PAPPA2

Summary

PAPPA2 (pappalysin 2, HGNC:14615) is a protein-coding gene on chromosome 1q25.2, encoding Pappalysin-2 (Q9BXP8). Metalloproteinase which specifically cleaves insulin-like growth factor binding protein (IGFBP)-5 at the ‘163-Ser-|-Lys-164’ bond.

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.

Source: NCBI Gene 60676 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Short stature, Dauber-Argente type (Strong, GenCC)
• GWAS associations: 40
• Clinical variants (ClinVar): 306 total — 9 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 17
• MANE Select transcript: NM_020318

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14615
Approved symbol	PAPPA2
Name	pappalysin 2
Location	1q25.2
Locus type	gene with protein product
Status	Approved
Aliases	PAPPE, PAPP-A2
Ensembl gene	ENSG00000116183
Ensembl biotype	protein_coding
OMIM	619485
Entrez	60676

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding_CDS_not_defined, 2 protein_coding

ENST00000367661, ENST00000367662, ENST00000479836, ENST00000486075, ENST00000493665

RefSeq mRNA: 2 — MANE Select: NM_020318 NM_020318, NM_021936

CCDS: CCDS41438, CCDS41439

Canonical transcript exons

ENST00000367662 — 23 exons

Exon	Start	End
ENSE00000790003	176791347	176791482
ENSE00000814734	176594524	176595595
ENSE00000814740	176695738	176695859
ENSE00000814741	176699100	176699589
ENSE00000814742	176702607	176702735
ENSE00000814743	176706359	176706450
ENSE00000814744	176709983	176710176
ENSE00000814745	176711835	176711981
ENSE00000814746	176739626	176739761
ENSE00000814747	176739980	176740196
ENSE00000814748	176765666	176765837
ENSE00000814749	176769607	176769784
ENSE00000814750	176770967	176771180
ENSE00000814751	176789809	176789977
ENSE00000814752	176840173	176840271
ENSE00001003316	176670970	176671115
ENSE00001003319	176690137	176690430
ENSE00001003324	176692126	176692318
ENSE00001445290	176842380	176845601
ENSE00001445292	176555407	176557241
ENSE00003488548	176793560	176793669
ENSE00003502304	176800061	176800132
ENSE00003847090	176463175	176463418

Expression profiles

Bgee: expression breadth ubiquitous, 176 present calls, max score 97.56.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 6.8115 / max 3338.1172, expressed in 126 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
6829	6.2483	16
6833	0.2492	77
6832	0.1119	34
6849	0.0519	12
6837	0.0292	12
6830	0.0260	5
6834	0.0259	4
6836	0.0252	6
6828	0.0170	6
6850	0.0119	2

Top tissues by expression

255 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
decidua	UBERON:0002450	97.56	gold quality
placenta	UBERON:0001987	96.67	gold quality
islet of Langerhans	UBERON:0000006	89.25	gold quality
diaphragm	UBERON:0001103	83.92	gold quality
cortical plate	UBERON:0005343	82.43	gold quality
cartilage tissue	UBERON:0002418	81.04	gold quality
ventricular zone	UBERON:0003053	80.72	gold quality
buccal mucosa cell	CL:0002336	80.67	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.06	gold quality
type B pancreatic cell	CL:0000169	78.03	gold quality
olfactory bulb	UBERON:0002264	77.84	gold quality
ganglionic eminence	UBERON:0004023	75.24	gold quality
cervix squamous epithelium	UBERON:0006922	71.30	gold quality
hair follicle	UBERON:0002073	71.27	gold quality
adult mammalian kidney	UBERON:0000082	71.07	gold quality
embryo	UBERON:0000922	70.88	gold quality
vastus lateralis	UBERON:0001379	70.86	gold quality
quadriceps femoris	UBERON:0001377	70.80	gold quality
kidney	UBERON:0002113	70.32	gold quality
pancreatic ductal cell	CL:0002079	70.00	silver quality
stromal cell of endometrium	CL:0002255	69.73	gold quality
oocyte	CL:0000023	68.22	gold quality
tibialis anterior	UBERON:0001385	67.74	silver quality
CA1 field of hippocampus	UBERON:0003881	67.17	gold quality
mucosa of urinary bladder	UBERON:0001259	66.92	gold quality
secondary oocyte	CL:0000655	66.90	gold quality
pancreas	UBERON:0001264	66.84	gold quality
cervix epithelium	UBERON:0004801	66.56	gold quality
gall bladder	UBERON:0002110	66.12	gold quality
endothelial cell	CL:0000115	66.09	silver quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-ENAD-27	yes	1158.35
E-GEOD-81608	yes	540.38
E-GEOD-83139	yes	396.50
E-MTAB-5061	yes	30.40
E-HCAD-31	yes	29.04
E-GEOD-81547	yes	27.38
E-MTAB-6678	yes	17.85
E-ANND-3	yes	7.31

