ZFPM2

protein-coding

zinc finger protein, FOG family member 2, the group of Zinc fingers C2H2-type|SET domain containing|PR/SET domain family|Zinc fingers C2HC-type

Gene summary

The zinc finger protein encoded by this gene is a widely expressed member of the FOG family of transcription factors. The family members modulate the activity of GATA family proteins, which are important regulators of hematopoiesis and cardiogenesis in mammals. It has been demonstrated that the protein can both activate and down-regulate expression of GATA-target genes, suggesting different modulation in different promoter contexts. A related mRNA suggests an alternatively spliced product but this information is not yet fully supported by the sequence. [provided by RefSeq, Jul 2008]

MANE transcript

NM_012082.4

Inheritance

ClinVar variants

P:22U:302B:124

Top phenotype

46,XY sex reversal 9

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr8:104,590,733-105,804,539

External References & Databases

Ensembl (ENSG00000169946)

Transcript & Mutation Effects

hg38 • Region Span ~1,213.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

46,XY sex reversal 9STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014480

Submitter: Labcorp Genetics (formerly Invitae)

diaphragmatic hernia 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012431

Submitter: Labcorp Genetics (formerly Invitae)

diaphragmatic hernia 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012431

Submitter: PanelApp Australia

46,XY sex reversal 9NO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0014480

Submitter: PanelApp Australia

tetralogy of fallotLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0008542

Submitter: Labcorp Genetics (formerly Invitae)

diaphragmatic hernia 3DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012431

Submitter: ClinGen

*ZFPM2* was first reported in relation to autosomal dominant congenital diaphragmatic hernia in 2005 (Ackerman et al., PMID: 16103912). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, congenital heart disease (OMIM:187500), diaphragmatic hernia 3 (OMIM:610187), and 46,XY sex reversal 9 (OMIM:616067). The split curation for autosomal dominant congenital heart disease has been curated separately. Eleven variants (nonsense, missense, deletion, and frameshift) that have been reported in 11 probands in five publications (PMIDs: 16103912, 17568391, 24702427, 21525063, 29966037) are included in this curation. The mechanism of pathogenicity is currently unclear. This gene-disease relationship is also supported by an animal model showing that mice with a truncated Zfpm2 protein had pulmonary hypoplasia and abnormal diaphragmatic development (PMID:16103912). ZFPM2 is also expressed in the early amuscular diaphragm and muscularized diaphragm and is required for the induction of HGF in the developing diaphragm (PMID:16103912). In summary, there is definitive evidence supporting the relationship between *ZFPM2* and autosomal dominant congenital diaphragmatic hernia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date August 4, 2026 (SOP Version 12).

congenital heart diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*ZFPM2* was first reported in relation to autosomal dominant congenital heart disease in 2003 (Pizzuti et al., PMID: 14517948). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, congenital heart disease (OMIM:187500), diaphragmatic hernia 3 (OMIM:610187), and 46,XY sex reversal 9 (OMIM:616067). The split curation for autosomal dominant diaphragmatic hernia 3 will be curated separately. 13 missense variants that have been reported in 15 probands in five publications (PMIDs: 24469719, 28372585, 31028076, 29018978, 21919901) are included in this curation. The mechanism of pathogenicity is unclear. This gene-disease relationship is also supported by a *Zfpm2*-null mouse model (PMID:10888889), rescue in cardiomyocytes of *Zfpm2*-null mouse embryos (PMID:10892744), and biochemical function data showing that ZFPM2 interacts with the adenovirus-associated protein p300 and competes with GATA4 for binding p300 (PMID:15220332). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date on July 7, 2026. (SOP Version 12).

46,XY partial gonadal dysgenesisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016674

Submitter: Orphanet

tetralogy of fallotMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008542

Submitter: PanelApp Australia

tetralogy of fallotSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008542

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

46,XY sex reversal 9AD

Manifestation: Cardiovascular; Genitourinary; Musculoskeletal; Neurologic; Pulmonary

Intervention: Oncologic

Rationale: Individuals may be at risk for gonadal tumors, and awareness may allow preventive measures and early management

Refs: 14517948; 16103912; 17568391; 20807224; 24549039; 24702427; 25996639; 29018978; 29264446; 29536580; 31028076; 31962012

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZFPM2 variants in ClinVar

10 Conditions Cataloged

46,XY sex reversal 9Total: 251

Inborn genetic diseasesTotal: 137

not providedTotal: 109

ZFPM2-related disorderTotal: 38

not specifiedTotal: 34

Diaphragmatic hernia 3Total: 23

Tetralogy of FallotTotal: 16

46,XY sex reversal 3Total: 10

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012082.4. 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 clinvar	77 clinvar	5 clinvar	83
missense	4 clinvar	1 clinvar	283 clinvar	36 clinvar	6 clinvar	330
nonsense	2 clinvar	6 clinvar	4 clinvar			12
start loss						0
frameshift	2 clinvar	5 clinvar	8 clinvar			15
splice donor/acceptor (+/-2bp)		2 clinvar	6 clinvar			8
Total	8	14	302	113	11	448

Highest pathogenic variant AF is 0.0000013689516

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012082.4	RefSeq	NP_036214.2	8	MANE Select
ENST00000407775.7	Ensembl	ENSP00000384179.2	8	MANE Select
NM_001362836.2	RefSeq	NP_001349765.1	7	Standard
NM_001362837.2	RefSeq	NP_001349766.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

MicroRNAs in cancer - Homo sapiens (human)
Factors involved in megakaryocyte development and platelet production
Hemostasis

Biological Process

negative regulation of transcription by RNA polymerase II
vasculogenesis
in utero embryonic development
outflow tract septum morphogenesis
right ventricular cardiac muscle tissue morphogenesis

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
RNA polymerase II transcription factor binding
DNA binding
transcription coactivator activity
transcription corepressor activity

Cellular Component

nucleus
nucleoplasm
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000407775
Coding exons: 8
Length: 485841
Individuals with no LoFs: 124639
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 124649
p: 0.0000401

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.213	581	596	0.975	0.0000317	7616
Missense (PolyPhen)		220	241.06	0.91262		3051
Synonymous	0.216	220	224	0.982	0.0000128	2185
Loss of Function	5.82	2	43.3	0.0461	0.00000245	528

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00020	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000056	0.000056	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.0000090	0.0000088	rare
South Asian	0.000066	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription regulator that plays a central role in heart morphogenesis and development of coronary vessels from epicardium, by regulating genes that are essential during cardiogenesis. Essential cofactor that acts via the formation of a heterodimer with transcription factors of the GATA family GATA4, GATA5 and GATA6. Such heterodimer can both activate or repress transcriptional activity, depending on the cell and promoter context. Also required in gonadal differentiation, possibly be regulating expression of SRY. Probably acts a corepressor of NR2F2 (By similarity). {ECO:0000250, ECO:0000269|PubMed:10438528}.;
Disease: 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:14517948, ECO:0000269|PubMed:20807224}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Diaphragmatic hernia 3 (DIH3) [MIM:610187]: Form of congenital diaphragmatic hernia (CDH). CDH refers to a group of congenital defects in the structural integrity of the diaphragm associated with often lethal pulmonary hypoplasia and pulmonary hypertension. {ECO:0000269|PubMed:16103912}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 46,XY sex reversal 9 (SRXY9) [MIM:616067]: A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females or have ambiguous external genitalia. {ECO:0000269|PubMed:24549039}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Conotruncal heart malformations (CTHM) [MIM:217095]: A group of congenital heart defects involving the outflow tracts. Examples include truncus arteriosus communis, double-outlet right ventricle and transposition of great arteries. Truncus arteriosus communis is characterized by a single outflow tract instead of a separate aorta and pulmonary artery. In transposition of the great arteries, the aorta arises from the right ventricle and the pulmonary artery from the left ventricle. In double outlet of the right ventricle, both the pulmonary artery and aorta arise from the right ventricle. {ECO:0000269|PubMed:20807224}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.264

Intolerance Scores

LoFtool: 0.188
RVIS EVS: 0.52
RVIS percentile EVS: 80.37

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.911

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium