PVRIG

Summary

PVRIG (PVR related immunoglobulin domain containing, HGNC:32190) is a protein-coding gene on chromosome 7q22.1, encoding Transmembrane protein PVRIG (Q6DKI7). Cell surface receptor for NECTIN2.

Enables phosphatase binding activity and signaling receptor activity. Involved in negative regulation of T cell receptor signaling pathway. Located in plasma membrane.

Source: NCBI Gene 79037 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 67 total
• MANE Select transcript: NM_001397246

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:32190
Approved symbol	PVRIG
Name	PVR related immunoglobulin domain containing
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC2463, C7orf15, CD112R
Ensembl gene	ENSG00000213413
Ensembl biotype	protein_coding
OMIM	617012
Entrez	79037

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000317271, ENST00000696640, ENST00000699088, ENST00000889719, ENST00000940883

RefSeq mRNA: 3 — MANE Select: NM_001397246 NM_001387134, NM_001397246, NM_024070

CCDS: CCDS5690, CCDS94154

Canonical transcript exons

ENST00000699088 — 5 exons

Exon	Start	End
ENSE00001144884	100220928	100221490
ENSE00002505199	100220547	100220673
ENSE00002507386	100220114	100220464
ENSE00003508310	100220760	100220820
ENSE00003975612	100219949	100220028

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 92.64.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2385 / max 39.8654, expressed in 93 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
79945	0.2236	89
79944	0.0149	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	92.64	gold quality
blood	UBERON:0000178	88.58	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.15	gold quality
spleen	UBERON:0002106	85.13	gold quality
skeletal muscle tissue	UBERON:0001134	84.72	gold quality
lymph node	UBERON:0000029	84.68	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.69	silver quality
gastrocnemius	UBERON:0001388	82.92	gold quality
hindlimb stylopod muscle	UBERON:0004252	82.54	gold quality
muscle of leg	UBERON:0001383	82.18	gold quality
vermiform appendix	UBERON:0001154	79.69	gold quality
muscle tissue	UBERON:0002385	79.37	gold quality
right hemisphere of cerebellum	UBERON:0014890	79.25	gold quality
cerebellar hemisphere	UBERON:0002245	77.64	gold quality
cerebellar cortex	UBERON:0002129	77.63	gold quality
cerebellum	UBERON:0002037	77.47	gold quality
cortical plate	UBERON:0005343	77.39	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	76.98	gold quality
body of pancreas	UBERON:0001150	76.25	gold quality
corpus callosum	UBERON:0002336	76.06	gold quality
primary visual cortex	UBERON:0002436	75.80	gold quality
left ovary	UBERON:0002119	75.28	gold quality
pituitary gland	UBERON:0000007	74.31	gold quality
ovary	UBERON:0000992	73.96	gold quality
right ovary	UBERON:0002118	73.93	gold quality
substantia nigra	UBERON:0002038	73.30	gold quality
right uterine tube	UBERON:0001302	73.06	gold quality
small intestine Peyer’s patch	UBERON:0003454	72.96	gold quality
ganglionic eminence	UBERON:0004023	72.72	gold quality
adenohypophysis	UBERON:0002196	72.50	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	95.89
E-CURD-122	yes	46.41
E-MTAB-6678	yes	24.13
E-HCAD-10	yes	24.07
E-CURD-120	no	8.66
E-CURD-112	no	3.62
E-ANND-3	no	0.76

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

14 targeting PVRIG, 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-9718	99.94	68.91	918
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-761	98.71	68.07	2051
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-3136-5P	98.53	67.68	793
HSA-MIR-4439	98.53	67.53	793
HSA-MIR-5008-5P	98.42	65.87	1019
HSA-MIR-628-5P	98.36	67.74	844
HSA-MIR-4443	98.02	66.25	1928
HSA-MIR-342-3P	96.44	67.48	1344
HSA-MIR-6890-5P	92.89	65.83	442

Literature-anchored findings (GeneRIF, showing 8)

• Describe CD112R, a member of poliovirus receptor-like proteins, as a new coinhibitory receptor for T cells. CD112R is preferentially expressed on T cells and inhibits T cell receptor-mediated signals. (PMID:26755705)
• Blockade of TIGIT or CD112R, separately or together, enhances trastuzumab-triggered antitumor response by human NK cells. (PMID:28623459)
• we demonstrate that PVRIG and PVRL2 are expressed in human cancers and the PVRIG-PVRL2 and TIGIT-PVR pathways are nonredundant inhibitory signaling pathways. (PMID:30659054)
• PVRIG is a novel NK cell immune checkpoint receptor in acute myeloid leukemia. (PMID:33147937)
• Hitting the complexity of the TIGIT-CD96-CD112R-CD226 axis for next-generation cancer immunotherapy. (PMID:33298247)
• COM902, a novel therapeutic antibody targeting TIGIT augments anti-tumor T cell function in combination with PVRIG or PD-1 pathway blockade. (PMID:33903974)
• Nonredundant Upregulation of CD112R (PVRIG) and PD-1 on Cytotoxic T Lymphocytes Located in T Cell Nests of Colorectal Cancer. (PMID:36788088)
• Structural basis for the immune recognition and selectivity of the immune receptor PVRIG for ligand Nectin-2. (PMID:38626767)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pvrig	ENSMUSG00000109713
rattus_norvegicus	Pvrig	ENSRNOG00000051906

Protein

Protein identifiers

Transmembrane protein PVRIG — Q6DKI7 (reviewed: Q6DKI7)

Alternative names: CD112 receptor, Poliovirus receptor-related immunoglobulin domain-containing protein

All UniProt accessions (2): A0A8V8TN58, Q6DKI7

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface receptor for NECTIN2. May act as a coinhibitory receptor that suppresses T-cell receptor-mediated signals. Following interaction with NECTIN2, inhibits T-cell proliferation. Competes with CD226 for NECTIN2-binding.

Subunit / interactions. Interacts with NECTIN2, hence competing with CD226.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in some types of immune cells. Expressed at low levels on the surface of freshly isolated T-cells and natural killer (NK) cells, predominantly on CD8+ T-cells (mainly memory/effector, but not naive cells) and on both CD16+ and CD16- NK cells. T-cell expression levels are variable among individuals. Not detected in B-cells, naive or helper T-cells, monocytes, nor neutrophils (at protein level). Not detected in dendritic cells.

Induction. In T-cells, up-regulated by activation induced by treatment with anti-CD3 and anti-CD28 antibodies.

Miscellaneous. Was named PVRIG for the homology observed between its second exon and the variable immunoglobulin domain of the polio virus receptor (PVR/CD155) and polio virus receptor-like (PVRL) genes.

RefSeq proteins (3): NP_001374063, NP_001384175, NP_076975 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR034452	TM_PVRIG	Family
IPR057367	Ig_PVRIG	Domain

Pfam: PF25456

UniProt features (21 total): strand 9, transmembrane region 3, turn 3, mutagenesis site 2, chain 1, region of interest 1, modified residue 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8X6B	X-RAY DIFFRACTION	2
9E6Y	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6DKI7-F1	61.56	0.15

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 (1): 233

Mutagenesis-validated functional residues (2):

Position	Phenotype
233	reduced phosphorylation.
293	no effect on global phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 66 (showing top): GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_T_CELL_RECEPTOR_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, SMID_BREAST_CANCER_LUMINAL_B_DN, GOMF_PHOSPHATASE_BINDING, GOBP_ACTIVATION_OF_IMMUNE_RESPONSE, LEE_DIFFERENTIATING_T_LYMPHOCYTE, GOBP_IMMUNE_RESPONSE_REGULATING_SIGNALING_PATHWAY, SMIRNOV_RESPONSE_TO_IR_6HR_DN, ZWANG_DOWN_BY_2ND_EGF_PULSE

GO Biological Process (1): negative regulation of T cell receptor signaling pathway (GO:0050860)

GO Molecular Function (3): phosphatase binding (GO:0019902), signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
T cell receptor signaling pathway	1
regulation of T cell receptor signaling pathway	1
negative regulation of antigen receptor-mediated signaling pathway	1
enzyme binding	1
molecular transducer activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

668 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PVRIG	NECTIN2	Q92692	993
PVRIG	PVR	P15151	776
PVRIG	NECTIN1	Q15223	730
PVRIG	CD226	Q15762	728
PVRIG	NECTIN3	Q9NQS3	670
PVRIG	CD96	P40200	667
PVRIG	TIGIT	Q495A1	647
PVRIG	NECTIN4	Q96NY8	522
PVRIG	KLRC1	P26715	520
PVRIG	LAG3	P18627	435
PVRIG	HAVCR2	Q8TDQ0	434
PVRIG	FAM163A	Q96GL9	418
PVRIG	CTLA4	P16410	400
PVRIG	AGFG2	O95081	379
PVRIG	PILRB	Q9UKJ0	378

IntAct

10 interactions, top by confidence:

A	B	Type	Score
PVRIG	OLFM4	psi-mi:“MI:0915”(physical association)	0.560
FCN1	PVRIG	psi-mi:“MI:0915”(physical association)	0.370
PVRIG	CFTR	psi-mi:“MI:0915”(physical association)	0.370
CFTR	PVRIG	psi-mi:“MI:0915”(physical association)	0.370
PVRIG	CLSTN1	psi-mi:“MI:0914”(association)	0.350
PVRIG	ATP1A3	psi-mi:“MI:0914”(association)	0.350
OLFM4	PVRIG	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (38): CLTCL1 (Affinity Capture-MS), SLC39A11 (Affinity Capture-MS), CLSTN1 (Affinity Capture-MS), LRIG3 (Affinity Capture-MS), TTC17 (Affinity Capture-MS), SUPT6H (Affinity Capture-MS), SPCS2 (Affinity Capture-MS), ARFGEF1 (Affinity Capture-MS), TUBB8 (Affinity Capture-MS), FRAS1 (Affinity Capture-MS), PLXNB2 (Affinity Capture-MS), LCLAT1 (Affinity Capture-MS), SPCS1 (Affinity Capture-MS), SUPT6H (Affinity Capture-MS), CLTCL1 (Affinity Capture-MS)

ESM2 similar proteins: D3YX43, D7PDD4, O14931, O70394, O70540, O95866, P0CAN6, P11911, P11912, P15391, P18627, P40293, P61484, Q02242, Q07763, Q13291, Q14773, Q28173, Q2YFS3, Q495A1, Q5BK54, Q5JXA9, Q5NKT8, Q5R8H1, Q60837, Q61790, Q61826, Q6DKI7, Q6MG59, Q6SJQ7, Q86YW5, Q8K1T1, Q8K558, Q8MII8, Q8MJ02, Q8N386, Q8NET5, Q8VD31, Q920A9, Q95MM9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	48
Likely benign	13
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1140 predictions. Top by Δscore:

Variant	Effect	Δscore
7:100219394:G:GG	donor_gain	1.0000
7:100220025:GCGG:G	donor_gain	1.0000
7:100220112:A:AG	acceptor_gain	1.0000
7:100220112:AG:A	acceptor_gain	1.0000
7:100220113:G:GG	acceptor_gain	1.0000
7:100220113:GG:G	acceptor_gain	1.0000
7:100220542:CCCA:C	acceptor_loss	1.0000
7:100220543:CCA:C	acceptor_loss	1.0000
7:100220544:CAGG:C	acceptor_loss	1.0000
7:100220545:A:AC	acceptor_loss	1.0000
7:100220545:A:AG	acceptor_gain	1.0000
7:100220545:AG:A	acceptor_gain	1.0000
7:100220545:AGG:A	acceptor_gain	1.0000
7:100220546:G:GG	acceptor_gain	1.0000
7:100220546:GG:G	acceptor_gain	1.0000
7:100220546:GGG:G	acceptor_gain	1.0000
7:100220670:ACCGG:A	donor_loss	1.0000
7:100220673:GGTGA:G	donor_loss	1.0000
7:100220674:G:GA	donor_loss	1.0000
7:100220674:G:GG	donor_gain	1.0000
7:100220675:T:A	donor_loss	1.0000
7:100220759:GCCCT:G	acceptor_gain	1.0000
7:100219389:GCCCA:G	donor_gain	0.9900
7:100220027:GG:G	donor_gain	0.9900
7:100220027:GGGT:G	donor_loss	0.9900
7:100220028:GG:G	donor_gain	0.9900
7:100220028:GGTG:G	donor_loss	0.9900
7:100220029:G:GG	donor_gain	0.9900
7:100220029:GT:G	donor_loss	0.9900
7:100220030:TGAG:T	donor_loss	0.9900

AlphaMissense

1929 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:100220402:T:G	F136C	0.993
7:100220401:T:C	F136L	0.992
7:100220403:T:A	F136L	0.992
7:100220403:T:G	F136L	0.992
7:100220319:G:C	W108C	0.985
7:100220319:G:T	W108C	0.985
7:100220402:T:C	F136S	0.981
7:100220410:T:C	F139L	0.974
7:100220412:C:A	F139L	0.974
7:100220412:C:G	F139L	0.974
7:100220185:T:C	F64L	0.973
7:100220187:C:A	F64L	0.973
7:100220187:C:G	F64L	0.973
7:100220389:T:C	F132L	0.969
7:100220391:C:A	F132L	0.969
7:100220391:C:G	F132L	0.969
7:100220261:C:A	A89D	0.963
7:100221123:T:C	F285L	0.962
7:100221125:T:A	F285L	0.962
7:100221125:T:G	F285L	0.962
7:100220396:G:A	C134Y	0.958
7:100220179:T:C	C62R	0.953
7:100220395:T:C	C134R	0.953
7:100220395:T:A	C134S	0.952
7:100220396:G:C	C134S	0.952
7:100220397:C:G	C134W	0.951
7:100220411:T:G	F139C	0.948
7:100220179:T:A	C62S	0.947
7:100220180:G:C	C62S	0.947
7:100220260:G:C	A89P	0.947

dbSNP variants (sampled 300 via entrez): RS1000344522 (7:100220389 T>A), RS1000608811 (7:100219275 A>C,T), RS1000632331 (7:100219475 A>G,T), RS1002212119 (7:100217818 A>G), RS1002265872 (7:100218061 C>T), RS1002922852 (7:100221690 G>A), RS1003109429 (7:100221514 G>A), RS1004218444 (7:100218319 T>C,G), RS1004599742 (7:100217452 A>C), RS1005090408 (7:100221758 A>AT), RS1007106320 (7:100219745 G>A), RS1007438747 (7:100218441 C>G), RS1007473033 (7:100218856 A>G), RS1007503946 (7:100219191 C>G,T), RS1009172187 (7:100217753 A>C)

Disease associations

OMIM: gene MIM:617012 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002882_6	Ticagrelor levels in individuals with acute coronary syndromes treated with ticagrelor	9.000000e-10
GCST010002_259	Refractive error	3.000000e-16
GCST010702_48	Subcortical volume (MOSTest)	6.000000e-10
GCST010703_289	Brain morphology (MOSTest)	6.000000e-15

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007007	ticagrelor measurement
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Other immune checkpoint proteins

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
abrine	increases expression	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Demecolcine	decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Nickel	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Urethane	increases expression	1
Valproic Acid	increases methylation	1
Vincristine	decreases expression	1
Gold Compounds	increases expression	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	increases expression	1
Lactic Acid	increases expression	1
Acrylamide	decreases expression	1

Cellosaurus cell lines

4 cell lines: 2 cancer cell line, 1 spontaneously immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7VF	Abcam Jurkat PVRIG KO	Cancer cell line	Male
CVCL_E6RK	Genomeditech CHO-K1 H_PVRIG(CD112R)	Spontaneously immortalized cell line	Female
CVCL_E6US	Genomeditech HEK-293 H_PVRIG(CD112R)	Transformed cell line	Female
CVCL_E6VY	Genomeditech Jurkat H_PVRIG(CD112R) Reporter	Cancer cell line	Male

Clinical trials (associated diseases)

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