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

46 targeting PAPPA2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-3199	99.17	65.19	696
HSA-MIR-8052	99.17	65.01	719
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-1228-3P	99.00	66.53	857
HSA-MIR-3127-3P	98.94	67.34	1055
HSA-MIR-6756-3P	98.94	66.79	1104
HSA-MIR-4716-5P	98.82	68.57	1168
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-299-5P	98.56	71.14	1140
HSA-MIR-3184-5P	98.56	67.13	1491

Literature-anchored findings (GeneRIF, showing 33)

• Seven placental transcripts characterize HELLP-syndrome. (PMID:18374411)
• PAPP-A2 in syncytiotrophoblast cells was dramatically increased in pre-eclampsia. Maternal serum concentrations of PAPP-A2 were also significantly elevated in pre-eclampsia as compared with uncomplicated pregnancy. (PMID:18805800)
• Preeclampsia involves changes in the gene expression of PAPPA2 in placental cytotrophoblasts. (PMID:18818296)
• PAPPA2 is expressed in the syncytiotrophoblast layer of human placental villi and is also detected in some invasive extravillous trophoblasts in the first trimester (PMID:19474058)
• Circulating IGFBP-5 is proteolyzed by PAPP-A2 during pregnancy, resulting in increased IGF bioavailability, which may have important consequences for the development of the fetus and/or the well-being of the mother. (PMID:20103653)
• factors previously known to be highly expressed in preeclamptic placentae (PGE2 and TNF-alpha), contribute to the upregulation of PAPPA2. results are consistent with the hypothesis that PAPPA2 is upregulated as a consequence of placental pathology (PMID:21496272)
• Association of a single nucleotide polymorphism in pregnancy-associated plasma protein-A2 with developmental dysplasia of the hip (PMID:22037112)
• PAPPA2 may be upregulated in severe pre-eclampsia and, functionally, this may be mediated via increased placental hypoxia known to occur with this pregnancy disorder. (PMID:23484525)
• The existence of this assay will enable an assessment of the biomarker potential of PAPP-A2 in pre-eclampsia as well as other clinical conditions. (PMID:23804707)
• The upregulation of PAPP-A2 observed in preeclampsia at term occurs early in pregnancy, before the symptoms develop. (PMID:24336677)
• The association between this PAPPA2 single nucleotide polymorphism and developmental dysplasia of the hip was evaluated. (PMID:24672801)
• overexpression in Down syndrome from placental mRNA to maternal serum protein (PMID:25154785)
• PAPP-A2 is differentially expressed in different trophoblast populations and shows strong down regulation in the mid second trimester in chorionic villous samples. (PMID:26748159)
• These patients provide important insights into the regulation of longitudinal growth in humans, documenting the critical role of PAPP-A2 in releasing IGF-I from its binding proteins. (PMID:26902202)
• in situ hybridization (ISH) and immunohistochemistry (IHC) were employed to examine the spatial and temporal expression of PAPPA2 in the human fetomaternal interface. (PMID:27525857)
• Short-term treatment with progressive doses of rhIGF1 (recombinant human insulin-like growth factor-1) improved growth in two siblings with deficiency of PAPP-A2 (pregnancy-associated plasma protein-A2) [due to a homozygous loss-of-function frameshift mutation in exon 3 of the PAPP-A2 gene (p.D643fs25*)] that resulted in postnatal growth failure due to resulting decrease in IGF1 bioavailability. [CASE REPORT] (PMID:27648969)
• PAPP-A2 is increased in Hemodialysis patients and interacts with PAPP-A on patients prognosis. (PMID:28854436)
• Pregnancy associated plasma protein-A (PAPP-A) appears to be a potentially useful biomarker for short-term risk stratification of patients presenting with chest pain of ischemic origin (Review). (PMID:29144175)
• This review evaluates the current data concerning PAPP-A2 function, and particularly the effect of PAPP-A2 mutation on growth. (PMID:29238946)
• The findings suggest a possible pathophysiological link between the development of Fetal growth restriction and the expression of PAPPA, PAPPA2 and PLAC-1. (PMID:29532882)
• PAPP-A2 mutation is associated with idiopathic short stature. (PMID:29653372)
• The potential role of pregnancy-associated plasma protein-A2 in angiogenesis and development of preeclampsia. (PMID:30816319)
• Total IGFBP 5, PAPPA, PAPPA2 and Stanniocalcin-2. (PMID:31103608)
• PAPP-A2 consistently decreased throughout childhood. PAPP-A2 levels positively correlated with the percent free IGF-I and negatively with intact IGFBP-3. correlative findings suggest that PAPP-A2 is an important regulator of the percent free IGF-I which can be a marker of perturbations in the GH/IGF-I axis. (PMID:31961798)
• Uteroplacental Ischemia Is Associated with Increased PAPP-A2. (PMID:31994005)
• Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine Tumors. (PMID:32004755)
• Disorders caused by genetic defects associated with GH-dependent genes: PAPPA2 defects. (PMID:32739295)
• PAPP-A2 and Inhibin A as Novel Predictors for Pregnancy Complications in Women With Suspected or Confirmed Preeclampsia. (PMID:32990126)
• Associations of plasma PAPP-A2 and genetic variations with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults. (PMID:33783375)
• Serum Inhibin-A and PAPP-A2 in the prediction of pre-eclampsia during the first and second trimesters in high-risk women. (PMID:34116346)
• Genetic Study of IL6, GDF5 and PAPPA2 in Association with Developmental Dysplasia of the Hip. (PMID:34203285)
• Short stature with low insulin-like growth factor 1 availability due to pregnancy-associated plasma protein A2 deficiency in a Saudi family. (PMID:34272725)
• Dynamic Changes in Serum IGF-I and Growth During Infancy: Associations to Body Fat, Target Height, and PAPPA2 Genotype. (PMID:34476481)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pappa2	ENSDARG00000076020
mus_musculus	Pappa2	ENSMUSG00000073530
rattus_norvegicus	Pappa2	ENSRNOG00000042860

Paralogs (39): CFH (ENSG00000000971), SELE (ENSG00000007908), C8B (ENSG00000021852), C6 (ENSG00000039537), SEZ6 (ENSG00000063015), CFHR2 (ENSG00000080910), APOH (ENSG00000091583), SEZ6L (ENSG00000100095), SUSD6 (ENSG00000100647), SRPX (ENSG00000101955), SRPX2 (ENSG00000102359), C7 (ENSG00000112936), C9 (ENSG00000113600), CFHR3 (ENSG00000116785), CR2 (ENSG00000117322), CD46 (ENSG00000117335), CSMD2 (ENSG00000121904), C4BPA (ENSG00000123838), C4BPB (ENSG00000123843), CFHR4 (ENSG00000134365), CFHR5 (ENSG00000134389), F13B (ENSG00000143278), SUSD4 (ENSG00000143502), C8A (ENSG00000157131), SUSD3 (ENSG00000157303), CSMD3 (ENSG00000164796), SVEP1 (ENSG00000165124), C2 (ENSG00000166278), SELP (ENSG00000174175), SEZ6L2 (ENSG00000174938), PRF1 (ENSG00000180644), PAPPA (ENSG00000182752), CSMD1 (ENSG00000183117), SELL (ENSG00000188404), CD55 (ENSG00000196352), CR1L (ENSG00000197721), CR1 (ENSG00000203710), CFB (ENSG00000243649), CFHR1 (ENSG00000244414)

Protein

Protein identifiers

Pappalysin-2 — Q9BXP8 (reviewed: Q9BXP8)

Alternative names: Pregnancy-associated plasma protein A2, Pregnancy-associated plasma protein E1

All UniProt accessions (1): Q9BXP8

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Monomer.

Subcellular location. Secreted.

Tissue specificity. Expressed abundantly in placenta, and non-pregnant mammary gland with low expression in the kidney, fetal brain and pancreas.

Disease relevance. Short stature, Dauber-Argente type (SSDA) [MIM:619489] An autosomal recessive disorder characterized by progressive postnatal growth failure, moderate microcephaly, thin long bones, mildly decreased bone density, and elevated serum levels of total IGF1, IGFBP3 and IGFBP5. Levels of circulating free IGF1 are reduced. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Similarity. Belongs to the peptidase M43B family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BXP8-1	1, Papp-e(1)	yes
Q9BXP8-2	2, Papp-e(2)

RefSeq proteins (2): NP_064714, NP_068755 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000436	Sushi_SCR_CCP_dom	Domain
IPR000800	Notch_dom	Domain
IPR006558	LamG-like	Domain
IPR008754	Peptidase_M43	Domain
IPR011936	Myxo_disulph_rpt	Repeat
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR035976	Sushi/SCR/CCP_sf	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR043543	PAPPA/PAPPA2	Family
IPR058897	PAPPA_SD_C	Domain

Pfam: PF00066, PF00084, PF05572, PF13385, PF25900

UniProt features (160 total): strand 51, disulfide bond 35, helix 21, glycosylation site 15, turn 9, domain 5, sequence conflict 5, sequence variant 4, region of interest 3, binding site 3, compositionally biased region 2, splice variant 2, signal peptide 1, propeptide 1, active site 1, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8SL1	ELECTRON MICROSCOPY	3.13

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BXP8-F1	72.65	0.18

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 734

Ligand- & substrate-binding residues (3): 733; 737; 743

Disulfide bonds (35): 312–403, 499–793, 504–828, 586–600, 596–612, 628–644, 645–656, 754–771, 758–783, 881–1045, 884–1048, 924–1003, 946–951, 1115–1143, 1128–1139, 1151–1158, 1167–1179, 1205–1238, 1219–1318, 1371–1385 …

Glycosylation sites (15): 311, 562, 574, 679, 813, 857, 941, 1243, 1308, 1326, 1344, 1408, 1456, 1476, 1694

Mutagenesis-validated functional residues (1):

Position	Phenotype
734	loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)

MSigDB gene sets: 129 (showing top): GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_GROWTH, MORF_RAD51L3, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_BONE_DEVELOPMENT, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_RESPONSE_TO_SALT_STRESS, GNF2_KISS1, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, GOCC_APICAL_PLASMA_MEMBRANE, GNF2_CDKN1C, GOBP_BONE_MORPHOGENESIS, GOBP_RESPONSE_TO_OSMOTIC_STRESS, GOBP_SKELETAL_SYSTEM_MORPHOGENESIS

GO Biological Process (5): regulation of cell growth (GO:0001558), proteolysis (GO:0006508), cell surface receptor signaling pathway (GO:0007166), response to salt stress (GO:0009651), bone morphogenesis (GO:0060349)

GO Molecular Function (7): metalloendopeptidase activity (GO:0004222), metallopeptidase activity (GO:0008237), zinc ion binding (GO:0008270), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), apical plasma membrane (GO:0016324), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
protein metabolic process	1
signal transduction	1
response to osmotic stress	1
animal organ morphogenesis	1
skeletal system morphogenesis	1
bone development	1
endopeptidase activity	1
metallopeptidase activity	1
peptidase activity	1
transition metal ion binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cation binding	1
cellular anatomical structure	1
apical part of cell	1
plasma membrane region	1
extracellular vesicle	1

Protein interactions and networks

STRING

688 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAPPA2	IGFBP5	P24593	784
PAPPA2	IGFBP4	P22692	720
PAPPA2	IGF1	P01343	669
PAPPA2	IGF2	P01344	632
PAPPA2	IGFBP3	P17936	507
PAPPA2	STC2	O76061	505
PAPPA2	SIGLEC6	O43699	483
PAPPA2	IGFALS	P35858	448
PAPPA2	HTRA4	P83105	447
PAPPA2	PLAC1	Q9HBJ0	439
PAPPA2	FSTL3	O95633	438
PAPPA2	SERPINE1	P05121	433
PAPPA2	IGFBP2	P18065	421
PAPPA2	INHA	P05111	416
PAPPA2	ADAM12	O43184	409

IntAct

5 interactions, top by confidence:

A	B	Type	Score
ZNF512B	PAPPA2	psi-mi:“MI:0915”(physical association)	0.370
ATF7IP	PAPPA2	psi-mi:“MI:0915”(physical association)	0.370
PAPPA2	SMAD4	psi-mi:“MI:0915”(physical association)	0.370
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): PAPPA2 (Synthetic Lethality), IGFBP3 (Biochemical Activity), PAPPA2 (Protein-peptide), PAPPA2 (Affinity Capture-MS), PAPPA2 (Two-hybrid), PAPPA2 (Two-hybrid)

ESM2 similar proteins: A1A5X5, A4IH36, D4AB34, O93449, O95150, O97605, O97626, P04088, P04924, P09529, P10600, P15203, P16047, P17125, P17491, P27093, P36939, P36940, P41047, P42917, P48023, P50591, P50592, P59694, P59695, P63306, P63307, P63308, Q04999, Q07258, Q5UBV8, Q5XIG2, Q6PGN1, Q80WL1, Q861W5, Q8BGU2, Q8BMF8, Q8IUK8, Q8K3Y7, Q8R2Z0

Diamond homologs: A4RGT4, B0XPZ1, B2AC45, C4K014, C5FL47, C5FQJ4, C5P3X6, C9S5C6, C9SSK8, D1ZSU8, D4ALW9, D4ATD1, D4DI84, D4DIV0, E3QJV4, E3QKH9, E4USP0, E4V4I7, E5QZI4, Q13219, Q2UBF0, Q4WJ01, Q871C5, Q8R4K8, Q8TL28, Q9BXP8

SIGNOR signaling

0 interactions.

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

306 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	2
Uncertain significance	227
Likely benign	27
Benign	8

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1202641	NM_020318.3(PAPPA2):c.1928_1929insAT (p.Asp643fs)	Pathogenic
1202642	NM_020318.3(PAPPA2):c.3098C>T (p.Ala1033Val)	Pathogenic
1202643	NM_020318.3(PAPPA2):c.2656G>T (p.Glu886Ter)	Pathogenic
1339833	NM_020318.3(PAPPA2):c.1732C>T (p.Arg578Ter)	Pathogenic
2066135	NM_020318.3(PAPPA2):c.3376G>T (p.Glu1126Ter)	Pathogenic
2084784	NM_020318.3(PAPPA2):c.2305_2306del (p.Asp769fs)	Pathogenic
2142340	NM_020318.3(PAPPA2):c.4392C>A (p.Cys1464Ter)	Pathogenic
2165523	NM_020318.3(PAPPA2):c.3754C>T (p.Gln1252Ter)	Pathogenic
2186891	NM_020318.3(PAPPA2):c.4729_4744del (p.Ile1577fs)	Pathogenic
3342438	NM_020318.3(PAPPA2):c.1967G>A (p.Cys656Tyr)	Likely pathogenic
4845794	NM_020318.3(PAPPA2):c.2958del (p.Leu987fs)	Likely pathogenic

SpliceAI

6122 predictions. Top by Δscore:

Variant	Effect	Δscore
1:176555395:C:A	acceptor_gain	1.0000
1:176595593:GAG:G	donor_gain	1.0000
1:176670964:CTCTA:C	acceptor_loss	1.0000
1:176670965:TCTAG:T	acceptor_loss	1.0000
1:176670966:CTA:C	acceptor_loss	1.0000
1:176670967:TA:T	acceptor_loss	1.0000
1:176670968:AG:A	acceptor_gain	1.0000
1:176670969:G:C	acceptor_loss	1.0000
1:176670969:GG:G	acceptor_gain	1.0000
1:176670969:GGGC:G	acceptor_gain	1.0000
1:176671114:GG:G	donor_gain	1.0000
1:176671115:GG:G	donor_gain	1.0000
1:176690135:AGGT:A	acceptor_gain	1.0000
1:176690136:GGTG:G	acceptor_gain	1.0000
1:176690336:GA:G	donor_gain	1.0000
1:176706354:TCTAG:T	acceptor_loss	1.0000
1:176706355:CTAG:C	acceptor_loss	1.0000
1:176706357:A:AG	acceptor_gain	1.0000
1:176706357:A:T	acceptor_loss	1.0000
1:176706358:G:GT	acceptor_gain	1.0000
1:176706358:GGA:G	acceptor_gain	1.0000
1:176706358:GGAGA:G	acceptor_gain	1.0000
1:176706447:GTAG:G	donor_gain	1.0000
1:176706449:AGGT:A	donor_loss	1.0000
1:176706450:GGTA:G	donor_loss	1.0000
1:176706451:G:GC	donor_loss	1.0000
1:176706451:G:GG	donor_gain	1.0000
1:176706452:T:A	donor_loss	1.0000
1:176711978:CAAA:C	donor_gain	1.0000
1:176711980:AA:A	donor_gain	1.0000

AlphaMissense

11763 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:176791379:G:C	W1639C	0.999
1:176791379:G:T	W1639C	0.999
1:176800088:T:A	W1720R	0.999
1:176800088:T:C	W1720R	0.999
1:176800090:G:C	W1720C	0.999
1:176800090:G:T	W1720C	0.999
1:176840194:T:A	C1742S	0.999
1:176840195:G:C	C1742S	0.999
1:176840213:G:C	R1748P	0.999
1:176840221:T:A	C1751S	0.999
1:176840222:G:C	C1751S	0.999
1:176840242:T:A	C1758S	0.999
1:176840243:G:C	C1758S	0.999
1:176840245:T:A	C1759S	0.999
1:176840246:G:C	C1759S	0.999
1:176671090:G:C	W704C	0.998
1:176671090:G:T	W704C	0.998
1:176699144:T:A	W931R	0.998
1:176699144:T:C	W931R	0.998
1:176699146:G:C	W931C	0.998
1:176699146:G:T	W931C	0.998
1:176789848:G:C	W1585C	0.998
1:176789848:G:T	W1585C	0.998
1:176840194:T:C	C1742R	0.998
1:176840221:T:C	C1751R	0.998
1:176840223:C:G	C1751W	0.998
1:176840242:T:C	C1758R	0.998
1:176840244:C:G	C1758W	0.998
1:176840247:C:G	C1759W	0.998
1:176842422:T:A	C1782S	0.998

dbSNP variants (sampled 300 via entrez): RS1000002419 (1:176546287 C>T), RS1000004999 (1:176694978 C>G,T), RS1000005668 (1:176652347 G>A), RS1000016401 (1:176676373 T>C), RS1000023585 (1:176790800 A>G), RS1000028463 (1:176631207 G>A), RS1000056185 (1:176790589 G>A), RS1000057541 (1:176546670 C>T), RS1000067683 (1:176613833 A>T), RS1000076662 (1:176831478 T>C), RS1000079979 (1:176591071 A>G), RS1000094132 (1:176584603 T>C), RS1000100278 (1:176721230 A>G), RS1000111531 (1:176760897 C>G,T), RS1000114275 (1:176675491 G>A)

Disease associations

OMIM: gene MIM:619485 | disease phenotypes: MIM:619489

GenCC curated gene-disease

Disease	Classification	Inheritance
Short stature, Dauber-Argente type	Strong	Autosomal recessive

Mondo (1): Short stature, Dauber-Argente type (MONDO:0859182)

Orphanet (0):

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000325	Triangular face
HP:0000331	Short chin
HP:0000684	Delayed eruption of teeth
HP:0000938	Osteopenia
HP:0001166	Arachnodactyly
HP:0001328	Specific learning disability
HP:0003621	Juvenile onset
HP:0004322	Short stature
HP:0004349	Reduced bone mineral density
HP:0008283	Fasting hyperinsulinemia
HP:0008897	Postnatal growth retardation
HP:0010511	Long toe
HP:0031107	Decreased fibular diameter
HP:0034184	Increased insulin like growth factor binding protein acid labile subunit concentration
HP:0100807	Long fingers

GWAS associations

40 associations (top):

Study	Trait	p-value
GCST000817_129	Height	1.000000e-09
GCST002304_25	Fractional exhaled nitric oxide (childhood)	3.000000e-06
GCST002702_111	Height	5.000000e-11
GCST002892_1	Perioperative myocardial infarction in coronary artery bypass surgery	5.000000e-06
GCST002892_2	Perioperative myocardial infarction in coronary artery bypass surgery	5.000000e-06
GCST002892_3	Perioperative myocardial infarction in coronary artery bypass surgery	6.000000e-06
GCST002892_4	Perioperative myocardial infarction in coronary artery bypass surgery	3.000000e-06
GCST002892_5	Perioperative myocardial infarction in coronary artery bypass surgery	3.000000e-06
GCST002892_6	Perioperative myocardial infarction in coronary artery bypass surgery	3.000000e-06
GCST002892_7	Perioperative myocardial infarction in coronary artery bypass surgery	3.000000e-06
GCST002892_8	Perioperative myocardial infarction in coronary artery bypass surgery	3.000000e-06
GCST002892_9	Perioperative myocardial infarction in coronary artery bypass surgery	2.000000e-06
GCST004567_115	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	6.000000e-08
GCST004567_56	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	2.000000e-07
GCST004576_44	Waist-to-hip ratio adjusted for body mass index	5.000000e-07
GCST004576_45	Waist-to-hip ratio adjusted for body mass index	2.000000e-08
GCST004577_7	Waist-to-hip ratio adjusted for BMI in inactive individuals	5.000000e-06
GCST005166_8	GIP levels in response to oral glucose tolerance test (120 minutes)	5.000000e-07
GCST005951_39	Body mass index	4.000000e-08
GCST007096_32	Pulse pressure	4.000000e-08
GCST007269_59	Pulse pressure	2.000000e-10
GCST007329_14	Automobile speeding propensity	6.000000e-09
GCST008362_94	Birth weight	2.000000e-10
GCST008363_23	Offspring birth weight	4.000000e-07
GCST008839_271	Height	3.000000e-24
GCST010241_233	Apolipoprotein A1 levels	2.000000e-09
GCST011830_2	Pediatric central nervous system tumors (late onset)(pleiotropy)	1.000000e-07
GCST011832_3	Pediatric central nervous system tumors (pleiotropy)	3.000000e-07
GCST012227_1166	Hip circumference adjusted for BMI	1.000000e-10
GCST012227_1168	Hip circumference adjusted for BMI	1.000000e-08

EFO canonical traits (15, from GWAS)

EFO ID	Trait name
EFO:0005536	nitric oxide exhalation measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008002	physical activity measurement
EFO:0004307	glucose tolerance test
EFO:0008464	glucose-dependent insulinotropic peptide measurement
EFO:0004340	body mass index
EFO:0005763	pulse pressure measurement
EFO:0008579	risk-taking behaviour
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004531	urate measurement
EFO:0007701	spine bone mineral density
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs77977790	PAPPA2		0.00	0

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	3
sodium arsenite	decreases expression, increases expression	2
Zoledronic Acid	affects cotreatment, increases expression, decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
aristolochic acid I	decreases expression	1
perfluorooctanoic acid	increases expression	1
tobacco tar	decreases reaction, increases expression	1
diallyl disulfide	decreases reaction, increases expression	1
allyl sulfide	decreases reaction, increases expression	1
avobenzone	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
NSC 689534	affects binding, increases expression	1
Sunitinib	decreases expression	1
Fluvastatin	increases expression, affects cotreatment	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Cisplatin	affects response to substance	1
Copper	affects binding, increases expression	1
Diethylhexyl Phthalate	increases expression	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	decreases expression	1
Naled	affects expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1
Sodium Selenite	increases expression	1
Particulate Matter	increases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.