XPNPEP2

protein-coding

X-prolyl aminopeptidase 2, the group of M24 metallopeptidase family|Aminopeptidases

Gene summary

Aminopeptidase P is a hydrolase specific for N-terminal imido bonds, which are common to several collagen degradation products, neuropeptides, vasoactive peptides, and cytokines. Structurally, the enzyme is a member of the 'pita bread fold' family and occurs in mammalian tissues in both soluble and GPI-anchored membrane-bound forms. A membrane-bound and soluble form of this enzyme have been identified as products of two separate genes. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003399.6

Inheritance

ClinVar variants

U:131B:20

Top phenotype

Angioedema induced by ACE inhibitors, susceptibility to

gnomAD constraint

pLI —, LoF o/e 0.78

Max pathogenic AF

—

Genomic locus

chrX:129,738,949-129,769,536

External References & Databases

Ensembl (ENSG00000122121)

Transcript & Mutation Effects

hg38 • Region Span ~30.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

Clinical Genomic Database (CGD)

Angioedema induced by ACE inhibitors, susceptibility toXL

Manifestation: General

Intervention: Pharmacogenomic

Rationale: Medication selection would be impacted in individuals with relevant variants

Refs: 16175507

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to XPNPEP2 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 88

not providedTotal: 15

Premature ovarian failureTotal: 1

Susceptibility to angioedema induced by ACE inhibitorsTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003399.6. 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	14 clinvar		24
missense			106 clinvar	6 clinvar		112
nonsense			4 clinvar			4
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			11 clinvar			11
Total	0	0	131	20	0	151

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 13 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003399.6	RefSeq	NP_003390.4	21	MANE Select
ENST00000371106.4	Ensembl	ENSP00000360147.3	21	MANE Select
ENST00000880528.1	Ensembl	ENSP00000550587.1	20	Standard
ENST00000880528.2	Ensembl	ENSP00000550587.1	20	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein digestion and absorption - Homo sapiens (human)
Post-translational modification: synthesis of GPI-anchored proteins
Post-translational protein modification
Metabolism of proteins

Biological Process

proteolysis

Molecular Function

aminopeptidase activity
metal ion binding
metalloaminopeptidase activity

Cellular Component

extracellular region
cytoplasm
plasma membrane
membrane
anchored component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000371106
Coding exons: 21
Length: 30565
Individuals with no LoFs: 125666
Homozygous LoFs: 36
Heterozygous LoFs: 45
Defined: 125747
p: 0.000322

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.338	288	272	1.06	0.0000216	4371
Missense (PolyPhen)		94	92.749	1.0135		1432
Synonymous	-0.779	117	107	1.10	0.00000874	1325
Loss of Function	1.10	23	29.4	0.782	0.00000214	465

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00023	0.00018	rare
Latino/Admixed American	0.00026	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0014	0.0011	notable
Finnish	0	0.0	absent
European (Non-Finnish)	0.00043	0.00031	rare
South Asian	0.00074	0.00046	rare
Other	0.00044	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Membrane-bound metalloprotease which catalyzes the removal of a penultimate prolyl residue from the N-termini of peptides, such as Arg-Pro-Pro. May play a role in the metabolism of the vasodilator bradykinin. {ECO:0000269|PubMed:15361070}.;
Disease: DISEASE: Angioedema induced by ACE inhibitors (AEACEI) [MIM:300909]: A potentially life-threatening side effect of ACE inhibitors that appears in a subset of patients taking these drugs for hypertension and cardiovascular disease treatment. AEACEI is characterized by swelling of the face, lips, tongue, and airway that can lead to suffocation and death if severe. {ECO:0000269|PubMed:16175507, ECO:0000269|PubMed:20625347, ECO:0000269|PubMed:21898657}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.138

Intolerance Scores

LoFtool: 0.783
RVIS EVS: -0.38
RVIS percentile EVS: 28.11

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.130

Gene Damage Prediction

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