Family

Pfam: PF00010

UniProt features (7 total): compositionally biased region 2, splice variant 2, chain 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P61296-F1	67.30	0.22

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8878166	Transcriptional regulation by RUNX2
R-HSA-9733709	Cardiogenesis

MSigDB gene sets: 301 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_CELL_MIGRATION_INVOLVED_IN_HEART_DEVELOPMENT, FREAC2_01, BENPORATH_ES_WITH_H3K27ME3, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_BEHAVIOR, GOBP_CORONARY_VASCULATURE_DEVELOPMENT, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, GOBP_CELLULAR_RESPONSE_TO_LIPID

GO Biological Process (51): angiogenesis (GO:0001525), osteoblast differentiation (GO:0001649), in utero embryonic development (GO:0001701), heart looping (GO:0001947), suckling behavior (GO:0001967), outflow tract morphogenesis (GO:0003151), cardiac right ventricle formation (GO:0003219), cardiac neural crest cell migration involved in outflow tract morphogenesis (GO:0003253), regulation of secondary heart field cardioblast proliferation (GO:0003266), apoptotic process involved in heart morphogenesis (GO:0003278), noradrenergic neuron differentiation (GO:0003357), regulation of transcription by RNA polymerase II (GO:0006357), heart development (GO:0007507), adult heart development (GO:0007512), mesenchymal cell proliferation (GO:0010463), positive regulation of cardiac muscle hypertrophy (GO:0010613), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), negative regulation of cardiac muscle cell apoptotic process (GO:0010667), regulation of tissue remodeling (GO:0034103), norepinephrine biosynthetic process (GO:0042421), odontogenesis of dentin-containing tooth (GO:0042475), embryonic digit morphogenesis (GO:0042733), tongue development (GO:0043586), negative regulation of osteoblast differentiation (GO:0045668), positive regulation of transcription by RNA polymerase II (GO:0045944), sympathetic nervous system development (GO:0048485), thymus development (GO:0048538), embryonic skeletal system development (GO:0048706), peripheral nervous system neuron development (GO:0048935), cartilage morphogenesis (GO:0060536), coronary artery morphogenesis (GO:0060982), visceral serous pericardium development (GO:0061032), cardiac neural crest cell development involved in outflow tract morphogenesis (GO:0061309), cell proliferation involved in outflow tract morphogenesis (GO:0061325), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to retinoic acid (GO:0071300), positive regulation of p38MAPK cascade (GO:1900745), primary palate development (GO:1903929), epithelial cell apoptotic process (GO:1904019)

GO Molecular Function (15): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription coactivator binding (GO:0001223), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), minor groove of adenine-thymine-rich DNA binding (GO:0003680), protein homodimerization activity (GO:0042803), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), E-box binding (GO:0070888), sequence-specific double-stranded DNA binding (GO:1990837), transcription cis-regulatory region binding (GO:0000976), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), protein dimerization activity (GO:0046983)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), transcription regulator complex (GO:0005667), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Generic Transcription Pathway	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
heart morphogenesis	2
regulation of DNA-templated transcription	2
gene expression	2
regulation of gene expression	2
transcription cis-regulatory region binding	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
ossification	1
cell differentiation	1
chordate embryonic development	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
feeding behavior	1
anatomical structure morphogenesis	1
cardiac ventricle formation	1
cardiac right ventricle morphogenesis	1
neural crest cell migration	1
outflow tract morphogenesis	1
cell migration involved in heart development	1
cardiac neural crest cell development involved in outflow tract morphogenesis	1
regulation of cardioblast proliferation	1
apoptotic process involved in morphogenesis	1
neuron differentiation	1
transcription by RNA polymerase II	1
animal organ development	1
circulatory system development	1
heart development	1
cell population proliferation	1
cardiac muscle hypertrophy	1
regulation of cardiac muscle hypertrophy	1
positive regulation of muscle hypertrophy	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
cardiac muscle cell apoptotic process	1
negative regulation of striated muscle cell apoptotic process	1
regulation of cardiac muscle cell apoptotic process	1
tissue remodeling	1
regulation of multicellular organismal process	1
chromatin	1

Protein interactions and networks

STRING

1782 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HAND2	GATA4	P43694	985
HAND2	NKX2-5	P52952	981
HAND2	TBX5	Q99593	885
HAND2	MEF2C	Q06413	880
HAND2	TBX20	Q9UMR3	861
HAND2	PHOX2B	Q99453	823
HAND2	MYOCD	Q8IZQ8	820
HAND2	NEBL	O76041	797
HAND2	SMYD1	Q8NB12	785
HAND2	ISL1	P20663	779
HAND2	IRX4	P78413	770
HAND2	FOXP4	Q8IVH2	765
HAND2	GATA6	P78327	754
HAND2	TBX2	Q13207	737
HAND2	MEF2A	Q02078	732

IntAct

7 interactions, top by confidence:

A	B	Type	Score
HAND2	TCF4	psi-mi:“MI:0915”(physical association)	0.670
TCF4	HAND2	psi-mi:“MI:0915”(physical association)	0.670
HAND2	TCF4	psi-mi:“MI:0914”(association)	0.670
HAND2	RAD21	psi-mi:“MI:0915”(physical association)	0.400
HAND2	TCF3	psi-mi:“MI:0914”(association)	0.350

BioGRID (39): HAND2 (Two-hybrid), HAND2 (Reconstituted Complex), HAND2 (Two-hybrid), COPS5 (Two-hybrid), PPP2R5D (Reconstituted Complex), HAND2 (Biochemical Activity), HAND2 (Biochemical Activity), HAND2 (Reconstituted Complex), PHOX2A (Affinity Capture-Western), HAND2 (Reconstituted Complex), HAND2 (Affinity Capture-Western), EP300 (Reconstituted Complex), HAND2 (Two-hybrid), HAND2 (Two-hybrid), HAND2 (Two-hybrid)

ESM2 similar proteins: A3KMR8, A7Z017, B3DM47, B4R090, D3ZNT6, O35317, O35984, O42290, O57342, O75030, O75444, P10083, P23091, P25932, P40424, P40425, P40426, P41778, P54841, P54842, P54843, P54844, P56224, P57102, P61295, P61296, P79745, P79746, Q05192, Q0V9K1, Q27350, Q2PFS4, Q32NP8, Q4U1U2, Q504L8, Q61039, Q6DE84, Q6PFG8, Q789F3, Q7RTU3

Diamond homologs: A8E5T6, B6VQA1, O13125, O13126, O16867, O35437, O42202, O42606, O43680, O57598, O60682, O73615, O73823, O88940, O93507, O96004, O96642, P13903, P17542, P22091, P24899, P26687, P46581, P48985, P48987, P57100, P57101, P57102, P59101, P61295, P61296, P70661, P79765, P79782, P97831, P97832, Q02575, Q02576, Q02577, Q0VCE2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
HAND2	“up-regulates activity”	HAND2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	53
Likely benign	14
Benign	6

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
545687	NM_021973.3(HAND2):c.199G>T (p.Glu67Ter)	Pathogenic
139597	NM_021973.3(HAND2):c.390C>A (p.Pro130=)	Likely pathogenic

SpliceAI

431 predictions. Top by Δscore:

Variant	Effect	Δscore
4:173528734:CCAG:C	donor_gain	1.0000
4:173527661:A:AC	donor_gain	0.9900
4:173527662:C:CC	donor_gain	0.9900
4:173528729:A:AC	donor_gain	0.9900
4:173528730:C:CC	donor_gain	0.9900
4:173528731:TGA:T	donor_loss	0.9900
4:173528732:GA:G	donor_loss	0.9900
4:173528733:A:AC	donor_gain	0.9900
4:173528734:C:CA	donor_loss	0.9900
4:173528734:C:CC	donor_gain	0.9900
4:173528746:T:TA	donor_gain	0.9900
4:173527661:ACT:A	donor_gain	0.9800
4:173527662:CTC:C	donor_gain	0.9800
4:173527376:C:CC	acceptor_gain	0.9700
4:173527662:CT:C	donor_gain	0.9700
4:173527372:CGTT:C	acceptor_gain	0.9600
4:173527664:C:CA	donor_gain	0.9600
4:173527899:C:CT	acceptor_gain	0.9600
4:173527399:G:T	acceptor_gain	0.9500
4:173528730:CTGA:C	donor_gain	0.9500
4:173527374:TT:T	acceptor_gain	0.9400
4:173527393:G:T	acceptor_gain	0.9400
4:173527899:C:T	acceptor_gain	0.9400
4:173527900:A:T	acceptor_gain	0.9400
4:173527371:TCGTT:T	acceptor_gain	0.9300
4:173527372:CGTTC:C	acceptor_gain	0.9300
4:173527375:TC:T	acceptor_loss	0.9300
4:173527376:C:A	acceptor_loss	0.9300
4:173527377:T:G	acceptor_loss	0.9300
4:173527392:C:CT	acceptor_gain	0.9300

AlphaMissense

1425 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:173527287:A:G	L215P	1.000
4:173527291:C:T	E214K	1.000
4:173527293:A:G	L213P	1.000
4:173527297:C:G	A212P	1.000
4:173527298:C:A	W211C	1.000
4:173527298:C:G	W211C	1.000
4:173527299:C:G	W211S	1.000
4:173527300:A:G	W211R	1.000
4:173527300:A:T	W211R	1.000
4:173527302:A:T	V210D	1.000
4:173527311:G:A	P207L	1.000
4:173527311:G:C	P207R	1.000
4:173527311:G:T	P207Q	1.000
4:173527312:G:A	P207S	1.000
4:173527312:G:C	P207A	1.000
4:173527312:G:T	P207T	1.000
4:173527313:C:A	W206C	1.000
4:173527313:C:G	W206C	1.000
4:173527314:C:G	W206S	1.000
4:173527315:A:G	W206R	1.000
4:173527315:A:T	W206R	1.000
4:173527317:C:A	G205V	1.000
4:173527317:C:T	G205D	1.000
4:173527318:C:A	G205C	1.000
4:173527318:C:G	G205R	1.000
4:173527318:C:T	G205S	1.000
4:173527320:G:A	T204M	1.000
4:173527323:C:A	R203L	1.000
4:173527324:G:C	R203G	1.000
4:173527326:C:T	G202D	1.000

dbSNP variants (sampled 300 via entrez): RS1000057185 (4:173527051 C>T), RS1000104805 (4:173530455 A>G), RS1000197403 (4:173529600 C>A,T), RS1001028117 (4:173526063 C>A), RS1001544287 (4:173529885 C>A,G), RS1001874312 (4:173531339 C>A,T), RS10024737 (4:173526992 T>C), RS1002781144 (4:173530420 G>GA,GC,GT), RS1003258010 (4:173528011 C>T), RS1004462118 (4:173527591 G>A), RS1005779393 (4:173530990 T>C), RS1006239593 (4:173531440 A>C,T), RS1006396636 (4:173526252 G>A,C), RS1006693851 (4:173526035 C>A,T), RS1006746355 (4:173531650 C>A,T)

Disease associations

OMIM: gene MIM:602407 | disease phenotypes: MIM:115200

GenCC curated gene-disease

Disease	Classification	Inheritance
HAND2 related congenital heart defect	Moderate	Autosomal dominant
congenital heart disease	Moderate	Autosomal dominant
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant
congenital heart defects, multiple types	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
HAND2 related congenital heart defect	Moderate	AD

Mondo (5): dilated cardiomyopathy 1A (MONDO:0007269), congenital heart defects, multiple types (MONDO:0000119), HAND2 related congenital heart defect (MONDO:0800476), (MONDO:0015470), congenital heart disease (MONDO:0005453)

Orphanet (1): Familial dilated cardiomyopathy with conduction defect due to LMNA mutation (Orphanet:300751)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000407	Sensorineural hearing impairment
HP:0000969	Edema
HP:0001635	Congestive heart failure
HP:0001644	Dilated cardiomyopathy
HP:0001727	Thromboembolic stroke
HP:0002875	Exertional dyspnea
HP:0003198	Myopathy
HP:0003457	EMG abnormality
HP:0011675	Arrhythmia
HP:0012378	Fatigue
HP:0012764	Orthopnea
HP:0025169	Left ventricular systolic dysfunction
HP:0100578	Lipoatrophy

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST003989_16	Chin dimples	3.000000e-17
GCST003989_35	Chin dimples	2.000000e-11
GCST004352_2	Early onset atrial fibrillation	1.000000e-12
GCST004373_1	Atrial fibrillation	3.000000e-10
GCST004373_7	Atrial fibrillation	8.000000e-16
GCST004735_40	Epstein-Barr virus copy number in lymphoblastoid cell lines	5.000000e-06
GCST006061_109	Atrial fibrillation	9.000000e-12
GCST006061_110	Atrial fibrillation	8.000000e-10
GCST006414_107	Atrial fibrillation	6.000000e-10
GCST006414_89	Atrial fibrillation	3.000000e-13
GCST010321_135	PR interval	3.000000e-20
GCST010796_1851	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_1852	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-09
GCST010796_1853	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-10
GCST010796_1854	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-11
GCST010796_1855	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-10
GCST010796_1856	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-10
GCST010796_1857	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-10
GCST010796_1858	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-11
GCST012460_5	Atrial fibrillation	2.000000e-13

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
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

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

Chemical	Actions (top 5)	PubMed papers
Progesterone	affects cotreatment, increases expression	3
bisphenol A	decreases methylation, affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	2
bisphenol F	increases expression, affects cotreatment	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
ascorbate-2-phosphate	affects binding, affects cotreatment, increases expression	1
arsenite	increases methylation	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
Chir 99021	affects cotreatment, increases expression, affects binding	1
bisphenol S	affects methylation	1
XAV939	affects binding, affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
3-(4-pyridyl)-1H-indole	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Ascorbic Acid	affects cotreatment, increases expression, affects binding	1
Cadmium	decreases expression	1
Copper	affects cotreatment, increases expression	1
Cytarabine	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Fluorouracil	increases expression	1
Hydrocortisone	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Teratogens	increases expression	1
Tetrachlorodibenzodioxin	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A7RX	WAe009-A-59	Embryonic stem cell	Female

Clinical trials (associated diseases)

301 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