EPAS1

endothelial PAS domain protein 1, the group of PAS domain containing|Basic helix-loop-helix proteins

Basic information

Region (hg38): 2:46293666-46386697

Links

ENSG00000116016 ∙ NCBI:2034 ∙ OMIM:603349 ∙ HGNC:3374 ∙ Uniprot:Q99814 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• erythrocytosis, familial, 4 (Strong), mode of inheritance: AD
• autosomal dominant secondary polycythemia (Supportive), mode of inheritance: AD
• erythrocytosis, familial, 4 (Moderate), mode of inheritance: AD
• erythrocytosis, familial, 4 (Strong), mode of inheritance: AD
• erythrocytosis, familial, 4 (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Erthyrocytosis, familial 4	AD	Hematologic; Oncologic	Individuals can present with manifestations secondary to erythrocytosis (eg, a DVT has been described in one individual), and interventions related to erythrocytosis (eg, venesection) have been described as beneficial; Due to a reported increased risk of neoplasms (eg, pheochromocytoma/paraganglioma), awareness may allow early detection and management, which may decrease associated morbidity and mortality	Hematologic; Oncologic	7747773; 18184961; 18456918; 18378852; 23090011
While presentation is typically described in adulthood, surveillance and treatment may be indicated in the pediatric time period

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the EPAS1 gene.

• Inborn genetic diseases (1125 variants)
• Erythrocytosis, familial, 4 (138 variants)
• not provided (118 variants)
• Familial erythrocytosis (20 variants)
• not specified (3 variants)
• Teratoma (1 variants)
• sorafenib response - Toxicity (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the EPAS1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	468	4	475
missense	2		610	43	4	659
nonsense						0
start loss						0
frameshift			1			1
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			3	12	5	20
non coding			49	17	72	138
Total	2	0	663	528	80

Variants in EPAS1

This is a list of pathogenic ClinVar variants found in the EPAS1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-46297151-G-C			Benign (Jun 21, 2019)
2-46297251-T-C			Benign (Jun 15, 2019)
2-46297264-G-C			Benign (Jun 15, 2019)
2-46297273-G-A			Benign (Jun 15, 2019)
2-46297440-G-A		Familial erythrocytosis	Uncertain significance (Jun 14, 2016)
2-46297441-C-T		Erythrocytosis, familial, 4	Benign (Jun 15, 2019)
2-46297460-A-C		Erythrocytosis, familial, 4	Uncertain significance (Jan 12, 2018)
2-46297511-G-A		Erythrocytosis, familial, 4	Uncertain significance (Jan 12, 2018)
2-46297555-G-C		Erythrocytosis, familial, 4	Uncertain significance (Jan 13, 2018)
2-46297561-C-CT		Familial erythrocytosis	Benign (Jun 14, 2016)
2-46297565-T-G		Erythrocytosis, familial, 4	Uncertain significance (Jan 13, 2018)
2-46297596-C-A		Erythrocytosis, familial, 4	Uncertain significance (Jan 13, 2018)
2-46297657-G-T		Erythrocytosis, familial, 4	Uncertain significance (Jan 13, 2018)
2-46297675-C-G		Erythrocytosis, familial, 4	Uncertain significance (Mar 16, 2018)
2-46297681-C-G		Erythrocytosis, familial, 4	Uncertain significance (Jan 13, 2018)
2-46297712-A-C		Erythrocytosis, familial, 4	Uncertain significance (Jan 13, 2018)
2-46297772-G-A		Erythrocytosis, familial, 4	Benign (Feb 01, 2023)
2-46297774-G-T		Erythrocytosis, familial, 4	Uncertain significance (Jan 12, 2018)
2-46297801-G-C		Erythrocytosis, familial, 4	Uncertain significance (Jan 13, 2018)
2-46297810-C-G		Erythrocytosis, familial, 4	Uncertain significance (Jan 12, 2018)
2-46297820-G-A		Erythrocytosis, familial, 4	Uncertain significance (Jan 12, 2018)
2-46297826-C-T		Erythrocytosis, familial, 4	Uncertain significance (Jan 12, 2018)
2-46297848-G-GC		Familial erythrocytosis	Benign (Sep 25, 2018)
2-46297908-G-A		Erythrocytosis, familial, 4	Benign/Likely benign (Mar 01, 2022)
2-46297911-A-G			Uncertain significance (Jan 01, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
EPAS1	protein_coding	protein_coding	ENST00000263734	16	93031

