PAPPA

Summary

PAPPA (pappalysin 1, HGNC:8602) is a protein-coding gene on chromosome 9q33.1, encoding Pappalysin-1 (Q13219). Metalloproteinase which specifically cleaves IGFBP-4 and IGFBP-5, resulting in release of bound IGF.

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.

Source: NCBI Gene 5069 — RefSeq curated summary.

At a glance

• GWAS associations: 16
• Clinical variants (ClinVar): 263 total
• Phenotypes (HPO): 1
• MANE Select transcript: NM_002581

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8602
Approved symbol	PAPPA
Name	pappalysin 1
Location	9q33.1
Locus type	gene with protein product
Status	Approved
Aliases	PAPP-A, PAPPA1, IGFBP-4ase, PAPA, ASBABP2, DIPLA1
Ensembl gene	ENSG00000182752
Ensembl biotype	protein_coding
OMIM	176385
Entrez	5069

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000328252, ENST00000460463, ENST00000483254

RefSeq mRNA: 1 — MANE Select: NM_002581 NM_002581

CCDS: CCDS6813

Canonical transcript exons

ENST00000328252 — 22 exons

Exon	Start	End
ENSE00000722962	116302757	116302950
ENSE00000926934	116331244	116331357
ENSE00000926935	116332333	116332468
ENSE00000926937	116344543	116344711
ENSE00000926938	116347026	116347209
ENSE00000926939	116352706	116352916
ENSE00000926940	116353622	116353793
ENSE00000926941	116362592	116362739
ENSE00000926942	116367645	116367754
ENSE00001293994	116235139	116235637
ENSE00001294696	116187154	116188216
ENSE00001299881	116207456	116207601
ENSE00001305170	116219937	116220129
ENSE00001314388	116396509	116402321
ENSE00001324336	116211639	116211932
ENSE00001326971	116227431	116227552
ENSE00001379817	116153791	116154587
ENSE00003463010	116265857	116265985
ENSE00003556399	116271325	116271416
ENSE00003567995	116377576	116377647
ENSE00003577764	116334861	116335074
ENSE00003655016	116382395	116382493

Expression profiles

Bgee: expression breadth ubiquitous, 244 present calls, max score 99.21.

FANTOM5 (CAGE): breadth broad, TPM avg 14.5507 / max 3780.6575, expressed in 853 samples.

FANTOM5 promoters (38 alternative TSS)

Promoter ID	TPM avg	Samples expressed
98234	5.4203	518
98233	2.3413	371
98230	1.1941	446
98227	0.9656	339
98235	0.8290	245
98272	0.7165	242
98239	0.6335	399
98232	0.4324	236
98237	0.2148	101
98265	0.1822	90

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
decidua	UBERON:0002450	99.21	gold quality
placenta	UBERON:0001987	98.28	gold quality
buccal mucosa cell	CL:0002336	97.94	gold quality
stromal cell of endometrium	CL:0002255	93.45	gold quality
tendon of biceps brachii	UBERON:0008188	91.61	gold quality
cartilage tissue	UBERON:0002418	90.20	gold quality
pericardium	UBERON:0002407	89.74	gold quality
renal medulla	UBERON:0000362	88.33	gold quality
parietal pleura	UBERON:0002400	87.94	gold quality
tibia	UBERON:0000979	87.11	gold quality
mucosa of paranasal sinus	UBERON:0005030	85.47	gold quality
trabecular bone tissue	UBERON:0002483	83.28	gold quality
pleura	UBERON:0000977	83.07	gold quality
nipple	UBERON:0002030	82.52	gold quality
vena cava	UBERON:0004087	82.09	gold quality
gingiva	UBERON:0001828	82.08	gold quality
gingival epithelium	UBERON:0001949	81.08	gold quality
pylorus	UBERON:0001166	80.19	gold quality
cardia of stomach	UBERON:0001162	78.54	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.28	gold quality
smooth muscle tissue	UBERON:0001135	78.02	gold quality
germinal epithelium of ovary	UBERON:0001304	77.93	gold quality
mammalian vulva	UBERON:0000997	77.28	gold quality
lower lobe of lung	UBERON:0008949	77.22	gold quality
skin of hip	UBERON:0001554	76.58	gold quality
frontal pole	UBERON:0002795	76.39	gold quality
paraflocculus	UBERON:0005351	76.14	silver quality
superior surface of tongue	UBERON:0007371	76.08	gold quality
visceral pleura	UBERON:0002401	75.77	gold quality
upper leg skin	UBERON:0004262	75.70	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	1611.82
E-CURD-119	yes	1607.14
E-MTAB-10662	yes	531.00
E-MTAB-8205	yes	138.19
E-MTAB-6678	yes	17.10
E-ANND-3	yes	6.88
E-MTAB-8530	no	364.25

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PGR, PPARG, TP53

miRNA regulators (miRDB)

362 targeting PAPPA, 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-5011-5P	100.00	83.46	5820
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784

Literature-anchored findings (GeneRIF, showing 40)

• phorbol ester tumor promoters and simian virus 40 transformation regulate IGFBP-4 proteolysis in human fibroblasts through induction of a novel inhibitor of PAPP-A, pro-MBP (PMID:11897673)
• Fetal trisomies 21, 18, and 13 are associated with a reduction in second-trimester maternal PAPP-A levels (PMID:11914564)
• association of maternal PAPP-A levels and fetal growth/birth weight (PMID:12087395)
• the PAPP-A mRNA level in mouse placenta was lower compared to that in human placenta by at least two orders of magnitude (PMID:12213189)
• substrate specificity of the metalloproteinase pregnancy-associated plasma protein-A (PAPP-A) assessed by mutagenesis and analysis of synthetic peptides (PMID:12241545)
• IGF bioactivity is regulated by reversible cell surface binding of PAPP-A, which in turn is regulated by proMBP (PMID:12370176)
• data demonstrate the presence of an IGF-II- and metal-dependent IGFBP-4 protease activity in human trophoblast plasma membranes, identified as PAPP-A (PMID:12414897)
• PAPP-A’s structure is described, and its ability to dimerize and to bind to pro-major basic protein with disulfide bonds explained (PMID:12421832)
• Elevated serum PAPP-A levels represent a potential marker of the degree of echogenicity of carotid atherosclerotic plaques in asymptomatic hyperlipidemic patients at high cardiovascular risk. (PMID:12524241)
• TGF-beta and IGF-II in the bone microenvironment coordinately amplify IGF-I bioavailability through controlled IGFBP-4 protease, which may be a means to promote bone formation. (PMID:12817760)
• PAPP-A may play an important role in an integrated insulin-like growth factor system in wound healing and tissue remodeling in vivo (PMID:12970325)
• Plasma PAPP-A, a zinc-binding matrix metalloproteinase, is a strong independent predictor of ischemic cardiac events and need of revascularization in patients who present with suspected myocardial infarction but remain troponin negative (PMID:14530192)
• PAPP-A expression is regulated by inflammatory cytokines in adult human fibroblasts, with functional consequences on IGFBP-4 protease activity and IGF-I bioavailability (PMID:14657012)
• Partially purified PAPP-A400 exhibited a 4-fold reduction in IGFBP-4 proteolytic activity compared with PAPP-A470. A novel mechanism, conversion of PAPP-A470 to the less-active PAPP-A400, could account for the TPA-induced suppression of PAPP-A activity. (PMID:14705967)
• Proform of eosinophil major basic protein forms a covalent complex with PAPPA in which PAPPA is inhibited. (PMID:14988014)
• PAPP-A and proMBP are regulated in malignant ovarian epithelial cells,altering IGFBP-4 proteolysis and local regulation of IGF availability (PMID:15146551)
• PAPPA Lin12-notch repeats bind calcium and determine its proteolytic specificity (PMID:15262980)
• women who experienced spontaneous abortions had significantly different mean PAPP-A serum levels at 10(+1) to 14(+6) weeks gestation (PMID:15305104)
• the proform of eosinophil major basic protein inhibits the proteolytic activity of PAPP-A (PMID:15647258)
• findings underscore a novel mechanism whereby glucocorticoids increase IGF responses in bone cells via PAPP-A-induced IGFBP-4 proteolysis (PMID:15754336)
• PAPP-A functions in the formation of mineralized tissues through direct up-regulation of key genes and is involved in the formation of new blood vessels, which is essential for proper bone regeneration (PMID:15919757)
• maternal serum PAPP-A at 11-13(+6) of gestation is significantly lower in adverse pregnancy outcomes (PMID:16086443)
• PAPP-A increased the proliferation and differentiation of myoblasts, its myogenic effect is governed by its proteolytic activity, and it promotes skeletal myogenesis by increasing the amount of free IGFs. (PMID:16115888)
• We suggest that PPARgamma-mediated inhibition of PAPP-A might decrease the amount of bioactive IGFII, a factor known to promote trophoblast invasion. (PMID:16388849)
• PAPP-A may be involved in the regulation of bone development in the first trimester. (PMID:16959807)
• Preliminary evidence suggests that first-trimester uterine artery Doppler measurements do not correlate with maternal serum levels of free beta-hCG and PAPP-A. (PMID:16963045)
• PAPP-A requires the formation of intermolecular proteinase-inhibitor disulfide bonds and glycosaminoglycan covalently bound to the inhibitor (PMID:17145752)
• the IGF system may have a limited role in the pathogenesis of GCT with PAPP-A subserving a function other than IGFBP-4 proteolysis (PMID:17177834)
• Proform eosinophilic major basic protein is involved in processes preceding vulnerable plaque development in acute coronary syndrome. (PMID:17223728)
• We demonstrated that after successful TX, PAPP-A and sRAGE decrease and early chronic vascular changes in the kidney TX are associated with elevation of their serum levels. (PMID:17237617)
• PAPP-A2 LNR1-2, but not LNR3, are functionally conserved with respect to insulin-like growth factor -binding proteins proteolysis (PMID:17314100)
• Maternal systemic lupus erythematosus does not affect first trimester level. (PMID:17437322)
• Maternal serum PAPP-A levels in the late first trimester of pregnancy are associated with subsequent fetal growth,both physiologic variation and abnormal growth. (PMID:17509577)
• Phage display was used to discover fully human antibody inhibitors of PAPP-A activity towards IGFBP4 cleavage (PMID:17516846)
• PAPP-A may contribute to airway smooth muscle hyperplasia (PMID:17565927)
• PAPP-A IVS6+95 C allele is an independent risk factor for acute myocardial infarction even after adjustment for traditional risk factors. (PMID:17700210)
• Patients with hyperechoic or isoechoic carotid plaques exhibit significantly higher PAPP-A levels than those with hypoechoic early carotid lesions. (PMID:17714879)
• Human coronary artery ECs express PAPP-A mRNA and functional protein when activated by the pro-inflammatory cytokine, TNF-alpha (PMID:17936662)
• PAPP-A level is elevated in renal transplant patients and high levels of PAPP-A may be a prognostic marker associated with high serum levels of urea, creatinine, uric acid, and C-reactive protein. (PMID:18089325)
• high PAPP-A levels (>4.8 mIU/L) showed an association with all-cause mortality during long-term follow-up of chronic stable angina patients; study showed existence of a threshold effect of PAPP-A levels that may be useful in predicting clinical outcome (PMID:18267116)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pappab	ENSDARG00000059858
danio_rerio	pappaa	ENSDARG00000101090
mus_musculus	Pappa	ENSMUSG00000028370
rattus_norvegicus	Pappa	ENSRNOG00000033527

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), PAPPA2 (ENSG00000116183), 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), CSMD1 (ENSG00000183117), SELL (ENSG00000188404), CD55 (ENSG00000196352), CR1L (ENSG00000197721), CR1 (ENSG00000203710), CFB (ENSG00000243649), CFHR1 (ENSG00000244414)

Protein

Protein identifiers

Pappalysin-1 — Q13219 (reviewed: Q13219)

Alternative names: Insulin-like growth factor-dependent IGF-binding protein 4 protease, Pregnancy-associated plasma protein A

All UniProt accessions (1): Q13219

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Homodimer; disulfide-linked. In pregnancy serum, predominantly found as a disulfide-linked 2:2 heterotetramer with the proform of PRG2.

Subcellular location. Secreted.

Tissue specificity. High levels in placenta and pregnancy serum. In placenta, expressed in X cells in septa and anchoring villi, and in syncytiotrophoblasts in the chorionic villi. Lower levels are found in a variety of other tissues including kidney, myometrium, endometrium, ovaries, breast, prostate, bone marrow, colon, fibroblasts and osteoblasts.

Post-translational modifications. There appear to be no free sulfhydryl groups.

Activity regulation. Inhibited by complexation with the proform of PRG2.

Cofactor. Binds 1 zinc ion per subunit.

Induction. By 8-bromoadenosine-3’,5’-phosphate.

Similarity. Belongs to the peptidase M43B family.

RefSeq proteins (1): NP_002572* (*=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
IPR043543	PAPPA/PAPPA2	Family
IPR058897	PAPPA_SD_C	Domain

Pfam: PF00084, PF05572, PF13385, PF25900

Enzyme classification (BRENDA):

• EC 3.4.24.79 — pappalysin-1 (BRENDA: 13 organisms, 47 substrates, 23 inhibitors, 7 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
IGFBP-5	0.0003–0.0006	3
IGFBP-4	0.0004–0.0016	2

UniProt features (243 total): strand 103, disulfide bond 39, helix 38, turn 25, glycosylation site 14, domain 5, sequence variant 4, region of interest 3, binding site 3, sequence conflict 3, compositionally biased region 2, signal peptide 1, propeptide 1, active site 1, chain 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
8A7D	ELECTRON MICROSCOPY	3.06
7UFG	ELECTRON MICROSCOPY	3.28
8D8O	ELECTRON MICROSCOPY	3.35
7Y5N	ELECTRON MICROSCOPY	3.45
8HGG	ELECTRON MICROSCOPY	3.64
7Y5Q	ELECTRON MICROSCOPY	3.8
8HGH	ELECTRON MICROSCOPY	4.16
8A7E	ELECTRON MICROSCOPY	5.02

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13219-F1	79.62	0.30

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): 563

Ligand- & substrate-binding residues (3): 562; 566; 572

Disulfide bonds (39): 144–235, 327–622, 332–657, 414–428, 424–440, 457–473, 461, 474–485, 583–600, 587–612, 710–878, 713–881, 732, 753–835, 775–781, 947–975, 960–971, 983–990, 999–1011, 1036–1070 …

Glycosylation sites (14): 390, 402, 429, 480, 601, 619, 725, 825, 1026, 1222, 1226, 1323, 1465, 1519

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: 282 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GGGACCA_MIR133A_MIR133B, FREAC2_01, BENPORATH_ES_WITH_H3K27ME3, STAEGE_EWING_FAMILY_TUMOR, GOMF_METALLOPEPTIDASE_ACTIVITY, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, TATTATA_MIR374, FOXO1_01, CACCAGC_MIR138, BONCI_TARGETS_OF_MIR15A_AND_MIR16_1, TTGGGAG_MIR150, NFKB_Q6, PAX8_B, NFKB_C

GO Biological Process (3): proteolysis (GO:0006508), cell surface receptor signaling pathway (GO:0007166), female pregnancy (GO:0007565)

GO Molecular Function (8): metalloendopeptidase activity (GO:0004222), metallopeptidase activity (GO:0008237), zinc ion binding (GO:0008270), endopeptidase activity (GO:0004175), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

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
peptidase activity	2
protein metabolic process	1
signal transduction	1
multi-organism reproductive process	1
multi-multicellular organism process	1
endopeptidase activity	1
metallopeptidase 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

Protein interactions and networks

STRING

910 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAPPA	PRG2	P13727	991
PAPPA	IGFBP4	P22692	960
PAPPA	LGALS13	Q9UHV8	875
PAPPA	IGF1	P01343	824
PAPPA	PGF	P49763	798
PAPPA	AFP	P02771	730
PAPPA	IGFBP3	P17936	724
PAPPA	TNNI3	P19429	721
PAPPA	CRP	P02741	711
PAPPA	PSG3	Q16557	666
PAPPA	ADAM12	O43184	665
PAPPA	PSG11	Q9UQ72	663
PAPPA	PSG6	Q00889	647
PAPPA	PSG1	P11462	643
PAPPA	IGFBP5	P24593	627

IntAct

12 interactions, top by confidence:

A	B	Type	Score
PRG2	PAPPA	psi-mi:“MI:0915”(physical association)	0.590
STC1	PAPPA	psi-mi:“MI:0407”(direct interaction)	0.440
PAPPA	PLEC	psi-mi:“MI:0915”(physical association)	0.400
PAPPA	SMAD2	psi-mi:“MI:0915”(physical association)	0.370
PAPPA	SKIL	psi-mi:“MI:0915”(physical association)	0.370
PAPPA	SMAD3	psi-mi:“MI:0915”(physical association)	0.370
ATF7IP	PAPPA	psi-mi:“MI:0915”(physical association)	0.370
PAPPA	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
IGHM	APOL1	psi-mi:“MI:0914”(association)	0.350
IGHG1	PDPK1	psi-mi:“MI:0914”(association)	0.350

BioGRID (20): PAPPA (Co-fractionation), PAPPA (Co-fractionation), PAPPA (Affinity Capture-RNA), PLEC (Proximity Label-MS), PAPPA (Proximity Label-MS), PAPPA (Biochemical Activity), PAPPA (Two-hybrid), PRG2 (Co-purification), PRG2 (Co-purification), PRG2 (Co-purification), PAPPA (Two-hybrid), PAPPA (Co-fractionation), PAPPA (Co-fractionation), PAPPA (Co-fractionation), PAPPA (Affinity Capture-MS)

ESM2 similar proteins: A0A0D3QS98, A0A0D3QS99, A4D0V7, C5H5C4, F6Q1T7, O70309, O75354, P17405, P18084, P18424, P22413, P50747, P52850, P58242, P61642, P80747, Q04519, Q0VBD0, Q0VD19, Q13219, Q52KP5, Q58CQ9, Q5QQ51, Q5STE3, Q64687, Q6DFZ6, Q6KFX9, Q6MZW2, Q6P988, Q6UWX4, Q6YGZ1, Q6ZXD2, Q71RP1, Q812F8, Q8BJQ9, Q8C1F4, Q8C419, Q8N5D6, Q8N6G5, Q8R116

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

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	228
Likely benign	15
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

4040 predictions. Top by Δscore:

Variant	Effect	Δscore
9:116207454:A:AG	acceptor_gain	1.0000
9:116207455:G:GG	acceptor_gain	1.0000
9:116207455:GA:G	acceptor_gain	1.0000
9:116207598:TTAGG:T	donor_loss	1.0000
9:116207599:TAGG:T	donor_loss	1.0000
9:116207600:AGGTG:A	donor_loss	1.0000
9:116207602:G:GA	donor_loss	1.0000
9:116207602:G:GG	donor_gain	1.0000
9:116207603:T:G	donor_loss	1.0000
9:116219935:A:AG	acceptor_gain	1.0000
9:116219936:G:GG	acceptor_gain	1.0000
9:116220126:AAAGG:A	donor_loss	1.0000
9:116220127:AAGGT:A	donor_loss	1.0000
9:116220128:AGGT:A	donor_loss	1.0000
9:116220130:GT:G	donor_loss	1.0000
9:116220131:T:A	donor_loss	1.0000
9:116235633:GACAT:G	donor_gain	1.0000
9:116235635:CAT:C	donor_gain	1.0000
9:116235636:AT:A	donor_gain	1.0000
9:116235638:G:GG	donor_gain	1.0000
9:116265983:AAA:A	donor_gain	1.0000
9:116265984:AA:A	donor_gain	1.0000
9:116265986:G:GG	donor_gain	1.0000
9:116271310:A:AG	acceptor_gain	1.0000
9:116271311:T:G	acceptor_gain	1.0000
9:116271312:ATCT:A	acceptor_gain	1.0000
9:116271313:T:G	acceptor_gain	1.0000
9:116302741:T:G	acceptor_gain	1.0000
9:116302745:A:AG	acceptor_gain	1.0000
9:116302746:A:G	acceptor_gain	1.0000

AlphaMissense

10767 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:116207576:G:C	W533C	1.000
9:116207576:G:T	W533C	1.000
9:116235183:T:A	W760R	1.000
9:116235183:T:C	W760R	1.000
9:116235185:G:C	W760C	1.000
9:116235185:G:T	W760C	1.000
9:116353641:T:A	C1399S	1.000
9:116353642:G:C	C1399S	1.000
9:116353661:G:C	W1405C	1.000
9:116353661:G:T	W1405C	1.000
9:116362636:G:C	W1464C	1.000
9:116362636:G:T	W1464C	1.000
9:116377605:G:C	W1545C	1.000
9:116377605:G:T	W1545C	1.000
9:116382408:A:C	D1564A	1.000
9:116382408:A:T	D1564V	1.000
9:116382416:T:A	C1567S	1.000
9:116382417:G:A	C1567Y	1.000
9:116382417:G:C	C1567S	1.000
9:116382443:T:A	C1576S	1.000
9:116382444:G:C	C1576S	1.000
9:116382453:A:T	D1579V	1.000
9:116382464:T:A	C1583S	1.000
9:116382464:T:C	C1583R	1.000
9:116382465:G:C	C1583S	1.000
9:116382467:T:A	C1584S	1.000
9:116382468:G:C	C1584S	1.000
9:116187978:T:A	C414S	0.999
9:116187978:T:C	C414R	0.999
9:116187979:G:A	C414Y	0.999

