PAPPA2

protein-coding

pappalysin 2, the group of Pappalysins|Sushi domain containing

Gene summary

This gene encodes a member of the pappalysin family of metzincin metalloproteinases. The encoded protein cleaves insulin-like growth factor-binding protein 5 and is thought to be a local regulator of insulin-like growth factor (IGF) bioavailability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2010]

Previous symbols:

PLAC3

MANE transcript

NM_020318.3

Inheritance

ClinVar variants

P:14U:258B:52

Top phenotype

Short stature, Dauber-Argente type

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr1:176,463,171-176,845,601

External References & Databases

Ensembl (ENSG00000116183)

Transcript & Mutation Effects

hg38 • Region Span ~382.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Short stature, Dauber-Argente typeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859182

Submitter: Ambry Genetics

Short stature, Dauber-Argente typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859182

Submitter: PanelApp Australia

Short stature, Dauber-Argente typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859182

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Short stature, Dauber-Argente typeAR

Manifestation: Craniofacial; Endocrine; Musculoskeletal; Neurologic

Intervention: Endocrine

Rationale: The condition can involve decreased growth, and response to prepubertal administration of growth hormone has been described

Refs: 26902202; 27648969; 29029190; 34272725

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PAPPA2 variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 257

not providedTotal: 46

not specifiedTotal: 35

Short stature, Dauber-Argente typeTotal: 8

PAPPA2-related disorderTotal: 3

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020318.3. 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			6 clinvar	18 clinvar	2 clinvar	26
missense	1 clinvar	1 clinvar	250 clinvar	31 clinvar	1 clinvar	284
nonsense	5 clinvar	1 clinvar				6
start loss						0
frameshift	3 clinvar	2 clinvar				5
splice donor/acceptor (+/-2bp)		1 clinvar	2 clinvar			3
Total	9	5	258	49	3	324

Highest pathogenic variant AF is 0.000017347495

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020318.3	RefSeq	NP_064714.2	22	MANE Select
ENST00000367662.5	Ensembl	ENSP00000356634.3	22	MANE Select
NM_021936.3	RefSeq	NP_068755.2	4	Standard
ENST00000367661.7	Ensembl	ENSP00000356633.3	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pappa2	Danio rerio	Structure: cranial neural crest cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

pappa2

Danio rerio

Structure: cranial neural crest cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of proteins
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)

Biological Process

regulation of cell growth
proteolysis
response to salt stress
cellular protein metabolic process
bone morphogenesis

Molecular Function

metalloendopeptidase activity
metallopeptidase activity
zinc ion binding

Cellular Component

extracellular region
cytosol
apical plasma membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367662
Coding exons: 22
Length: 382429
Individuals with no LoFs: 124771
Homozygous LoFs: 0
Heterozygous LoFs: 45
Defined: 124816
p: 0.000180

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.09	921	1.02e+3	0.904	0.0000583	11715
Missense (PolyPhen)		280	381.34	0.73426		4470
Synonymous	0.707	377	395	0.955	0.0000230	3543
Loss of Function	5.27	27	76.8	0.351	0.00000363	924

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00013	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00011	0.00011	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00020	0.00019	rare
South Asian	0.000099	0.000098	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Metalloproteinase which specifically cleaves insulin- like growth factor binding protein (IGFBP)-5 at the '163-Ser-|- Lys-164' bond. Shows limited proteolysis toward IGFBP-3. {ECO:0000269|PubMed:11264294}.;

Recessive Scores

pRec: 0.117

Intolerance Scores

LoFtool: 0.594
RVIS EVS: -1.49
RVIS percentile EVS: 3.62

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.486

Gene Damage Prediction

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