GATA4
protein-codingGATA binding protein 4, the group of GATA zinc finger domain containing
Gene summary
This gene encodes a member of the GATA family of zinc-finger transcription factors. Members of this family recognize the GATA motif which is present in the promoters of many genes. This protein is thought to regulate genes involved in embryogenesis and in myocardial differentiation and function, and is necessary for normal testicular development. Mutations in this gene have been associated with cardiac septal defects. Additionally, alterations in gene expression have been associated with several cancer types. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~83.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0100164
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0004955
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0005021
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0016674
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0018054
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0010802
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0008542
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0100009
Submitter: ClinGen
*GATA4* was first reported in relation to autosomal dominant *GATA4*-related congenital heart disease with or without pancreatic hypoplasia or diabetes in 2003 (Garg et al., PMID:12845333). Variants in *GATA4* have been reported in individuals with both isolated and syndromic clinical presentations. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in the molecular mechanism or inheritance pattern between these phenotypes. Therefore, the following isolated and syndromic disease entities, which were previously split, have been lumped into a single disease entity: Atrial Septal Defect 2 (OMIM:607941), Atrioventricular Septal Defect 4 (OMIM: 614430), Tetralogy of Fallot (OMIM: 187500), Ventricular Septal Defect 1 (OMIM:614429), Testicular anomalies with or without congenital heart disease (OMIM:615542), and CHD with pancreatic agenesis/hypoplasia and neonatal diabetes. Twenty unique variants (missense, nonsense, frameshift) that have been reported in twenty two probands in thirteen publications (PMIDs: 15810002, 12845333, 18672102, 24000169, 28991257, 29377543, 20854389, 24696446, 21220346, 29670578, 35305867, 35134971, 41006196) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by mouse models, expression data, protein interaction studies with GATA6, and functional alteration data (PMIDs: 10330176, 17451603, 17643447, 15310850, 20854389, 31322241). In summary, *GATA4* is definitively associated with autosomal dominant *GATA4*-related congenital heart disease with or without pancreatic hypoplasia or diabetes. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Congenital Heart Disease GCEP on February 7th, 2023 (SOP Version 9). It was reevaluated on May 5th, 2026 (SOP Version 12). As a result of this reevaluation, the classification did not change. However, the disease entity was updated following a revised lumping and splitting assessment to include both isolated and syndromic presentations under a single clinical entity. New genetic and experimental evidence was also reviewed and scored to reflect the new lumped disease entity (20854389, 24696446, 21220346, 29670578, 35305867, 35134971, 41006196, 10330176, 17451603). **Monogenic Diabetes Gene Curation Expert Panel Addendum** Haploinsufficiency due to heterozygous loss of function variants in *GATA4* was reported as a cause of neonatal diabetes in association with congenital heart disease in 2010 (PMID: 20854389). In 2011, similar heterozygous LOF variants in *GATA6* were reported as the most common cause of pancreatic agenesis (PMID: 22158542), with 14/15 cases having congenital heart defects. Studies in mice have demonstrated that loss of both GATA6 and GATA4 expression results in failure of pancreas development, whereas several studies in humans have shown that loss of either *GATA6* (over 20 additional reports) or *GATA4* alone (PMID: 20854389, 24696446, 38375489, 38408297, 39457190, 41006196) can cause pancreatic agenesis/hypoplasia, highlighting species-specific dependence on these important transcription factors. Several cases with *GATA6* variants have also been reported to have congenital heart disease but had developed diabetes well after the neonatal period, even well into adulthood (PMID: 28938416, 31700519, 32245430, 32524025). In summary, *GATA4* is definitively associated with neonatal diabetes and usually involves pancreatic agenesis/hypoplasia and congenital heart disease with or without other features. Testing of *GATA4* (and *GATA6*) should also be considered in any individual who develops diabetes at any age but is also known to have a congenital heart defect. In individuals with a heart defect who are found to have pathogenic *GATA6* or *GATA4* variant should have ongoing monitoring for hyperglycemia and possible diabetes development. Pancreatic imaging and testing for exocrine pancreatic insufficiency could also be considered. This addendum was approved by the Monogenic Diabetes GCEP on the meeting date 02/25/2026
Inheritance Pattern: AD
Disease ID:MONDO:0014239
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0020525
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0011938
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0100009
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011938
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014239
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0016391
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Genitourinary
Intervention: Cardiovascular
Rationale: Individuals may present with frank, obvious congenital cardiac malformations that require interventions, and more subtle presentations in individuals with have also been described, including valvular anomalies and arrhythmias, and surveillance (eg, with electrocardiogram and echocardiogram) may allow early detection and treatment of manifestations
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GATA4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001308093.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 1 | 4 | 317 | 3 | 327 |
| missense | 12 | 14 | 509 | 24 | 3 | 562 |
| nonsense | 7 | 1 | 2 | 10 | ||
| start loss | 1 | 1 | ||||
| frameshift | 3 | 3 | 3 | 9 | ||
| splice donor/acceptor (+/-2bp) | 2 | 1 | 1 | 4 | ||
| Total | 26 | 20 | 520 | 341 | 6 | 913 |
Highest pathogenic variant AF is 0.000011151628
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001295022.1 | 6 | MANE Select | |
| Ensembl | ENSP00000435712.1 | 6 | MANE Select | |
| RefSeq | NP_001295023.1 | 5 | Standard | |
| RefSeq | NP_001361202.1 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gata4 | Danio rerio | Structure: caudal vein plexus Quality: malformed abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Tight junction - Homo sapiens (human)
- Thyroid hormone signaling pathway - Homo sapiens (human)
- cGMP-PKG signaling pathway - Homo sapiens (human)
- Cellular senescence - Homo sapiens (human)
- Physiological and Pathological Hypertrophy of the Heart
Biological Process
- heart looping
- aortic valve morphogenesis
- endocardial cushion development
- cardiac ventricle morphogenesis
- cardiac right ventricle morphogenesis
Molecular Function
- RNA polymerase II regulatory region sequence-specific DNA binding
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- RNA polymerase II transcription factor binding
- enhancer sequence-specific DNA binding
Cellular Component
- nucleus
- nucleoplasm
- nuclear body
- RNA polymerase II transcription factor complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000335135
- Coding exons
- 6
- Length
- 83044
- Individuals with no LoFs
- 125743
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 125747
- p
- 0.0000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.671 | 186 | 214 | 0.871 | 0.0000132 | 2767 |
| Missense (PolyPhen) | 40 | 74.49 | 0.53699 | 793 | ||
| Synonymous | -2.35 | 123 | 94.1 | 1.31 | 0.00000670 | 965 |
| Loss of Function | 2.83 | 3 | 14.7 | 0.204 | 8.10e-7 | 169 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000026 | 0.000026 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcriptional activator that binds to the consensus sequence 5'-AGATAG-3' and plays a key role in cardiac development and function (PubMed:24000169, PubMed:27984724). In cooperation with TBX5, it binds to cardiac super-enhancers and promotes cardiomyocyte gene expression, while it downregulates endocardial and endothelial gene expression (PubMed:27984724). Involved in bone morphogenetic protein (BMP)-mediated induction of cardiac- specific gene expression. Binds to BMP response element (BMPRE) DNA sequences within cardiac activating regions (By similarity). Acts as a transcriptional activator of ANF in cooperation with NKX2-5 (By similarity). Promotes cardiac myocyte enlargement (PubMed:20081228). Required during testicular development (PubMed:21220346). May play a role in sphingolipid signaling by regulating the expression of sphingosine-1-phosphate degrading enzyme, spingosine-1-phosphate lyase (PubMed:15734735). {ECO:0000250|UniProtKB:P46152, ECO:0000250|UniProtKB:Q08369, ECO:0000269|PubMed:15734735, ECO:0000269|PubMed:20081228, ECO:0000269|PubMed:21220346, ECO:0000269|PubMed:24000169, ECO:0000269|PubMed:27984724}.;
- Disease
- DISEASE: Atrial septal defect 2 (ASD2) [MIM:607941]: A congenital heart malformation characterized by incomplete closure of the wall between the atria resulting in blood flow from the left to the right atria. Patients show other heart abnormalities including ventricular and atrioventricular septal defects, pulmonary valve thickening or insufficiency of the cardiac valves. The disease is not associated with defects in the cardiac conduction system or non-cardiac abnormalities. {ECO:0000269|PubMed:12845333, ECO:0000269|PubMed:15810002, ECO:0000269|PubMed:17643447, ECO:0000269|PubMed:18055909, ECO:0000269|PubMed:20347099, ECO:0000269|PubMed:20659440, ECO:0000269|PubMed:27984724}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ventricular septal defect 1 (VSD1) [MIM:614429]: A common form of congenital cardiovascular anomaly that may occur alone or in combination with other cardiac malformations. It can affect any portion of the ventricular septum, resulting in abnormal communications between the two lower chambers of the heart. Classification is based on location of the communication, such as perimembranous, inlet, outlet (infundibular), central muscular, marginal muscular, or apical muscular defect. Large defects that go unrepaired may give rise to cardiac enlargement, congestive heart failure, pulmonary hypertension, Eisenmenger's syndrome, delayed fetal brain development, arrhythmias, and even sudden cardiac death. {ECO:0000269|PubMed:18672102, ECO:0000269|PubMed:21110066, ECO:0000269|PubMed:21637914, ECO:0000269|PubMed:22101736}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Tetralogy of Fallot (TOF) [MIM:187500]: A congenital heart anomaly which consists of pulmonary stenosis, ventricular septal defect, dextroposition of the aorta (aorta is on the right side instead of the left) and hypertrophy of the right ventricle. In this condition, blood from both ventricles (oxygen-rich and oxygen-poor) is pumped into the body often causing cyanosis. {ECO:0000269|PubMed:18672102, ECO:0000269|PubMed:21110066, ECO:0000269|PubMed:24000169}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Atrioventricular septal defect 4 (AVSD4) [MIM:614430]: A congenital heart malformation characterized by a common atrioventricular junction coexisting with deficient atrioventricular septation. The complete form involves underdevelopment of the lower part of the atrial septum and the upper part of the ventricular septum; the valve itself is also shared. A less severe form, known as ostium primum atrial septal defect, is characterized by separate atrioventricular valvar orifices despite a common junction. {ECO:0000269|PubMed:17643447}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Testicular anomalies with or without congenital heart disease (TACHD) [MIM:615542]: A 46,XY disorder of sex development with variable clinical presentation and defects in testicular differentiation and function. Clinical features include ambiguous genitalia, fused labioscrotal folds, hypospadias, microphallus, and bilateral inguinal hernia containing gonads. {ECO:0000269|PubMed:21220346}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=GATA4 mutations can predispose to dilated cardiomyopathy (CMD), a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. {ECO:0000269|PubMed:24041700, ECO:0000269|PubMed:25017055}.;
Recessive Scores
- pRec
- 0.712
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.956
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |