PZP

protein-coding

PZP alpha-2-macroglobulin like, the group of Alpha-2-macroglobulin family

Gene summary

The protein encoded by this gene is highly expressed in late-pregnancy serum and is similar in structure to alpha-2-macroglobulin. The encoded protein, which acts as a homotetramer, inhibits the activity of all four classes of proteinases. This protein contains cleavage sites for several proteinases. Upon binding of a proteinase, the conformation of this protein changes to trap the proteinase, limiting its activity. This protein appears to be elevated in the sera of presymptomatic Alzheimer's disease patients. [provided by RefSeq, Dec 2016]

MANE transcript

NM_002864.3

Inheritance

—

ClinVar variants

U:177B:29

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.79

Max pathogenic AF

—

Genomic locus

chr12:9,148,840-9,208,395

External References & Databases

Ensembl (ENSG00000126838)

Transcript & Mutation Effects

hg38 • Region Span ~59.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PZP variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 191

not providedTotal: 11

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002864.3. 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	6 clinvar	3 clinvar	10
missense			176 clinvar	18 clinvar	1 clinvar	195
nonsense				1 clinvar		1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	177	25	4	206

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002864.3	RefSeq	NP_002855.2	36	MANE Select
ENST00000261336.7	Ensembl	ENSP00000261336.2	36	MANE Select
ENST00000535230.5	Ensembl	ENSP00000440811.1	3	Standard
ENST00000882536.1	Ensembl	ENSP00000552595.1	35	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

female pregnancy
negative regulation of endopeptidase activity

Molecular Function

endopeptidase inhibitor activity
serine-type endopeptidase inhibitor activity

Cellular Component

extracellular region
collagen-containing extracellular matrix
extracellular exosome
blood microparticle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261336
Coding exons: 36
Length: 59531
Individuals with no LoFs: 123514
Homozygous LoFs: 69
Heterozygous LoFs: 2165
Defined: 125748
p: 0.00892

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.366	756	785	0.963	0.0000396	9634
Missense (PolyPhen)		262	262.37	0.9986		3401
Synonymous	-0.990	323	301	1.07	0.0000159	2934
Loss of Function	1.73	64	80.8	0.792	0.00000414	961

Population LoF Frequency

Population	CAF	p-value	Status
African	0.011	0.011	notable
Latino/Admixed American	0.0059	0.0059	notable
Ashkenazi Jewish	0.0048	0.0048	notable
East Asian	0.089	0.088	notable
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.0013	0.0013	notable
South Asian	0.0030	0.0029	notable
Other	0.0043	0.0042	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Is able to inhibit all four classes of proteinases by a unique 'trapping' mechanism. This protein has a peptide stretch, called the 'bait region' which contains specific cleavage sites for different proteinases. When a proteinase cleaves the bait region, a conformational change is induced in the protein which traps the proteinase. The entrapped enzyme remains active against low molecular weight substrates (activity against high molecular weight substrates is greatly reduced). Following cleavage in the bait region a thioester bond is hydrolyzed and mediates the covalent binding of the protein to the proteinase.;

Intolerance Scores

LoFtool: 0.988
RVIS EVS: 0.26
RVIS percentile EVS: 70.26

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.233

Gene Damage Prediction

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