dbSNP variants (sampled 300 via entrez): RS1000027712 (9:116363430 G>A,C,T), RS1000043299 (9:116337597 C>G,T), RS1000045827 (9:116253451 C>A,T), RS1000046094 (9:116386561 T>G), RS1000054500 (9:116179795 A>G), RS1000078477 (9:116163729 G>A,C), RS1000080931 (9:116219447 G>A), RS1000100728 (9:116379913 C>G), RS1000114170 (9:116339092 T>C), RS1000124015 (9:116242969 T>C), RS1000137882 (9:116337938 A>G), RS1000146397 (9:116204774 A>C), RS1000150522 (9:116259369 A>G,T), RS1000204507 (9:116310401 G>T), RS1000227758 (9:116225089 A>T)

Disease associations

OMIM: gene MIM:176385 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): hyperlipoproteinemia (MONDO:0037748)

Orphanet (0):

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0010980	Hyperlipoproteinemia

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000176_12	Height	1.000000e-06
GCST000817_150	Height	7.000000e-10
GCST002438_4	Conotruncal heart defects	3.000000e-06
GCST006288_303	Heel bone mineral density	3.000000e-06
GCST006288_621	Heel bone mineral density	2.000000e-10
GCST006629_72	Pulse pressure	3.000000e-12
GCST008163_549	Height	8.000000e-10
GCST008362_188	Birth weight	6.000000e-11
GCST009391_1941	Metabolite levels	8.000000e-06
GCST010703_3	Brain morphology (MOSTest)	3.000000e-34
GCST012001_2	Symptoms in placebo-treated COVID-19 outpatients at risk of severe disease (time to remission)	3.000000e-08
GCST012006_4	Intralaminar thalamic nuclei volume	1.000000e-10
GCST012227_446	Hip circumference adjusted for BMI	8.000000e-10
GCST90000025_423	Appendicular lean mass	1.000000e-84
GCST90000025_424	Appendicular lean mass	2.000000e-09
GCST90014033_93	Haemorrhoidal disease	6.000000e-11

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0005763	pulse pressure measurement
EFO:0004344	birth weight
EFO:0009766	asparagine measurement
EFO:0004346	neuroimaging measurement
EFO:0008344	response to placebo
EFO:0600020	time to remission of COVID-19 symptoms
EFO:0006935	thalamus volume
EFO:0008039	BMI-adjusted hip circumference
EFO:0004980	appendicular lean mass

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006951	Hyperlipoproteinemias	C18.452.584.500.500.644

