ERAP1

protein-coding

endoplasmic reticulum aminopeptidase 1, the group of Aminopeptidases|Minor histocompatibility antigens|M1 metallopeptidases

Gene summary

The protein encoded by this gene is an aminopeptidase involved in trimming HLA class I-binding precursors so that they can be presented on MHC class I molecules. The encoded protein acts as a monomer or as a heterodimer with ERAP2. This protein may also be involved in blood pressure regulation by inactivation of angiotensin II. Three transcript variants encoding two different isoforms have been found for this gene.[provided by RefSeq, Oct 2010]

MANE transcript

NM_001040458.3

Inheritance

—

ClinVar variants

U:115B:33

Top phenotype

Long QT syndrome

gnomAD constraint

pLI —, LoF o/e 0.88

Max pathogenic AF

—

Genomic locus

chr5:96,760,810-96,808,100

External References & Databases

Ensembl (ENSG00000164307)

Transcript & Mutation Effects

hg38 • Region Span ~47.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ERAP1 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 110

not providedTotal: 30

Long QT syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001040458.3. 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				10 clinvar	9 clinvar	19
missense			108 clinvar	11 clinvar	3 clinvar	122
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	0	0	115	21	12	148

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001040458.3	RefSeq	NP_001035548.1	18	MANE Select
ENST00000443439.7	Ensembl	ENSP00000406304.2	18	MANE Select
NM_001198541.3	RefSeq	NP_001185470.1	18	Standard
NM_001349244.2	RefSeq	NP_001336173.1	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

angiogenesis
adaptive immune response
antigen processing and presentation of peptide antigen via MHC class I
proteolysis
membrane protein ectodomain proteolysis

Molecular Function

endopeptidase activity
aminopeptidase activity
interleukin-6 receptor binding
interleukin-1, type II receptor binding
protein binding

Cellular Component

extracellular region
extracellular space
cytoplasm
endoplasmic reticulum
endoplasmic reticulum lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000296754
Coding exons: 19
Length: 47283
Individuals with no LoFs: 124532
Homozygous LoFs: 5
Heterozygous LoFs: 1211
Defined: 125748
p: 0.00485

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.529	470	503	0.934	0.0000256	6269
Missense (PolyPhen)		150	164.73	0.9106		2130
Synonymous	-0.0410	190	189	1.00	0.0000106	1779
Loss of Function	0.794	43	49.0	0.878	0.00000245	567

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0087	0.0088	notable
Latino/Admixed American	0.0094	0.0093	notable
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.0076	0.0076	notable
Finnish	0.0017	0.0017	notable
European (Non-Finnish)	0.0039	0.0039	notable
South Asian	0.0037	0.0036	notable
Other	0.0039	0.0039	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I- binding peptides. Peptide trimming is essential to customize longer precursor peptides to fit them to the correct length required for presentation on MHC class I molecules. Strongly prefers substrates 9-16 residues long. Rapidly degrades 13-mer to a 9-mer and then stops. Preferentially hydrolyzes the residue Leu and peptides with a hydrophobic C-terminus, while it has weak activity toward peptides with charged C-terminus. May play a role in the inactivation of peptide hormones. May be involved in the regulation of blood pressure through the inactivation of angiotensin II and/or the generation of bradykinin in the kidney. {ECO:0000269|PubMed:15908954, ECO:0000269|PubMed:16286653, ECO:0000269|PubMed:21478864}.;

Recessive Scores

pRec: 0.116

Intolerance Scores

LoFtool: 0.999
RVIS EVS: 1.08
RVIS percentile EVS: 91.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.517

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High