FOXA2
protein-codingforkhead box A2, the group of Forkhead boxes
Gene summary
This gene encodes a member of the forkhead class of DNA-binding proteins. These hepatocyte nuclear factors are transcriptional activators for liver-specific genes such as albumin and transthyretin, and they also interact with chromatin. Similar family members in mice have roles in the regulation of metabolism and in the differentiation of the pancreas and liver. This gene has been linked to sporadic cases of maturity-onset diabetes of the young. Transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Oct 2008]
- HNF3B
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013099
Submitter: ClinGen
*FOXA2* was first reported in relation to autosomal dominant combined pituitary hormone deficiencies in 2017 (Giri et al., PMID: 28973288). Probands with this condition present with various types of structural congenital heart disease, including patent ductus arteriosus, and double outlet right ventricle. Six variants (5 missense, 1 nonsense) that have been reported in six probands in five publications (PMIDs: 28973288, 29329447, 30414530, 33729509, 31294511) are included in this curation. Variants were reported to be de novo for all cases in which parents were available for testing; for two of the missense variants, supporting evidence for reduced function is available (PMIDs: 28973288, 29329447). Thus far, reported missense variants appear to cluster in or near the forkhead domain, which may affect the DNA binding ability of this transcriptional activator (PMID: 33729509). At least two probands with a similar phenotype and de novo deletions encompassing *FOXA2* have been reported, but were not scored in this curation (PMIDs: 31294511, 32277595). Therefore, the mechanism of pathogenicity appears to be LOF leading to haploinsufficiency. This gene-disease association is also supported by expression studies in both mouse and human embryos (PMID: 28973288). In summary, there is moderate evidence to support the relationship between *FOXA2* and autosomal dominant combined pituitary hormone deficiencies. This classification was approved by the ClinGen Brain Malformations gene curation expert panel on November 22, 2022 (SOP 9), and the Congenital Heart Disease Gene Curation Expert Panel on October 8, 2025 (SOP 11).
Inheritance Pattern: AD
Disease ID:MONDO:0013099
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0002177
Submitter: PanelApp Australia
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FOXA2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_021784.5. 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 | 1 | 29 | 4 | 34 | ||
| missense | 1 | 101 | 18 | 6 | 126 | |
| nonsense | 1 | 5 | 6 | |||
| start loss | 0 | |||||
| frameshift | 1 | 8 | 9 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 3 | 115 | 47 | 10 | 175 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_068556.2 | 2 | MANE Select | |
| Ensembl | ENSP00000400341.3 | 2 | MANE Select | |
| RefSeq | NP_710141.1 | 2 | Standard | |
| Ensembl | ENSP00000366319.4 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| foxa2 | Danio rerio | Structure: exocrine pancreas Quality: decreased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Longevity regulating pathway - multiple species - Homo sapiens (human)
- Maturity onset diabetes of the young - Homo sapiens (human)
- Heart Development
- Cardiac Progenitor Differentiation
- Endoderm Differentiation
Biological Process
- positive regulation of transcription from RNA polymerase II promoter by glucose
- cell fate specification
- chromatin organization
- regulation of transcription by RNA polymerase II
- adult locomotory behavior
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA binding
- DNA-binding transcription factor activity
- transcription factor binding
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- cell junction
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000419308
- Coding exons
- 2
- Length
- 4451
- Individuals with no LoFs
- 125701
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 125705
- p
- 0.0000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.378 | 248 | 265 | 0.935 | 0.0000120 | 3000 |
| Missense (PolyPhen) | 75 | 111.36 | 0.67351 | 1280 | ||
| Synonymous | -1.80 | 143 | 118 | 1.21 | 0.00000575 | 922 |
| Loss of Function | 2.86 | 2 | 13.2 | 0.151 | 5.70e-7 | 141 |
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) | 0.000039 | 0.000035 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcription factor that is involved in embryonic development, establishment of tissue-specific gene expression and regulation of gene expression in differentiated tissues. Is thought to act as a 'pioneer' factor opening the compacted chromatin for other proteins through interactions with nucleosomal core histones and thereby replacing linker histones at target enhancer and/or promoter sites. Binds DNA with the consensus sequence 5'-[AC]A[AT]T[AG]TT[GT][AG][CT]T[CT]-3' (By similarity). In embryonic development is required for notochord formation. Involved in the development of multiple endoderm-derived organ systems such as the liver, pancreas and lungs; FOXA1 and FOXA2 seem to have at least in part redundant roles. Originally described as a transcription activator for a number of liver genes such as AFP, albumin, tyrosine aminotransferase, PEPCK, etc. Interacts with the cis-acting regulatory regions of these genes. Involved in glucose homeostasis; regulates the expression of genes important for glucose sensing in pancreatic beta-cells and glucose homeostasis. Involved in regulation of fat metabolism. Binds to fibrinogen beta promoter and is involved in IL6-induced fibrinogen beta transcriptional activation. {ECO:0000250}.;
Recessive Scores
- pRec
- 0.659
Intolerance Scores
- LoFtool
- 0.0183
- RVIS EVS
- 0.04
- RVIS percentile EVS
- 56.92
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |