NFE2

protein-coding

nuclear factor, erythroid 2, the group of Basic leucine zipper proteins

Gene summary

Enables WW domain binding activity; identical protein binding activity; and sequence-specific double-stranded DNA binding activity. Contributes to cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including labyrinthine layer blood vessel development; negative regulation of bone mineralization; and positive regulation of peptidyl-lysine acetylation. Part of protein-DNA complex. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_001136023.3

Inheritance

ClinVar variants

U:40B:2

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr12:54,292,111-54,301,015

External References & Databases

Ensembl (ENSG00000123405)

Transcript & Mutation Effects

hg38 • Region Span ~8.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

thrombocytopeniaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0002049

Submitter: ClinGen

*NFE2* was first reported in relation to inherited thrombocytopenia in 2020 (Luk et al, 2020 PMID: 31951293). *NFE2* is a DNA binding transcription factor involved in gene expression in erythroid and megakaryocytic cells. To date, there has been one report of a variant in *NFE2* causing severe thrombocytopenia with mild effects on erythroid cells. Additionally, somatic variants in *NFE2* have been well described in myeloproliferative neoplasms and are not included in this curation. Evidence supporting this gene-disease curation includes case level data and experimental data. Summary of Case Level Data (2 points): One homozygous frameshift variant causing gene truncation has been reported in a single proband (Luk et al, 2020 PMID: 31951293). Summary of Experimental Evidence (3.5 points): The gene-disease relationship is supported by expression studies (Andrews et al, 1993 PMID: 8469283), cell culture model system (Lecine et al, 1998 PMID: 9716588) and a mouse model system (Shivdasani el al, 1995 PMID: 7774011). 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 gene-disease relationship was curated by the ClinGen Hemostasis and Thrombosis (H/T) Gene Curation Expert Panel using Gene Clinical Validity Standard Operating Procedures (SOP), Version 11.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NFE2 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 39

not providedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001136023.3. 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				1 clinvar		1
missense			40 clinvar	1 clinvar		41
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	40	2	0	42

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001136023.3	RefSeq	NP_001129495.1	2	MANE Select
ENST00000435572.7	Ensembl	ENSP00000397185.2	2	MANE Select
NM_001261461.2	RefSeq	NP_001248390.1	2	Standard
NM_001400365.1	RefSeq	NP_001387294.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
nfe2	Danio rerio	Structure: nucleate erythrocyte Quality: low saturation abnormal

Gene / Model

Organism

Observed Phenotype

nfe2

Danio rerio

Structure: nucleate erythrocyte

Quality: low saturation

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Hematopoietic Stem Cell Differentiation
Steatosis AOP
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function
Gene expression (Transcription)
Generic Transcription Pathway

Biological Process

nucleosome disassembly
regulation of transcription by RNA polymerase II
multicellular organism development
blood coagulation
hemostasis

Molecular Function

transcription regulatory region sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
proximal promoter sequence-specific DNA binding
DNA binding
DNA-binding transcription factor activity

Cellular Component

nucleus
nucleoplasm
cytoplasm
PML body
protein-DNA complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000540264
Coding exons: 2
Length: 9011
Individuals with no LoFs: 125735
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125743
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.22	176	228	0.772	0.0000146	2352
Missense (PolyPhen)		55	86.017	0.63941		809
Synonymous	0.327	91	95.1	0.957	0.00000529	831
Loss of Function	2.71	2	12.2	0.163	7.06e-7	142

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0.000049	0.000046	rare
European (Non-Finnish)	0.000010	0.0000088	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the NF-E2 complex essential for regulating erythroid and megakaryocytic maturation and differentiation. Binds to the hypersensitive site 2 (HS2) of the beta-globin control region (LCR). This subunit (NFE2) recognizes the TCAT/C sequence of the AP-1-like core palindrome present in a number of erythroid and megakaryocytic gene promoters. Requires MAFK or other small MAF proteins for binding to the NF-E2 motif. May play a role in all aspects of hemoglobin production from globin and heme synthesis to procurement of iron. {ECO:0000269|PubMed:11154691, ECO:0000269|PubMed:16287851}.;

Recessive Scores

pRec: 0.360

Intolerance Scores

LoFtool: 0.0570
RVIS EVS: -0.27
RVIS percentile EVS: 33.97

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