PIGR

Summary

PIGR (polymeric immunoglobulin receptor, HGNC:8968) is a protein-coding gene on chromosome 1q32.1, encoding Polymeric immunoglobulin receptor (P01833). Mediates selective transcytosis of polymeric IgA and IgM across mucosal epithelial cells.

This gene is a member of the immunoglobulin superfamily. The encoded poly-Ig receptor binds polymeric immunoglobulin molecules at the basolateral surface of epithelial cells; the complex is then transported across the cell to be secreted at the apical surface. A significant association was found between immunoglobulin A nephropathy and several SNPs in this gene.

Source: NCBI Gene 5284 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 111 total
• Druggable target: yes
• MANE Select transcript: NM_002644

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8968
Approved symbol	PIGR
Name	polymeric immunoglobulin receptor
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000162896
Ensembl biotype	protein_coding
OMIM	173880
Entrez	5284

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 21 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000356495, ENST00000487208, ENST00000491503, ENST00000860525, ENST00000860526, ENST00000860527, ENST00000860528, ENST00000860529, ENST00000860531, ENST00000860532, ENST00000860533, ENST00000860535, ENST00000860537, ENST00000860539, ENST00000942162, ENST00000942163, ENST00000942164, ENST00000942165, ENST00000942166, ENST00000942167, ENST00000942168, ENST00000942169, ENST00000942170

RefSeq mRNA: 1 — MANE Select: NM_002644 NM_002644

CCDS: CCDS1474

Canonical transcript exons

ENST00000356495 — 11 exons

Exon	Start	End
ENSE00001069596	206931497	206931555
ENSE00001069597	206935486	206935818
ENSE00001069601	206939119	206939463
ENSE00001069602	206934420	206934746
ENSE00001069604	206937095	206937751
ENSE00001069605	206932986	206933166
ENSE00001069606	206932456	206932577
ENSE00001069607	206931671	206931802
ENSE00001418275	206928522	206930413
ENSE00001443459	206940489	206940584
ENSE00001443460	206946336	206946466

Expression profiles

Bgee: expression breadth ubiquitous, 194 present calls, max score 99.98.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 19.2640 / max 5447.8567, expressed in 152 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17145	18.2464	82
17143	0.1855	27
17132	0.1047	20
17146	0.1015	19
17133	0.0999	9
17134	0.0968	10
17130	0.0629	20
17131	0.0614	19
17125	0.0595	21
17140	0.0511	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	99.98	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.94	gold quality
mucosa of transverse colon	UBERON:0004991	99.88	gold quality
colonic mucosa	UBERON:0000317	99.87	gold quality
rectum	UBERON:0001052	99.77	gold quality
bronchial epithelial cell	CL:0002328	99.74	gold quality
duodenum	UBERON:0002114	99.63	gold quality
pylorus	UBERON:0001166	99.61	gold quality
jejunal mucosa	UBERON:0000399	99.57	gold quality
gall bladder	UBERON:0002110	99.53	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.48	gold quality
cardia of stomach	UBERON:0001162	99.07	gold quality
urethra	UBERON:0000057	98.91	gold quality
nasal cavity mucosa	UBERON:0001826	98.86	gold quality
palpebral conjunctiva	UBERON:0001812	97.86	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.78	gold quality
trachea	UBERON:0003126	97.57	gold quality
ileal mucosa	UBERON:0000331	97.44	gold quality
bronchus	UBERON:0002185	97.23	gold quality
nasal cavity epithelium	UBERON:0005384	97.18	gold quality
epithelium of bronchus	UBERON:0002031	97.16	gold quality
epithelium of nasopharynx	UBERON:0001951	96.81	gold quality
saliva-secreting gland	UBERON:0001044	96.18	gold quality
minor salivary gland	UBERON:0001830	95.23	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.43	gold quality
small intestine	UBERON:0002108	94.41	gold quality
transverse colon	UBERON:0001157	94.36	gold quality
adult organism	UBERON:0007023	94.32	gold quality
lower lobe of lung	UBERON:0008949	94.27	gold quality
caecum	UBERON:0001153	94.22	gold quality

Single-cell (SCXA)

Detected in 23 experiment(s), a significant marker in 22.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	12138.15
E-MTAB-8495	yes	6539.83
E-MTAB-9543	yes	6207.31
E-MTAB-8410	yes	4504.97
E-GEOD-83139	yes	4246.98
E-CURD-88	yes	3745.32
E-CURD-7	yes	3427.84
E-ENAD-21	yes	3154.01
E-MTAB-6308	yes	3052.24
E-MTAB-9841	yes	2866.47
E-MTAB-10855	yes	2843.60
E-CURD-122	yes	2662.66
E-CURD-46	yes	2580.65
E-HCAD-1	yes	2146.81
E-CURD-114	yes	2011.74

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, IRF1, MYC, NFKB1, NR3C1, RELA, RELB, TFAP2A, USF1, USF2

miRNA regulators (miRDB)

94 targeting PIGR, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-30B-3P	99.70	65.76	2325

Literature-anchored findings (GeneRIF, showing 40)

• IL-4 responsiveness mediated by an enhancer located in intron 1; both direct and indirect involvement of STAT6 (PMID:11034397)
• A novel NF-kappa B/Rel site in intron 1 cooperates with proximal promoter elements to mediate TNF-alpha-induced transcription of the human polymeric Ig receptor (PMID:11714807)
• characterization of the human pIgR promoter and the essential role that eight different nuclear complexes have in controlling basal expression of this gene in Caco-2 cells (PMID:12121890)
• cooperative binding of multiple transcription factors regulates basal activity of the human PIGR promoter (PMID:12165516)
• facilitates invasion of epithelial cells by Streptococcus pneumoniae in a strain-specific and cell type-specific manner (PMID:12183558)
• The carboxyl-terminal domains of IgA and IgM direct isotype-specific polymerization and interaction with this receptor (PMID:12213814)
• This protein is cleaved by neutrophil serine proteinases but its epithelial production is increased by neutrophils through NF-kappa B- and p38 mitogen-activated protein kinase-dependent mechanisms. (PMID:12654638)
• It seems that a gene associated with susceptibility to immunoglobulin A nephropathy lies within or close to the PIGR gene locus on chromosome 1q in the Japanese population. (PMID:12740691)
• there is a conformational CbpA-binding motif in the D3/D4 region of human polymeric immunoglobulin receptor, which is functionally separated from the IgA-binding site (PMID:13679368)
• transcription factors upstream stimulatory factor (USF) and c-Myc may exert opposing effects on PIGR promoter activity (PMID:14644095)
• Ectodomains 3 and 4 of human polymeric Immunoglobulin receptor have a role in mediating adherence and internalization of Streptococcus pneumoniae into epithelial cells (PMID:14660617)
• TNF-induced up-regulation of the human pIgR critically depends on an NF-kappa B site and flanking sequences within a 204-bp region of the first intron in the pIgR gene, a region largely overlapping with a recently characterized IL-4-responsive enhancer. (PMID:15265917)
• USF1 and USF2 mRNA levels were reduced in non-small cell lung carcinoma; AP2-alpha levels were elevated; regression analysis demonstrated that reduced USF2 mRNA & increased AP2-alpha mRNA levels were predictive of downregulated PIGR mRNA expression (PMID:15864740)
• TLR3 and TLR4 signal primarily through NF-kappaB to enhance transcription of pIgR mRNA. (PMID:15972671)
• This review expands our view of the immunobiology of pIgR, a key component of the mucosal immune system that bridges innate and adaptive immune defense. (PMID:16048543)
• interaction of dimeric IgA (dIgA) (the predominant form of IgA polymer) with the pIgR (PMID:16272325)
• Secretory component (SC) is derived from the polymeric immunoglobulin receptor (pIgR). The purified free form of SC binds IgM with a physiological equilibrium dissociation constant of 4.6x10(-8) M and shares structural similarity to native SC. (PMID:16288892)
• This work represents the first analysis of the three-dimensional structure of full-length free secretory component (SC) and paves the way to a better understanding of the association between SC and its potential ligands. (PMID:17428798)
• In cultured Caco-2 cells, tumor necrosis factor-alpha (TNF-alpha) dose-dependently increased polymeric immunoglobulin receptor (pIg) mRNA. (PMID:17460948)
• Fcalpha/muR had different tissue distribution patterns to pIgR in the intestine. (PMID:19338768)
• Data illustrate the importance of a coordinated signaling between Src PTKs, ERK1/2, and JNK during pIgR-mediated uptake of pneumococci by host epithelial cells. (PMID:20829350)
• Streptococcus pneumoniae infection of host epithelial cells via polymeric immunoglobulin receptor transiently induces calcium release from intracellular stores. (PMID:21454571)
• Polymeric immunoglobulin receptor (PIGR)expression was lost in most lung cancers and pre-invasive bronchial lesions, suggesting that PIGR downregulation is an early event in lung tumourigenesis. PIGR overexpression inhibited cell proliferation. (PMID:21965228)
• Both native and phage-bound variable domain of camelid derived heavy chain only antibodies, were only able to get across polarized MDCK cells that express the human pIgR gene in a basolateral to apical fashion. (PMID:22022593)
• Results identify pIgR as a potential link between hepatitis B virus-derived hepatitis and HCC metastasis and provide evidence in support of pIgR as a prognostic biomarker for HCC and a potential therapeutic target. (PMID:22025622)
• The comparison of nonsmokers, smokers, and smokers with moderate COPD revealed 15 changed proteins with the majority, including polymeric immunoglobulin receptor (PIGR), being elevated in smokers and subjects with COPD. (PMID:22053820)
• Results indicated that the polymeric immunoglobulin receptor (pIgR) can be divided into several functionally distinct regions. (PMID:23809084)
• Report PIGR expression in human fallopian tubes, primary epithelial ovarian tumours and metastases. (PMID:24568264)
• High PIGR expression independently predicts a decreased risk of recurrence and an improved survival in patients with adenocarcinoma of the upper gastrointestinal tract (PMID:24694107)
• Polymeric immunoglobulin receptor expression is correlated with poor prognosis in patients with osteosarcoma. (PMID:24699841)
• pIgR down-regulation in chronic obstructive pulmonary disease correlates with severity. Bronchial epithelium in vitro retains aberrant imprinting for pIgR expression. pIgR down-regulation is linked to TGF-beta-driven reprogramming of bronchial epithelium. (PMID:25078120)
• Reduced expression of the polymeric immunoglobulin receptor in pancreatic and periampullary adenocarcinoma signifies tumour progression and poor prognosis. (PMID:25397670)
• In conclusion these data suggest that Streptococcus pneumoniae PspC-promoted uptake via the polymeric immunoglobulin receptor of epithelial cells is mediated by both clathrin and caveolin dependent pathway. (PMID:25455218)
• the polymeric immunoglobulin receptor (pIgR) is highly expressed by renal cyst-lining cells. pIgR expression is, in part, driven by aberrant STAT6 pathway activation. (PMID:25922073)
• Crohn disease patients were characterized as having decreased median expression of PIGR, in non-inflamed colonic mucosa. By contrast, Ulcerative colitis patients exhibited decreased expression of PIGR in colon mucosa. (PMID:25956706)
• Positive expression of pIgR was statistically significantly associated with poor prognosis of patients with colon carcinoma hepatic metastasis. (PMID:26176052)
• These results demonstrate that SLPI down-regulates pIgR expression through the NF-kappaB signaling pathway by inhibiting degradation of IkappaBbeta protein. (PMID:26239418)
• The polymeric immunoglobulin receptor secretory component structure comprises five immunoglobulin-like domains (D1-D5) arranged as a triangle, with an interface between ligand-binding domains D1 and D5. (PMID:26943617)
• We identified two SLN genes (PIGR and TFAP2A) that provided high prognostic accuracy in SLN-positive melanoma patients (AUC = 0.864). These two SLN genes, along with clinicopathological features, can differentiate the high- and low-risk groups in node-positive melanoma patients. (PMID:27663566)
• pIgR may be involved in pancreatic ductal adenocarcinoma progression and may be linked stromal activity. Further work on its precise role is mandated in in vivo models, to understand its influence on cancer progression. (PMID:28173980)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pigr	ENSMUSG00000026417
rattus_norvegicus	Pigr	ENSRNOG00000004405

Paralogs (13): TREM2 (ENSG00000095970), TMIGD3 (ENSG00000121933), CD300LG (ENSG00000161649), TREML1 (ENSG00000161911), FCMR (ENSG00000162894), FCAMR (ENSG00000162897), CD300C (ENSG00000167850), CD300A (ENSG00000167851), CD300LB (ENSG00000178789), CD300LF (ENSG00000186074), CD300E (ENSG00000186407), CD300LD (ENSG00000204345), CD300H (ENSG00000284690)

Protein

Protein identifiers

Polymeric immunoglobulin receptor — P01833 (reviewed: P01833)

Alternative names: Hepatocellular carcinoma-associated protein TB6

All UniProt accessions (1): P01833

UniProt curated annotations — full annotation on UniProt →

Function. Mediates selective transcytosis of polymeric IgA and IgM across mucosal epithelial cells. Binds polymeric IgA and IgM at the basolateral surface of epithelial cells. The complex is then transported across the cell to be secreted at the apical surface. During this process, a cleavage occurs that separates the extracellular (known as the secretory component) from the transmembrane segment. Through its N-linked glycans ensures anchoring of secretory IgA (sIgA) molecules to mucus lining the epithelial surface to neutralize extracellular pathogens. On its own (free form) may act as a non-specific microbial scavenger to prevent pathogen interaction with epithelial cells.

Subunit / interactions. Interacts (mainly via CDR1-like domain) with dimeric IgA. Interacts (mainly via CDR2-like domain) with pentameric IgM. Either free or part of the secretory IgA (sIgA) complex that consists of two, four or five IgA monomers, and two additional non-Ig polypeptides, namely the JCHAIN and the secretory component (the proteolytic product of PIGR). Free secretory component interacts with bacterial antigens toxA of C.difficile and eaeA of E.coli.

Subcellular location. Cell membrane Secreted.

Post-translational modifications. N-glycosylated. N-glycosylation is required for anchoring IgA molecules to mucus, but is not necessary for Ig binding.

Domain organisation. The Ig-like V-type 1/D1 domain contains three complementarity determining region-like loops CDR1-3, which mediate interaction with IgA and IgM.

RefSeq proteins (1): NP_002635* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050671	CD300_family_receptors	Family

Pfam: PF07686

UniProt features (128 total): strand 54, helix 11, disulfide bond 11, sequence conflict 10, turn 8, glycosylation site 7, domain 5, modified residue 4, mutagenesis site 4, compositionally biased region 3, sequence variant 3, chain 2, region of interest 2, topological domain 2, signal peptide 1, transmembrane region 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
3CHN	SOLUTION SCATTERING	0
3CM9	SOLUTION SCATTERING	0
1XED	X-RAY DIFFRACTION	1.9
5D4K	X-RAY DIFFRACTION	2.6
6UE7	ELECTRON MICROSCOPY	2.9
6UE9	ELECTRON MICROSCOPY	2.9
6UE8	ELECTRON MICROSCOPY	3
6UEA	ELECTRON MICROSCOPY	3
8SKV	ELECTRON MICROSCOPY	3.1
6LX3	ELECTRON MICROSCOPY	3.15
7YSG	ELECTRON MICROSCOPY	3.18
8SKU	ELECTRON MICROSCOPY	3.2
6LXW	ELECTRON MICROSCOPY	3.27
7K0C	ELECTRON MICROSCOPY	3.3
6KXS	ELECTRON MICROSCOPY	3.4
2OCW	SOLUTION SCATTERING

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01833-F1	77.24	0.46

Antibody-complex structures (SAbDab): 2 — 3CHN, 3CM9

Functional residue map

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

Post-translational modifications (4): 673, 682, 689, 735

Disulfide bonds (11): 40–110, 56–64, 152–220, 257–325, 271–279, 371–441, 385–395, 482–544, 486–520, 496–503, 503

Glycosylation sites (7): 83, 90, 135, 186, 421, 469, 499

Mutagenesis-validated functional residues (4):

Position	Phenotype
47	disrupts the interaction with pentameric igm; when associated with s-49.
49	disrupts the interaction with pentameric igm; when associated with n-47.
117	disrupts the interaction with pentameric igm; when associated with t-119.
119	disrupts the interaction with pentameric igm; when associated with n-117.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 224 (showing top): MORF_RAGE, MORF_FLT1, REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, MODULE_45, MODULE_64, MORF_ATRX, GOBP_SENSORY_PERCEPTION_OF_CHEMICAL_STIMULUS, GOBP_VESICLE_MEDIATED_TRANSPORT, MORF_ESR1, MODULE_16, GOBP_ORGAN_OR_TISSUE_SPECIFIC_IMMUNE_RESPONSE, NIKOLSKY_BREAST_CANCER_1Q32_AMPLICON, GOBP_REGULATION_OF_IMMUNE_RESPONSE

GO Biological Process (6): detection of chemical stimulus involved in sensory perception of bitter taste (GO:0001580), immunoglobulin transcytosis in epithelial cells mediated by polymeric immunoglobulin receptor (GO:0002415), signal transduction (GO:0007165), epidermal growth factor receptor signaling pathway (GO:0007173), Fc receptor signaling pathway (GO:0038093), receptor clustering (GO:0043113)

GO Molecular Function (3): polymeric immunoglobulin binding (GO:0001790), polymeric immunoglobulin receptor activity (GO:0001792), transmembrane signaling receptor activity (GO:0004888)

GO Cellular Component (11): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), azurophil granule membrane (GO:0035577), signaling receptor complex (GO:0043235), extracellular exosome (GO:0070062), secretory IgA immunoglobulin complex (GO:0071751), extracellular region (GO:0005576), endomembrane system (GO:0012505), membrane (GO:0016020), cytoplasmic vesicle membrane (GO:0030659), bounding membrane of organelle (GO:0098588)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
plasma membrane	2
detection of chemical stimulus involved in sensory perception of taste	1
sensory perception of bitter taste	1
mucosal immune response	1
immunoglobulin transcytosis in epithelial cells	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
ERBB signaling pathway	1
immune response-regulating cell surface receptor signaling pathway	1
protein localization to membrane	1
immunoglobulin binding	1
polymeric immunoglobulin binding	1
immunoglobulin receptor activity	1
signaling receptor activity	1
membrane	1
cell periphery	1
lysosomal membrane	1
secretory granule membrane	1
azurophil granule	1
protein-containing complex	1
extracellular vesicle	1
polymeric IgA immunoglobulin complex	1
vacuole	1
vesicle membrane	1
cytoplasmic vesicle	1
organelle membrane	1

Protein interactions and networks

STRING

1868 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIGR	JCHAIN	P01591	999
PIGR	PIGA	P37287	992
PIGR	RAB3B	P20337	911
PIGR	FCAR	P24071	905
PIGR	SFTPC	P11686	904
PIGR	FCGR1A	P12314	816
PIGR	LTF	P02788	815
PIGR	FCRL4	Q96PJ5	794
PIGR	FCRL5	Q96RD9	774
PIGR	FCRL2	Q96LA5	750
PIGR	FCRL1	Q96LA6	750
PIGR	FCRL3	Q96P31	750
PIGR	MAL2	Q969L2	695
PIGR	IGHV4-38-2	P0DP08	693
PIGR	FCGR3A	P08637	681

IntAct

93 interactions, top by confidence:

A	B	Type	Score
COMMD1	VPS26C	psi-mi:“MI:0914”(association)	0.730
AEBP2	EED	psi-mi:“MI:0914”(association)	0.650
APLP2	PIGR	psi-mi:“MI:0407”(direct interaction)	0.560
FRMD1	A2ML1	psi-mi:“MI:0914”(association)	0.530
DDX31	IGLL5	psi-mi:“MI:0914”(association)	0.530
HBM	SCGB2A1	psi-mi:“MI:0914”(association)	0.530
ICE2	HP	psi-mi:“MI:0914”(association)	0.530
RHOBTB1	CST4	psi-mi:“MI:0914”(association)	0.530
UCP2	CST4	psi-mi:“MI:0914”(association)	0.530
GTF2B	CST4	psi-mi:“MI:0914”(association)	0.530
PLEKHG6	CST4	psi-mi:“MI:0914”(association)	0.530
ZNF491	CST4	psi-mi:“MI:0914”(association)	0.530
GKN1	CST4	psi-mi:“MI:0914”(association)	0.530
ITPRID2	PIGR	psi-mi:“MI:0914”(association)	0.530
TMEM237	CLGN	psi-mi:“MI:0914”(association)	0.530
NPB	CST4	psi-mi:“MI:0914”(association)	0.530
RIBC1	CNOT1	psi-mi:“MI:0914”(association)	0.530
SCAMP2	SCAMP3	psi-mi:“MI:0914”(association)	0.530
ARMC6	SLC27A2	psi-mi:“MI:0914”(association)	0.530
MIS12	C1 segment	psi-mi:“MI:0915”(physical association)	0.400
Dynll1		psi-mi:“MI:0915”(physical association)	0.400
PIGR	LGALS1	psi-mi:“MI:0915”(physical association)	0.400
FCAR	PIGR	psi-mi:“MI:0915”(physical association)	0.400
ISLR2	PIGR	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (160): PIGR (Affinity Capture-MS), PIGR (Affinity Capture-MS), PIGR (Affinity Capture-MS), PIGR (Affinity Capture-MS), PIGR (Affinity Capture-MS), PIGR (Affinity Capture-MS), PIGR (Affinity Capture-MS), PIGR (Affinity Capture-MS), PIGR (Affinity Capture-MS), PIGR (Affinity Capture-MS), PIGR (Affinity Capture-MS), PIGR (Affinity Capture-MS), PIGR (Affinity Capture-MS), PIGR (Affinity Capture-MS), PIGR (Affinity Capture-MS)

ESM2 similar proteins: A0A140LHF2, A0JPB1, A8E0Y8, D3YX43, O00241, P01833, P01854, P01874, P01879, P01880, P0C788, P0DOX3, P0DOX4, P0DOX6, P0DUB1, P15083, P20273, P20768, P27931, P35590, P35916, P35917, P35969, P43121, P43303, P53767, P81265, Q06805, Q06806, Q15109, Q5FWR8, Q5TFQ8, Q5U5A3, Q62230, Q62786, Q6AYD4, Q8K135, Q8R2Y2, Q91ZT1, Q925F2

Diamond homologs: A0A0K2S4Q6, A2A7V7, A2TGX5, A5D7B2, A8K4G0, O70570, P01832, P01833, P0DUB1, P15083, P81265, Q08708, Q1ERP8, Q3LRV9, Q3U497, Q496F6, Q566E6, Q6SJQ0, Q6SJQ5, Q6SJQ7, Q6UXG3, Q6UXZ3, Q7TSN2, Q8K249, Q8TDQ1, Q8VCH2, Q99NH8, Q9UGN4, A1KXC4, O60667, Q2TB54, Q5M871, Q5R770, Q8WWV6, O95944, G3X8R9, P0DMS9, Q2LA85, Q86YW5, Q8K558

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	83
Likely benign	14
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1673 predictions. Top by Δscore:

Variant	Effect	Δscore
1:206930325:T:TA	donor_gain	1.0000
1:206930410:ATGA:A	acceptor_gain	1.0000
1:206930411:TGA:T	acceptor_gain	1.0000
1:206930412:GA:G	acceptor_gain	1.0000
1:206930414:C:CC	acceptor_gain	1.0000
1:206930414:C:CG	acceptor_loss	1.0000
1:206931480:T:TA	donor_gain	1.0000
1:206931668:TACC:T	donor_loss	1.0000
1:206931670:CCTT:C	donor_gain	1.0000
1:206931798:TCGGT:T	acceptor_gain	1.0000
1:206931799:CGGT:C	acceptor_gain	1.0000
1:206931799:CGGTC:C	acceptor_gain	1.0000
1:206931803:C:CC	acceptor_gain	1.0000
1:206931808:C:CT	acceptor_gain	1.0000
1:206931808:C:T	acceptor_gain	1.0000
1:206931809:G:T	acceptor_gain	1.0000
1:206932449:GACTC:G	donor_loss	1.0000
1:206932450:ACT:A	donor_loss	1.0000
1:206932451:CTC:C	donor_loss	1.0000
1:206932454:A:AC	donor_gain	1.0000
1:206932455:C:CC	donor_gain	1.0000
1:206932455:CCGA:C	donor_gain	1.0000
1:206932573:CAGAG:C	acceptor_gain	1.0000
1:206932575:GAG:G	acceptor_gain	1.0000
1:206932576:AG:A	acceptor_gain	1.0000
1:206932576:AGC:A	acceptor_loss	1.0000
1:206932577:GCTG:G	acceptor_loss	1.0000
1:206932578:C:CA	acceptor_loss	1.0000
1:206932578:C:CC	acceptor_gain	1.0000
1:206932980:CCTTA:C	donor_loss	1.0000

AlphaMissense

4979 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:206939340:C:G	C56S	0.994
1:206939341:A:T	C56S	0.994
1:206939389:A:G	C40R	0.994
1:206939178:C:G	C110S	0.993
1:206939179:A:T	C110S	0.993
1:206939388:C:G	C40S	0.993
1:206939389:A:T	C40S	0.993
1:206934631:C:A	W498C	0.992
1:206934631:C:G	W498C	0.992
1:206939344:A:G	W55R	0.992
1:206939344:A:T	W55R	0.992
1:206939387:G:C	C40W	0.991
1:206939179:A:G	C110R	0.990
1:206939388:C:T	C40Y	0.990
1:206939339:G:C	C56W	0.988
1:206934501:A:C	Y542D	0.987
1:206937481:C:G	C220S	0.987
1:206937482:A:T	C220S	0.987
1:206939341:A:G	C56R	0.987
1:206937166:C:G	C325S	0.986
1:206937167:A:T	C325S	0.986
1:206934494:C:G	C544S	0.985
1:206934495:A:T	C544S	0.985
1:206934638:C:G	C496S	0.985
1:206934639:A:T	C496S	0.985
1:206934642:A:G	W495R	0.985
1:206934642:A:T	W495R	0.985
1:206935752:C:G	C371S	0.985
1:206935753:A:T	C371S	0.985
1:206934640:C:A	W495C	0.984

dbSNP variants (sampled 300 via entrez): RS1000484321 (1:206946967 C>T), RS1000631681 (1:206947853 GT>G), RS1000732463 (1:206936328 G>A,C), RS1000853790 (1:206930134 A>G), RS1000960468 (1:206929489 G>A), RS1001003858 (1:206948120 C>T), RS1001185119 (1:206936158 G>T), RS1001417587 (1:206941923 C>T), RS1001467938 (1:206935871 T>C), RS1001609039 (1:206946840 T>C), RS1001650934 (1:206935288 T>A), RS1001802544 (1:206941007 C>A), RS1001846325 (1:206946437 G>C), RS1001877330 (1:206946237 G>A), RS1001891132 (1:206928415 A>C,T)

Disease associations

OMIM: gene MIM:173880 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): IgA glomerulonephritis (MONDO:0005342)

Orphanet (1): Immunoglobulin A nephropathy (Orphanet:34145)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001725_40	Inflammatory bowel disease	7.000000e-42
GCST004224_4	Coronary atherosclerosis (increased number of diseased vessels) (traffic exposure interaction)	2.000000e-06
GCST004224_5	Coronary atherosclerosis (increased number of diseased vessels) (traffic exposure interaction)	3.000000e-06
GCST006585_2822	Blood protein levels	5.000000e-30
GCST009182_2	Precuneus cortex volume	3.000000e-06
GCST009391_255	Metabolite levels	3.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007908	traffic air pollution measurement
EFO:0007938	coronary atherosclerosis measurement
EFO:0010426	triacylglycerol 54:8 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D005922	Glomerulonephritis, IGA	C12.050.351.968.419.570.363.608; C12.200.777.419.570.363.608; C12.950.419.570.363.608; C20.111.525

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295691 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	2
monomethylarsonous acid	decreases expression, increases expression	2
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	increases abundance, increases expression, increases response to substance	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Aflatoxin B1	decreases expression	2
sodium arsenate	decreases expression, increases abundance	1
arsenite	increases abundance, decreases expression	1
monomethylarsonic acid	decreases expression	1
arsenic acid	decreases expression, increases abundance	1
abrine	decreases expression	1
dimethylmonothioarsinic acid	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Zoledronic Acid	increases expression	1
Allergens	increases expression	1
Arsenic	affects expression	1
Vehicle Emissions	increases response to substance, increases abundance	1
Cacodylic Acid	decreases expression	1
Cadmium	increases abundance, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	affects expression	1
Tretinoin	increases expression	1
Valproic Acid	increases methylation	1
Cadmium Chloride	increases abundance, increases expression	1
Permethrin	increases expression	1
Particulate Matter	increases abundance, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4119035	Binding	Binding affinity to PIGR in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00319761	PHASE4	COMPLETED	Calcitriol in the Treatment of Immunoglobulin A (IgA) Nephropathy
NCT00367562	PHASE4	COMPLETED	Inhibition of the Renin Angiotensin System Plus Corticosteroids for the Treatment of Proteinuria in IGA Nephropathy
NCT00426348	PHASE4	COMPLETED	A Study of the Antioxidant Probucol Combined With Valsartan in Patients With IgA Nephropathy
NCT00498368	PHASE4	COMPLETED	Rituximab in Progressive Immunoglobulin A (IgA) Nephropathy
NCT00755859	PHASE4	COMPLETED	Steroids and Azathioprine Versus Steroids Alone in IgAN
NCT00863252	PHASE4	COMPLETED	Mycophenolate Mofetil for IgA Nephropathy
NCT00922311	PHASE4	COMPLETED	Aliskiren for Proteinuric IgAN Despite Angiotensin Blockade
NCT01103778	PHASE4	COMPLETED	Pilot Study of Velcade® in IgA Nephropathy
NCT01115426	PHASE4	COMPLETED	Inhibitors of Angiotensin II in Proteinuric Mesangioproliferative Glomerulonephritis
NCT01129557	PHASE4	TERMINATED	Aldosterone Breakthrough During Diovan, Tekturna, and Combination Therapy in Patients With Proteinuric Kidney Disease
NCT01758120	PHASE4	UNKNOWN	Treatment of Prednisone Plus Cyclophosphamide in Patients With Advanced-stage IgA Nephropathy
NCT02231125	PHASE4	UNKNOWN	Efficacy and Safety of Abelmoschus Manihot for IgA Nephropathy
NCT02351752	PHASE4	COMPLETED	Hydroxychloroquine Sulfate for Reduction of Proteinuria in Patients With IgA Nephropathy: a Self- Controlled Study
NCT02382523	PHASE4	WITHDRAWN	Acthar on Proteinuria in IgA Nephropathy Patients
NCT02571842	PHASE4	UNKNOWN	Rituximab in Recurrent IgA Nephropathy
NCT02765594	PHASE4	UNKNOWN	Hydroxychloroquine Sulfate Alleviates Persistent Proteinuria in IgA Nephropathy
NCT02981212	PHASE4	UNKNOWN	Efficacy and Safety of a Combination of Mycophenolate Mofetil and Corticosteroid in Advanced IgA Nephropathy
NCT03218852	PHASE4	UNKNOWN	Extended Follow-up of Treatment of Prednisone Plus Cyclophosphamide in Patients With Advanced-stage IgA Nephropathy
NCT04525729	PHASE4	COMPLETED	Rituximab and RASi in Patients with IgAN
NCT05824390	PHASE4	UNKNOWN	A Randomized, Controlled Clinical Study of Rituximab in Treatment of Primary IgA Nephropathy
NCT06676384	PHASE4	RECRUITING	Which of the Commonly Available and Approved Drugs in Addition to Standard of Care Can Significantly Improve the Slope of Estimated Glomerular Filtration Rate at Two Years When Compared to Standard of Care Alone in South-Asian Kidney Biopsy-proven Adult (≥18 Years) Primary IgA Nephropathy?
NCT06712407	PHASE4	RECRUITING	Efficacy and Safety of Extended TARPEYO® Treatment Beyond 9 Months in Adult Patients With Primary IgA Nephropathy
NCT07030894	PHASE4	RECRUITING	Nefecon and Ambrisentan in IgA Nephropathy
NCT07604311	PHASE4	NOT_YET_RECRUITING	Efficacy and Safety of Nefecon on Prevention of Relapse of IgA Nephropathy: a Randomized, Double-blinded, Placebo-Controlled Trial
NCT00318474	PHASE3	TERMINATED	Mycophenolate Mofetil (MMF) in Patients With IgA Nephropathy
NCT00549692	PHASE3	COMPLETED	Efficacy and Safety of Omega-3 Fatty Acids(Omacor®) for the Treatment of Immunoglobulin A Nephropathy
NCT00554502	PHASE3	COMPLETED	Supportive Versus Immunosuppressive Therapy for the Treatment Of Progressive IgA Nephropathy
NCT00599963	PHASE3	WITHDRAWN	Paricalcitol for the Treatment of Immunoglobulin A Nephropathy
NCT00657059	PHASE3	COMPLETED	Mycophenolate Mofetil (MMF) in Patients With IgA Nephropathy (IgAN)
NCT00870493	PHASE3	COMPLETED	Aliskiren for Immunoglobulin A (IgA) Nephropathy
NCT01392833	PHASE3	COMPLETED	Steroids and Azathioprine in Advanced IgAN
NCT02052219	PHASE3	WITHDRAWN	BRILLIANT-SC: A Study of the Efficacy and Safety of Blisibimod Administration in Subjects With IgA Nephropathy
NCT02187900	PHASE3	UNKNOWN	Treatment of IgAN With Multi-glycoside of Tripterygium Wilfordii HOOK. f.
NCT02282930	PHASE3	COMPLETED	Pilot Study of ACTH in the Treatment of Immunoglobulin A (IgA) Nephropathy at High Risk of Progression
NCT03188887	PHASE3	COMPLETED	Treatment of IgA Nephropathy According to Renal Lesions
NCT03608033	PHASE3	TERMINATED	Study of the Safety and Efficacy of OMS721 in Patients With Immunoglobulin A (IgA) Nephropathy
NCT03643965	PHASE3	COMPLETED	Efficacy and Safety of Nefecon in Patients With Primary IgA (Immunoglobulin A) Nephropathy
NCT04541043	PHASE3	COMPLETED	Efficacy and Safety in Patients With Primary IgA Nephropathy Who Have Completed Study Nef-301 (Nefigard-OLE)
NCT04557462	PHASE3	RECRUITING	A Rollover Extension Program (REP) to Evaluate the Long-term Safety and Tolerability of Open Label Iptacopan/LNP023 in Participants With Primary IgA Nephropathy
NCT04573478	PHASE3	ACTIVE_NOT_RECRUITING	Atrasentan in Patients With IgA Nephropathy