ETS1

protein-coding

ETS proto-oncogene 1, transcription factor, the group of ETS transcription factor family

Gene summary

This gene encodes a member of the ETS family of transcription factors, which are defined by the presence of a conserved ETS DNA-binding domain that recognizes the core consensus DNA sequence GGAA/T in target genes. These proteins function either as transcriptional activators or repressors of numerous genes, and are involved in stem cell development, cell senescence and death, and tumorigenesis. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.[provided by RefSeq, Jul 2011]

Previous symbols:

EWSR2

MANE transcript

NM_001143820.2

Inheritance

ClinVar variants

P:2U:32B:7

Top phenotype

systemic lupus erythematosus

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr11:128,458,761-128,587,558

External References & Databases

Ensembl (ENSG00000134954)

Transcript & Mutation Effects

hg38 • Region Span ~128.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Tourette syndromeNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0007661

Submitter: Labcorp Genetics (formerly Invitae)

congenital heart diseaseMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*ETS1* was first reported in relation to autosomal dominant congenital heart disease in 2014 (Glessner et al., 2014; PMID: 25205790). The phenotype may be syndromic, with neurological and facial symptoms as well. Four variants (frameshift, nonsense) that have been reported in four probands in three publications (PMIDs: 25205790, 31160359, 32368696; 3Billion internal data) are included in this curation. The mechanism of pathogenicity appears to be loss of function, with multiple frameshift variants occurring at residue 349, and truncating the protein about 20 amino acids down. This gene-disease relationship is also supported by experimental evidence (a mouse model, functional alteration evidence, expression-level evidence; PMIDs: 12915311, 19942620, 32810435). The mouse model has homozygous mutants showing the cardiac phenotype, as well as expression in the endocardium of healthy mice throughout the embryonic stage. Functional alteration evidence indicates impaired function in iPSCs (induced pluripotent stem cells) from patients with hypoplastic left heart syndrome. A chick embryo model shows cardiac expression. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease relationship was originally evaluated on 11/21/2023 (SOP Version 10). It was re-evaluated on 7/14/2026 (SOP Version 12). No new evidence was found, although a new publication reported additional phenotypic details for a proband originally scored. The classification remains at moderate.

systemic lupus erythematosusSUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0007915

Submitter: Orphanet

neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ETS1 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 29

not providedTotal: 6

ETS1-related disorderTotal: 3

11q partial monosomy syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001143820.2. 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 clinvar	4 clinvar	6
missense			29 clinvar	1 clinvar		30
nonsense		1 clinvar				1
start loss						0
frameshift	1 clinvar		1 clinvar			2
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	1	1	32	3	4	41

Highest pathogenic variant AF is 0.0000043410582

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001143820.2	RefSeq	NP_001137292.1	9	MANE Select
ENST00000392668.8	Ensembl	ENSP00000376436.3	9	MANE Select
NM_001162422.2	RefSeq	NP_001155894.1	4	Standard
NM_001330451.2	RefSeq	NP_001317380.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Renal cell carcinoma - Homo sapiens (human)
HTLV-I infection - Homo sapiens (human)
Ras signaling pathway - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)
Cellular senescence - Homo sapiens (human)

Biological Process

response to hypoxia
regulation of transcription by RNA polymerase II
immune response
female pregnancy
positive regulation of cell population proliferation

Molecular Function

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

Cellular Component

nucleus
nucleoplasm
transcription factor complex
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000392668
Coding exons: 9
Length: 128798
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125745
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.52	165	284	0.580	0.0000161	3212
Missense (PolyPhen)		47	125.67	0.374		1444
Synonymous	0.0561	105	106	0.993	0.00000614	888
Loss of Function	3.92	5	27.0	0.185	0.00000140	295

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.000068	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor. Directly controls the expression of cytokine and chemokine genes in a wide variety of different cellular contexts. May control the differentiation, survival and proliferation of lymphoid cells. May also regulate angiogenesis through regulation of expression of genes controlling endothelial cell migration and invasion. {ECO:0000269|PubMed:10698492, ECO:0000269|PubMed:11909962, ECO:0000269|PubMed:15247905, ECO:0000269|PubMed:15592518}.;

Recessive Scores

pRec: 0.726

Intolerance Scores

LoFtool: 0.0840
RVIS EVS: -0.2
RVIS percentile EVS: 38.82

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