PAPPA

protein-coding

pappalysin 1, the group of Pappalysins|Sushi domain containing

Gene summary

This gene encodes a secreted metalloproteinase which cleaves insulin-like growth factor binding proteins (IGFBPs). Following IGFBP cleavage, insulin growth factors dissociate from IGFBPs and bind to IGF receptors, resulting in activation of the IGF pathway. The encoded protein plays a role in bone formation, inflammation, wound healing and female fertility. Enhanced expression of this protein is associated with diabetic nephropathy in human patients and this protein may promote tumor invasion and growth in various human cancers. [provided by RefSeq, Aug 2017]

MANE transcript

NM_002581.5

Inheritance

—

ClinVar variants

U:235B:22

Top phenotype

Inborn genetic diseases

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr9:116,153,791-116,402,321

External References & Databases

Ensembl (ENSG00000182752)

Transcript & Mutation Effects

hg38 • Region Span ~248.5 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 PAPPA variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 236

not providedTotal: 13

Inborn genetic diseasesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002581.5. 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			3 clinvar	4 clinvar	3 clinvar	10
missense			229 clinvar	11 clinvar	4 clinvar	244
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	235	15	7	257

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002581.5	RefSeq	NP_002572.2	22	MANE Select
ENST00000328252.4	Ensembl	ENSP00000330658.3	22	MANE Select
ENST00001139107.1	Ensembl	ENSP00000807271.1	22	Standard
XM_006717129.4	RefSeq	XP_006717192.1	18	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pappaa	Danio rerio	Structure: post-vent region Quality: kinked abnormal

Gene / Model

Organism

Observed Phenotype

pappaa

Danio rerio

Structure: post-vent region

Quality: kinked

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

proteolysis
female pregnancy
response to follicle-stimulating hormone
cellular protein metabolic process
response to glucocorticoid

Molecular Function

metalloendopeptidase activity
metallopeptidase activity
zinc ion binding

Cellular Component

extracellular region
extracellular space

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000328252
Coding exons: 22
Length: 248519
Individuals with no LoFs: 125722
Homozygous LoFs: 0
Heterozygous LoFs: 26
Defined: 125748
p: 0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.21	710	897	0.792	0.0000521	10709
Missense (PolyPhen)		67	103.12	0.64976		1110
Synonymous	0.0896	354	356	0.994	0.0000213	3180
Loss of Function	6.01	17	72.1	0.236	0.00000369	808

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00014	0.00014	rare
South Asian	0.000033	0.000033	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Metalloproteinase which specifically cleaves IGFBP-4 and IGFBP-5, resulting in release of bound IGF. Cleavage of IGFBP-4 is dramatically enhanced by the presence of IGF, whereas cleavage of IGFBP-5 is slightly inhibited by the presence of IGF. {ECO:0000269|PubMed:10077652, ECO:0000269|PubMed:10913121, ECO:0000269|PubMed:11522292}.;

Recessive Scores

pRec: 0.233

Intolerance Scores

LoFtool: 0.471
RVIS EVS: -1.4
RVIS percentile EVS: 4.16

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.794

Gene Damage Prediction

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