HAND1

Summary

HAND1 (heart and neural crest derivatives expressed 1, HGNC:4807) is a protein-coding gene on chromosome 5q33.2, encoding Heart- and neural crest derivatives-expressed protein 1 (O96004). Transcription factor that plays an essential role in both trophoblast giant cell differentiation and in cardiac morphogenesis.

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, it has been suggested that this transcription factor may be required for early trophoblast differentiation.

Source: NCBI Gene 9421 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (Moderate, ClinGen)
• GWAS associations: 20
• Clinical variants (ClinVar): 181 total
• Transcription factor: yes — 66 downstream targets (CollecTRI)
• MANE Select transcript: NM_004821

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4807
Approved symbol	HAND1
Name	heart and neural crest derivatives expressed 1
Location	5q33.2
Locus type	gene with protein product
Status	Approved
Aliases	eHand, Thing1, Hxt, bHLHa27
Ensembl gene	ENSG00000113196
Ensembl biotype	protein_coding
OMIM	602406
Entrez	9421

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000231121, ENST00000878293

RefSeq mRNA: 1 — MANE Select: NM_004821 NM_004821

CCDS: CCDS4327

Canonical transcript exons

ENST00000231121 — 2 exons

Exon	Start	End
ENSE00000768215	154474972	154475910
ENSE00000972903	154477466	154478227

Expression profiles

Bgee: expression breadth broad, 74 present calls, max score 91.73.

FANTOM5 (CAGE): breadth broad, TPM avg 10.3904 / max 769.1995, expressed in 194 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
64459	9.9669	188
64460	0.3209	81
64461	0.1026	53

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
muscle layer of sigmoid colon	UBERON:0035805	91.73	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.81	gold quality
apex of heart	UBERON:0002098	88.46	gold quality
heart left ventricle	UBERON:0002084	87.79	gold quality
cardiac ventricle	UBERON:0002082	87.40	gold quality
amniotic fluid	UBERON:0000173	77.27	gold quality
heart right ventricle	UBERON:0002080	76.89	gold quality
myocardium	UBERON:0002349	75.49	silver quality
heart	UBERON:0000948	75.14	gold quality
left ventricle myocardium	UBERON:0006566	73.95	gold quality
colon	UBERON:0001155	70.20	gold quality
large intestine	UBERON:0000059	69.75	gold quality
buccal mucosa cell	CL:0002336	69.59	gold quality
vermiform appendix	UBERON:0001154	67.79	gold quality
right atrium auricular region	UBERON:0006631	67.68	gold quality
cardiac atrium	UBERON:0002081	67.32	gold quality
caecum	UBERON:0001153	64.85	gold quality
intestine	UBERON:0000160	64.36	gold quality
colonic epithelium	UBERON:0000397	64.24	gold quality
cervix squamous epithelium	UBERON:0006922	63.50	gold quality
transverse colon	UBERON:0001157	62.73	gold quality
smooth muscle tissue	UBERON:0001135	62.50	gold quality
pancreatic ductal cell	CL:0002079	62.47	silver quality
tibialis anterior	UBERON:0001385	61.96	silver quality
urinary bladder	UBERON:0001255	60.83	gold quality
diaphragm	UBERON:0001103	60.21	gold quality
ileal mucosa	UBERON:0000331	60.12	silver quality
germinal epithelium of ovary	UBERON:0001304	60.00	gold quality
tongue squamous epithelium	UBERON:0006919	57.98	gold quality
hair follicle	UBERON:0002073	56.63	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-8271	yes	1514.18
E-MTAB-8205	yes	1207.48
E-MTAB-9388	yes	849.59
E-MTAB-8060	yes	166.33
E-HCAD-10	yes	4.75
E-ANND-3	no	1.84

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

66 targets.

Target	Regulation
ASCL2	Unknown
CCR5
CCR9
CD4
CD44
CD74
CDKN1A
CDKN1B
CIITA
CLDN11
CLEC6A
CSH1	Unknown
CXCL10
CXCL11
DBH
DUSP16
EIF3K
FGF8
FOXP3
GHRHR
HAND1
HAND2
HAVCR2
HLA-E
ICOS
IFNG
IFNGR2
IL10
IL12RB1
IL17A

JASPAR motifs

Motif	Name	Family
MA2123.1	Hand1	Tal-related

JASPAR matrix evidence (PMIDs): PMID:20975697

Upstream regulators (CollecTRI, top): BCL6, BMP4, DNMT3A, ETS2, EZH2, FHL2, FOXC2, GATA3, HAND1, HAND2, HMGA1, PARP1, PAX3, PHOX2A, PHOX2B, PRDM1, SMAD1, SMAD5, STAT4, STAT6, TBX21, TCF3, TXK

miRNA regulators (miRDB)

73 targeting HAND1, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-25-3P	99.98	74.60	1817

Literature-anchored findings (GeneRIF, showing 26)

• effects of gene mutations on ventricular development (PMID:12858532)
• MEF2/HAND1 interaction results in synergistic activation of MEF2-dependent promoters, and MEF2 binding sites are sufficient to mediate this synergy (PMID:16043483)
• In 24 of 31 hypoplastic ventricles, a frameshift mutation was detected in the bHLH domain, which is necessary for DNA binding and combinatorial interactions; thus in hypoplastic human hearts HAND1 function is impaired. (PMID:18276607)
• HMGA1 proteins bind directly to Hand1 promoter both in vitro and in vivo and inhibit Hand1 promoter activity (PMID:19060921)
• HAND1 sequence mutations are frequent in human hearts with septation defects. (PMID:19586923)
• Hand1 lineage marks the proepicardial organ and epicardium necessary for epicardial and coronary vessel development, defining the epicardial precursors that are subsequently dependent on Hand2 function. (PMID:21350214)
• Our study shows no evidence of somatic NKX2-5, GATA4 and HAND1 mutations playing a role in the pathogenesis of Tetralogy of Fallot . Findings suggest that the GATA4 and HAND1 germline mutations are associated with non-syndromic congenital heart disease. (PMID:21519287)
• Mutations or sequence variations in HAND1 or NKX2-5 genes may play role in etiology or pathogenesis of atrial isomerism. (PMID:21561848)
• This is the first report of mutations in the HAND1 gene in Chinese patients with VSD and provides new insight into the etiology of VSD (PMID:22032825)
• Somatic mutations in NKX2-5, GATA4, and HAND1 are not a common cause of tetralogy of Fallot or hypoplastic left heart. (PMID:22043484)
• Hand1 is dispensable for normal tyrosine hydroxylase and dopamine beta-hydroxylase expression in sympathetic neurons, even when Hand2 gene dosage is concurrently reduced by half. (PMID:22323723)
• Increased methylation levels of HAND1 is associated with highly active Helicobacter pylori-related gastritis. (PMID:23292007)
• DNA methylation status of NKX2-5, GATA4 and HAND1 in patients with tetralogy of fallot (PMID:24182332)
• Nuclear translocation of Hand-1 acts as a molecular switch to regulate vascular radiosensitivity in medulloblastoma tumors. (PMID:24623737)
• These data show that miR-363 negatively regulates the expression of HAND1 (PMID:24906886)
• Combined expression of NKX2-5, HAND1, and NOTCH1 coordinately contribute to cardiac malformations in Hhypoplastic left heart syndrome. (PMID:25050861)
• HAND1 loss-of-function mutation is associated with familial dilated cardiomyopathy. (PMID:26581070)
• Strikingly, human pluripotent stem cell antibody array showed that Hand1 overexpression resulted in substantial decrease in pluripotency markers (Nanog, Oct3/4, Otx2, Flk1) suggesting that Hand1 expression may be essential to attenuate the EMT and our findings underscore a novel role for Hand1 in medulloblastoma metastasis. (PMID:27297109)
• association of HAND1 loss-of-function mutation with increased susceptibility to Tetralogy of Fallot (PMID:27942761)
• These findings expand the phenotypic spectrum linked to HAND1 mutations, suggesting potential implications for the development of novelo prophylactic and therapeutic strategies for DORV. (PMID:28112363)
• HAND1 and BARX1 Act as Transcriptional and Anatomic Determinants of Malignancy in Gastrointestinal Stromal Tumor. (PMID:33451979)
• Expression dynamics of HAND1/2 in in vitro human cardiomyocyte differentiation. (PMID:34297940)
• Human HAND1 inhibits the conversion of cholesterol to steroids in trophoblasts. (PMID:34391879)
• HAND1 knockdown disrupts trophoblast global gene expression. (PMID:36695714)
• Novel and deleterious nucleotide variations in the HAND1 gene probably affect miRNA target sites and protein function in pediatric patients with congenital heart disease. (PMID:38551686)
• HAND1 is essential driver of extra-embryonic mesenchyme derivation from human iPSCs-derived trophoblast and binds hominoid-specific regulatory elements. (PMID:40220298)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hand1	ENSMUSG00000037335
rattus_norvegicus	Hand1	ENSRNOG00000002582
drosophila_melanogaster	twi	FBGN0003900
drosophila_melanogaster	HLH54F	FBGN0022740
drosophila_melanogaster	Hand	FBGN0032209
drosophila_melanogaster	CG33557	FBGN0053557
caenorhabditis_elegans		WBGENE00001953

Paralogs (13): TCF21 (ENSG00000118526), TWIST1 (ENSG00000122691), TCF15 (ENSG00000125878), FERD3L (ENSG00000146618), TCF23 (ENSG00000163792), HAND2 (ENSG00000164107), PTF1A (ENSG00000168267), MSC (ENSG00000178860), FIGLA (ENSG00000183733), BHLHA9 (ENSG00000205899), TWIST2 (ENSG00000233608), SCX (ENSG00000260428), TCF24 (ENSG00000261787)

Protein

Protein identifiers

Heart- and neural crest derivatives-expressed protein 1 — O96004 (reviewed: O96004)

Alternative names: Class A basic helix-loop-helix protein 27, Extraembryonic tissues, heart, autonomic nervous system and neural crest derivatives-expressed protein 1

All UniProt accessions (1): O96004

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that plays an essential role in both trophoblast giant cell differentiation and in cardiac morphogenesis. Binds the DNA sequence 5’-NRTCTG-3’ (non-canonical E-box). Acts as a transcriptional repressor of SOX15. In the adult, could be required for ongoing expression of cardiac-specific genes.

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein. Forms homodimers and heterodimers with TCF3 gene products E12 and E47, HAND2 and HEY1, HEY2 and HEYL (hairy-related transcription factors). Interacts with MDFIC. Interacts with SOX15; the interaction enhances HAND1-induced differentiation of trophoblast giant cells.

Subcellular location. Nucleus. Nucleoplasm. Nucleolus.

Tissue specificity. Heart.

Post-translational modifications. Phosphorylation by PLK4 disrupts the interaction with MDFIC and leads to translocation into the nucleoplasm, allowing dimerization and transcription factor activity.

RefSeq proteins (1): NP_004812* (*=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 (8 total): region of interest 2, compositionally biased region 2, modified residue 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O96004-F1	65.87	0.21

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): 107, 109

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9733709	Cardiogenesis

MSigDB gene sets: 191 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, ACTACCT_MIR196A_MIR196B, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_CARTILAGE_DEVELOPMENT, GOBP_CARDIAC_LEFT_VENTRICLE_MORPHOGENESIS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, XU_GH1_AUTOCRINE_TARGETS_UP, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, MAHADEVAN_IMATINIB_RESISTANCE_DN

GO Biological Process (22): negative regulation of transcription by RNA polymerase II (GO:0000122), angiogenesis (GO:0001525), mesoderm formation (GO:0001707), blastocyst development (GO:0001824), trophectodermal cell differentiation (GO:0001829), heart looping (GO:0001947), embryonic heart tube formation (GO:0003144), cardiac left ventricle formation (GO:0003218), cardiac right ventricle formation (GO:0003219), regulation of transcription by RNA polymerase II (GO:0006357), heart development (GO:0007507), embryonic heart tube development (GO:0035050), odontogenesis of dentin-containing tooth (GO:0042475), positive regulation of transcription by RNA polymerase II (GO:0045944), ventricular cardiac muscle tissue morphogenesis (GO:0055010), cardiac septum morphogenesis (GO:0060411), mesenchyme development (GO:0060485), cartilage morphogenesis (GO:0060536), trophoblast giant cell differentiation (GO:0060707), in utero embryonic development (GO:0001701), cell differentiation (GO:0030154), determination of heart left/right asymmetry (GO:0061371)

GO Molecular Function (17): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription coregulator binding (GO:0001221), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), enzyme binding (GO:0019899), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), bHLH transcription factor binding (GO:0043425), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), 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 (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
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	4
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
protein binding	3
cellular anatomical structure	3
embryonic heart tube morphogenesis	2
cardiac ventricle formation	2
regulation of DNA-templated transcription	2
animal organ development	2
transcription cis-regulatory region binding	2
DNA-binding transcription factor activity, RNA polymerase II-specific	2
DNA-binding transcription factor binding	2
nuclear lumen	2
negative regulation of DNA-templated transcription	1
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
formation of primary germ layer	1
mesoderm morphogenesis	1
in utero embryonic development	1
anatomical structure development	1
blastocyst formation	1
cell differentiation	1
determination of heart left/right asymmetry	1
embryonic epithelial tube formation	1
cardiac left ventricle morphogenesis	1
cardiac right ventricle morphogenesis	1
circulatory system development	1
heart development	1
tube development	1
embryonic organ development	1
epithelium development	1
odontogenesis	1
positive regulation of DNA-templated transcription	1
cardiac ventricle morphogenesis	1
ventricular cardiac muscle tissue development	1
cardiac muscle tissue morphogenesis	1
cardiac chamber morphogenesis	1
cardiac septum development	1
anatomical structure morphogenesis	1
tissue development	1

Protein interactions and networks

STRING

450 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HAND1	FOXP4	Q8IVH2	939
HAND1	NKX2-5	P52952	688
HAND1	XYLT1	Q86Y38	620
HAND1	XYLT2	Q9H1B5	567
HAND1	GATA4	P43694	542
HAND1	SLC6A20	Q9NP91	507
HAND1	HK1	P19367	479
HAND1	HK2	P52789	471
HAND1	TBX5	Q99593	411
HAND1	LGALS2	P05162	400
HAND1	SORD	Q00796	400
HAND1	BZW1	Q7L1Q6	400
HAND1	XYLB	O75191	397
HAND1	LRIG3	Q6UXM1	393
HAND1	PHKA2	P46019	378

IntAct

26 interactions, top by confidence:

A	B	Type	Score
HAND1	KRTAP10-6	psi-mi:“MI:0915”(physical association)	0.560
HAND1	TCF12	psi-mi:“MI:0915”(physical association)	0.560
HAND1	TCF3	psi-mi:“MI:0915”(physical association)	0.560
HAND1	DMWD	psi-mi:“MI:0915”(physical association)	0.560
HAND1		psi-mi:“MI:0915”(physical association)	0.560
HAND1	PMP22	psi-mi:“MI:0915”(physical association)	0.560
TSC1	HAND1	psi-mi:“MI:0915”(physical association)	0.560
HAND1	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
TCF4	TRIM24	psi-mi:“MI:0914”(association)	0.350
HAND1	KRTAP10-6	psi-mi:“MI:0915”(physical association)	0.000
HAND1	TCF12	psi-mi:“MI:0915”(physical association)	0.000
HAND1	TCF3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): HAND1 (Affinity Capture-Western), MEF2A (Reconstituted Complex), TCF3 (Reconstituted Complex), HAND1 (Affinity Capture-MS), HAND1 (Reconstituted Complex), HAND1 (Two-hybrid), HAND1 (Biochemical Activity), HAND1 (Biochemical Activity), HAND1 (Two-hybrid), TCF12 (Two-hybrid), KRTAP10-6 (Two-hybrid), HEY2 (Reconstituted Complex), HEYL (Reconstituted Complex), HAND1 (Two-hybrid), HAND1 (Affinity Capture-Western)

ESM2 similar proteins: A0A1W2PRP0, A6NCS4, A7Y7W2, O14512, O43638, O57601, O70220, O96004, P07812, P09023, P10085, P10284, P17483, P22091, P24899, P50548, P52954, P52955, P55318, P57100, P63156, P63157, P70447, P79772, P97832, Q02346, Q05917, Q0VCE2, Q12952, Q1XID0, Q28555, Q3I5G5, Q3Y598, Q60688, Q61660, Q63244, Q63250, Q64279, Q64305, Q64731

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

8 interactions.

A	Effect	B	Mechanism
PRKCA	unknown	HAND1	phosphorylation
SMAD1	“up-regulates quantity”	HAND1	“transcriptional regulation”
SMAD5	“up-regulates quantity”	HAND1	“transcriptional regulation”
PRKACA	“down-regulates activity”	HAND1	phosphorylation
PRKACA	unknown	HAND1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	119
Likely benign	52
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

177 predictions. Top by Δscore:

Variant	Effect	Δscore
5:154477465:CCAG:C	donor_gain	1.0000
5:154475915:C:CT	acceptor_gain	0.9900
5:154475916:A:T	acceptor_gain	0.9900
5:154475924:C:CT	acceptor_gain	0.9900
5:154475926:C:CT	acceptor_gain	0.9900
5:154477459:GACT:G	donor_loss	0.9900
5:154477460:ACTCA:A	donor_loss	0.9900
5:154477463:CACC:C	donor_loss	0.9900
5:154477464:A:AC	donor_gain	0.9900
5:154477464:A:C	donor_loss	0.9900
5:154477465:C:CC	donor_gain	0.9900
5:154475906:TGCTG:T	acceptor_gain	0.9800
5:154475908:CTG:C	acceptor_gain	0.9800
5:154475911:C:CC	acceptor_gain	0.9800
5:154477471:C:CA	donor_gain	0.9800
5:154475915:C:T	acceptor_gain	0.9700
5:154475927:A:T	acceptor_gain	0.9700
5:154475909:TG:T	acceptor_gain	0.9600
5:154475907:GCTG:G	acceptor_loss	0.9500
5:154475910:GCTGC:G	acceptor_loss	0.9500
5:154475911:C:CA	acceptor_loss	0.9500
5:154475912:T:A	acceptor_loss	0.9500
5:154475922:C:CT	acceptor_gain	0.9500
5:154475903:TGCTG:T	acceptor_gain	0.9400
5:154477464:ACCAG:A	donor_gain	0.9400
5:154477465:CCAGC:C	donor_gain	0.9400
5:154476089:G:A	donor_gain	0.9100
5:154477464:AC:A	donor_gain	0.9100
5:154477465:CC:C	donor_gain	0.9100
5:154477465:CCA:C	donor_gain	0.9100

AlphaMissense

1398 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:154475827:C:A	W209C	1.000
5:154475827:C:G	W209C	1.000
5:154475829:A:G	W209R	1.000
5:154475829:A:T	W209R	1.000
5:154475842:C:A	W204C	1.000
5:154475842:C:G	W204C	1.000
5:154475844:A:G	W204R	1.000
5:154475844:A:T	W204R	1.000
5:154475846:C:T	G203D	1.000
5:154475849:G:A	T202I	1.000
5:154477560:A:G	L150P	1.000
5:154477572:A:G	L146P	1.000
5:154477581:A:C	I143S	1.000
5:154477581:A:T	I143N	1.000
5:154477584:T:C	Y142C	1.000
5:154477585:A:C	Y142D	1.000
5:154477585:A:G	Y142H	1.000
5:154477585:A:T	Y142N	1.000
5:154477593:G:A	A139V	1.000
5:154477593:G:T	A139D	1.000
5:154477594:C:G	A139P	1.000
5:154477596:A:G	L138P	1.000
5:154477596:A:T	L138Q	1.000
5:154477602:A:C	L136R	1.000
5:154477602:A:G	L136P	1.000
5:154477602:A:T	L136Q	1.000
5:154477607:C:A	K134N	1.000
5:154477607:C:G	K134N	1.000
5:154477611:A:C	I133S	1.000
5:154477611:A:G	I133T	1.000

dbSNP variants (sampled 300 via entrez): RS1000053407 (5:154480106 G>T), RS1000150040 (5:154475399 G>A), RS1000170227 (5:154476473 C>T), RS1002054105 (5:154477342 G>A), RS1002232509 (5:154479004 G>C), RS1002807220 (5:154478816 A>AC), RS1003732313 (5:154476117 G>A), RS1003766076 (5:154479846 A>C), RS1004106132 (5:154476373 G>A,T), RS1004594780 (5:154476426 C>G,T), RS1004696232 (5:154478737 C>G), RS1005293211 (5:154480035 G>A,C,T), RS1005651065 (5:154479747 A>G), RS1006144820 (5:154476673 C>T), RS10062037 (5:154479673 G>T)

Disease associations

OMIM: gene MIM:602406 | disease phenotypes: MIM:241550

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart disease	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital heart disease	Moderate	AD

Mondo (2): hypoplastic left heart syndrome (MONDO:0004933), congenital heart disease (MONDO:0005453)

Orphanet (1): Hypoplastic left heart syndrome (Orphanet:2248)

HPO phenotypes

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

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST002533_3	QRS duration	1.000000e-06
GCST003598_15	QRS duration	4.000000e-16
GCST003598_42	QRS duration	9.000000e-14
GCST003871_7	QRS complex (Cornell)	2.000000e-24
GCST003989_46	Chin dimples	1.000000e-08
GCST003996_34	Monobrow	2.000000e-20
GCST005905_4	Global electrical heterogeneity phenotypes	2.000000e-20
GCST005905_5	Global electrical heterogeneity phenotypes	9.000000e-09
GCST007227_5	QRS duration	1.000000e-18
GCST008422_5	QRS duration	3.000000e-11
GCST010796_5114	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-11
GCST010796_5115	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-11
GCST010796_5116	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-11
GCST010796_5117	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-13
GCST010796_5118	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-15
GCST010796_5119	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-09
GCST010796_5120	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-15
GCST010796_5121	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-08
GCST010796_5122	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST011010_41	Electrocardiographic traits (multivariate)	1.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005054	QRS complex
EFO:0007742	QRS amplitude
EFO:0007906	synophrys measurement
EFO:0004327	electrocardiography

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D018636	Hypoplastic Left Heart Syndrome	C14.240.400.625; C14.280.400.625; C16.131.240.400.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	5
entinostat	increases expression, affects cotreatment	2
bisphenol F	increases expression	1
methylmercuric chloride	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
kojic acid	increases expression	1
arsenite	increases methylation	1
sodium arsenite	increases expression	1
ferrous chloride	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
mercuric bromide	affects cotreatment, 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
nutlin 3	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Sunitinib	decreases expression	1
Leflunomide	increases expression	1
Panobinostat	affects cotreatment, increases expression	1
Arbutin	increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Cadmium	decreases expression	1
Camptothecin	increases expression	1
Cytarabine	decreases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	increases expression	1
Dimethyl Sulfoxide	decreases expression, increases expression	1
Doxorubicin	decreases expression	1
Fluorouracil	affects reaction, decreases expression	1
Lead	decreases expression	1

Clinical trials (associated diseases)

349 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
NCT02781922	PHASE3	RECRUITING	Cardiac Stem/Progenitor Cell Infusion in Univentricular Physiology (APOLLON Trial)
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