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.596	0.404	125733	1	14	125748	0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.154	490	481	1.02	0.0000299	5752
Missense in Polyphen		110	164.02	0.67067		2024
Synonymous	-3.94	276	204	1.35	0.0000140	1662
Loss of Function	4.50	8	37.9	0.211	0.00000203	452

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000181	0.000181
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.0000456	0.0000439
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000653	0.0000327
Other	0.000346	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcription factor involved in the induction of oxygen regulated genes. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation requires recruitment of transcriptional coactivators such as CREBBP and probably EP300. Interaction with redox regulatory protein APEX seems to activate CTAD (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:P97481}.
• Disease: DISEASE: Erythrocytosis, familial, 4 (ECYT4) [MIM:611783]: An autosomal dominant disorder characterized by increased serum red blood cell mass, elevated serum hemoglobin and hematocrit, and normal platelet and leukocyte counts. {ECO:0000269|PubMed:18184961, ECO:0000269|PubMed:18378852, ECO:0000269|PubMed:19208626, ECO:0000269|PubMed:22367913}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Renal cell carcinoma - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Adipogenesis;Transcriptional regulation of pluripotent stem cells;Amplification and Expansion of Oncogenic Pathways as Metastatic Traits;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;Type 2 papillary renal cell carcinoma;Oxygen-dependent asparagine hydroxylation of Hypoxia-inducible Factor Alpha;Signaling by PTK6;Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha;Regulation of gene expression by Hypoxia-inducible Factor;Regulation of Hypoxia-inducible Factor (HIF) by oxygen;Cellular response to hypoxia;Signal Transduction;Cellular responses to stress;Post-translational protein modification;Metabolism of proteins;HIF-2-alpha transcription factor network;PTK6 Expression;Cellular responses to external stimuli;Neddylation;Signaling by Non-Receptor Tyrosine Kinases (Consensus)

Recessive Scores

• pRec: 0.386

Intolerance Scores

• loftool: 0.0692
• rvis_EVS: -0.88
• rvis_percentile_EVS: 10.54

Haploinsufficiency Scores

• pHI: 0.245
• hipred: Y
• hipred_score: 0.786
• ghis: 0.544

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.920

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Epas1
• Phenotype: vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); skeleton phenotype; immune system phenotype; respiratory system phenotype; liver/biliary system phenotype; embryo phenotype; pigmentation phenotype; growth/size/body region phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: epas1b
• Affected structure: primary motor neuron
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: angiogenesis;response to hypoxia;embryonic placenta development;blood vessel remodeling;regulation of heart rate;regulation of transcription by RNA polymerase II;transcription by RNA polymerase II;mitochondrion organization;signal transduction;visual perception;erythrocyte differentiation;lung development;norepinephrine metabolic process;surfactant homeostasis;regulation of transcription from RNA polymerase II promoter in response to oxidative stress;post-translational protein modification;positive regulation of transcription by RNA polymerase II;cell maturation;myoblast fate commitment;iron ion homeostasis;regulation of transcription from RNA polymerase II promoter in response to hypoxia;cellular response to hypoxia;positive regulation of cold-induced thermogenesis
• Cellular component: nucleus;nucleoplasm;transcription factor complex;cytosol;nuclear speck
• Molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA binding;protein binding;transcription factor binding;histone acetyltransferase binding;sequence-specific DNA binding;protein heterodimerization activity