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

83 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Progesterone	decreases expression, affects cotreatment, increases expression, affects reaction, increases abundance	5
Valproic Acid	decreases expression, increases expression	5
methylmercuric chloride	increases expression, affects cotreatment	4
Estradiol	affects binding, increases expression, affects cotreatment	4
Benzo(a)pyrene	increases mutagenesis, affects methylation, decreases expression, decreases methylation, increases methylation	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression, decreases expression	3
bisphenol A	decreases methylation, increases expression	2
trichostatin A	increases expression	2
sodium arsenite	increases expression, decreases expression	2
entinostat	increases expression, affects cotreatment	2
Resveratrol	decreases reaction, increases activity, increases expression, decreases expression	2
Cisplatin	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Aflatoxin B1	decreases methylation	2
aristolochic acid I	decreases expression	1
afuresertib	increases expression	1
geldanamycin	increases expression	1
triphenyl phosphate	decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
N-methyladenosine	affects abundance, affects expression, affects methylation	1
testosterone undecanoate	decreases expression, affects cotreatment	1
3,4-dichloroaniline	increases expression	1
arsenite	increases methylation	1
trimellitic anhydride	increases expression	1
butyraldehyde	decreases expression	1
2-ethylhexyldiphenylphosphate	decreases expression	1
manganese chloride	increases expression	1
benzo(e)pyrene	decreases methylation	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D7WI	Ubigene A-549 PAPPA KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00473655	PHASE4	COMPLETED	Effect of Rosuvastatin on Triglyceride Levels in Mexican Hypertriglyceridemic Patients
NCT01239992	PHASE4	TERMINATED	Effect of Niacin/Laropiprant on Postprandial Lipoprotein Metabolism in Patients With Dyslipoproteinemia
NCT00000538	PHASE3	COMPLETED	Dietary Effects on Lipoproteins and Thrombogenic Activity
NCT00134498	PHASE3	COMPLETED	A Study Comparing The Efficacy & Safety Of Torcetrapib/Atorvastatin And Atorvastatin In Subjects With High Triglycerides
NCT00607373	PHASE3	COMPLETED	Study to Assess the Safety and Efficacy of ISIS 301012 (Mipomersen) in Homozygous Familial Hypercholesterolemia
NCT00694109	PHASE3	COMPLETED	An Open-label Extension Study to Assess the Long-term Safety and Efficacy of ISIS 301012 (Mipomersen) in Patients With Familial Hypercholesterolemia or Severe-Hypercholesterolemia
NCT01057654	PHASE3	COMPLETED	A Study Comparing the Mechanisms of Action of Lifibrol and Pravastatin
NCT01811082	PHASE3	COMPLETED	Comparison of Coenzyme A and Pantethine Capsule for Safety and Efficacy On Patients With Hyperlipidemia
NCT01878227	PHASE3	COMPLETED	Comparison of Coenzyme A and Fenofibrate for Safety and Efficacy On Patients With Hyperlipidemia
NCT02658175	PHASE3	COMPLETED	The Approach Open Label Study: A Study of Volanesorsen (Formerly IONIS-APOCIIIRx) in Participants With Familial Chylomicronemia Syndrome
NCT05305664	PHASE3	COMPLETED	A Multicenter Trial Assessing the Impact of Lipoprotein(a) Lowering With Pelacarsen (TQJ230) on the Rate of Weekly Lipoprotein Apheresis Sessions in Patients With Hyperlipoproteinemia(a) and Established Cardiovascular Disease in Germany
NCT05425745	PHASE3	COMPLETED	Evaluate the Effect of Obicetrapib in Patients With HeFH on Top of Maximum Tolerated Lipid-Modifying Therapies.
NCT05900141	PHASE3	ACTIVE_NOT_RECRUITING	An Open Label Extension (OLE) Study to Evaluate Long-term Safety and Tolerability of Pelacarsen (TQJ230)
NCT00477594	PHASE2	COMPLETED	Open Label Extension of ISIS 301012 (Mipomersen) to Treat Familial Hypercholesterolemia
NCT01645046	PHASE2	COMPLETED	The Effects of Coenzyme A on Serum Lipids in Patients With Hyperlipidemia
NCT03360747	PHASE2	COMPLETED	Phase 2 Study of AKCEA-ANGPTL3-LRx (ISIS 703802) in Participants With Familial Chylomicronemia Syndrome (FCS)
NCT04516291	PHASE2	COMPLETED	A Dose-Ranging Study With Vupanorsen (TRANSLATE-TIMI 70)
NCT05256654	PHASE2	COMPLETED	A Study of LY3561774 in Participants With Mixed Dyslipidemia
NCT01928342	PHASE2/PHASE3	UNKNOWN	The Effects of Coenzyme A Combined With Statin on Serum Lipids in Patients With Hyperlipidemia
NCT01146522	PHASE1/PHASE2	COMPLETED	Safety, Tolerability,Pharmacokinetics(PK)and Pharmacodynamics(PD)Assessment of LCQ908 in Patients With Severe Hypertriglyceridemia
NCT07172646	PHASE1/PHASE2	RECRUITING	A Study of SRSD216 in Patients With Elevated Lipoprotein (a)
NCT00001226	Not specified	COMPLETED	Lipoprotein Metabolism in Normal Volunteers and Patients With Abnormal Levels of Lipoproteins
NCT00005128	Not specified	COMPLETED	Lipid Research Clinics Population Studies
NCT00005368	Not specified	COMPLETED	Genetic Epidemiology of Hypertriglyceridemia
NCT01064934	Not specified	WITHDRAWN	Randomized Controlled Trial of Lipid Apheresis in Patients With Elevated Lipoprotein(a)
NCT02933138	Not specified	COMPLETED	Plasma Triglyceride Lipolysis in Multifactorial Chylomicronemia
NCT06163443	Not specified	COMPLETED	Evaluating the Impact of B Vitamin Supplementation (Soloways™) on Homocysteine and LDL-C Levels in Patients With MTHFR, MTR, and MTRR Polymorphisms.
NCT07405814	Not specified	RECRUITING	Clinical Trial On The Effect Of Artisterol On Risk Factors In Individuals With Suboptimal Cholesterol Levels