PRRG2

Summary

PRRG2 (proline rich and Gla domain 2, HGNC:9470) is a protein-coding gene on chromosome 19q13.33, encoding Transmembrane gamma-carboxyglutamic acid protein 2 (O14669). Vitamin K-dependent protein that is essential for calcium homeostasis and haemostasis.

The protein encoded by this gene is a single-pass transmembrane protein containing an N-terminal gamma-carboxyglutamic acid (Gla) domain and tandem Pro/Leu-Pro-Xaa-Tyr (PY) motifs at its C-terminal end. The Gla domain is exposed on the cell surface while the PY motifs are cytoplasmic. The PY motifs of the encoded protein have been shown to interact with YAP1, a WW domain-containing protein. Therefore, it is thought that the encoded protein may be part of a signal transduction pathway. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 5639 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 41 total
• MANE Select transcript: NM_000951

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9470
Approved symbol	PRRG2
Name	proline rich and Gla domain 2
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	PRGP2
Ensembl gene	ENSG00000126460
Ensembl biotype	protein_coding
OMIM	604429
Entrez	5639

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000246794, ENST00000543867, ENST00000596700, ENST00000596877, ENST00000597121, ENST00000874361, ENST00000874362, ENST00000874363, ENST00000874364, ENST00000874365, ENST00000874366, ENST00000874367, ENST00000967638

RefSeq mRNA: 2 — MANE Select: NM_000951 NM_000951, NM_001316335

CCDS: CCDS12773

Canonical transcript exons

ENST00000246794 — 7 exons

Exon	Start	End
ENSE00000864482	49583542	49583717
ENSE00001192563	49583207	49583304
ENSE00001626530	49581316	49581481
ENSE00003014884	49590371	49591004
ENSE00003562774	49583913	49583952
ENSE00003587943	49588497	49588632
ENSE00003638314	49589900	49590052

Expression profiles

Bgee: expression breadth ubiquitous, 174 present calls, max score 87.65.

FANTOM5 (CAGE): breadth broad, TPM avg 1.3068 / max 31.4959, expressed in 379 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
177023	0.7790	302
177024	0.5277	290

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	87.65	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.45	silver quality
islet of Langerhans	UBERON:0000006	86.73	gold quality
mucosa of transverse colon	UBERON:0004991	86.02	gold quality
right lobe of thyroid gland	UBERON:0001119	83.77	gold quality
body of pancreas	UBERON:0001150	83.60	gold quality
left lobe of thyroid gland	UBERON:0001120	83.26	gold quality
pancreas	UBERON:0001264	82.83	gold quality
adenohypophysis	UBERON:0002196	82.20	gold quality
esophagus mucosa	UBERON:0002469	81.81	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	81.45	gold quality
pituitary gland	UBERON:0000007	81.32	gold quality
thyroid gland	UBERON:0002046	81.27	gold quality
metanephros cortex	UBERON:0010533	80.99	gold quality
skin of abdomen	UBERON:0001416	80.77	gold quality
skin of leg	UBERON:0001511	80.54	gold quality
minor salivary gland	UBERON:0001830	80.53	gold quality
rectum	UBERON:0001052	79.61	gold quality
saliva-secreting gland	UBERON:0001044	79.04	gold quality
body of stomach	UBERON:0001161	77.43	gold quality
mouth mucosa	UBERON:0003729	77.12	gold quality
zone of skin	UBERON:0000014	76.97	gold quality
transverse colon	UBERON:0001157	75.23	gold quality
adult mammalian kidney	UBERON:0000082	75.13	gold quality
duodenum	UBERON:0002114	74.40	gold quality
stomach	UBERON:0000945	74.17	gold quality
right lobe of liver	UBERON:0001114	73.99	gold quality
gall bladder	UBERON:0002110	73.64	gold quality
small intestine Peyer’s patch	UBERON:0003454	72.80	gold quality
ileal mucosa	UBERON:0000331	72.68	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.31

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting PRRG2, 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-4795-3P	100.00	74.62	4024
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-6848-3P	99.64	66.49	885
HSA-MIR-6843-3P	99.26	66.42	915
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-210-5P	98.57	64.37	832
HSA-MIR-4731-3P	98.56	68.60	1860
HSA-MIR-10226	98.25	66.50	811
HSA-MIR-6742-3P	97.95	64.50	1490
HSA-MIR-4286	97.20	64.37	1587
HSA-MIR-6846-3P	94.80	65.19	389

Literature-anchored findings (GeneRIF, showing 2)

• PRGP2 may be involved in a signal transduction pathway, the impairment of which may be an unintended consequence of warfarin therapy (PMID:17502622)
• Cellular localization and characterization of cytosolic binding partners for Gla domain-containing proteins PRRG4 and PRRG2. (PMID:23873930)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	c1r	ENSDARG00000100248
danio_rerio	c1s.1	ENSDARG00000100599
mus_musculus	Prrg2	ENSMUSG00000007837
rattus_norvegicus	Prrg2	ENSRNOG00000020517

Paralogs (2): MASP2 (ENSG00000009724), MASP1 (ENSG00000127241)

Protein

Protein identifiers

Transmembrane gamma-carboxyglutamic acid protein 2 — O14669 (reviewed: O14669)

Alternative names: Proline-rich gamma-carboxyglutamic acid protein 2

All UniProt accessions (3): O14669, M0QXL9, M0QZA1

UniProt curated annotations — full annotation on UniProt →

Function. Vitamin K-dependent protein that is essential for calcium homeostasis and haemostasis.

Subunit / interactions. Interacts with NEDD4. Interacts (via cytoplasmic domain) with transcriptional coactivator YAP1.

Subcellular location. Cell membrane.

Tissue specificity. Widely expressed with highest levels in kidney. Also highly expressed in the thyroid.

Post-translational modifications. Carboxylated by vitamin K-dependent GGCX to form gamma-carboxyglutamate; these residues are essential for the binding of calcium.

RefSeq proteins (2): NP_000942, NP_001303264 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000294	GLA_domain	Domain
IPR017857	Coagulation_fac-like_Gla_dom	Homologous_superfamily
IPR035972	GLA-like_dom_SF	Homologous_superfamily
IPR050442	Peptidase_S1_coag_factors	Family

Pfam: PF00594

UniProt features (30 total): mutagenesis site 11, sequence variant 2, strand 2, topological domain 2, short sequence motif 2, signal peptide 1, propeptide 1, compositionally biased region 1, modified residue 1, disulfide bond 1, chain 1, turn 1, helix 1, transmembrane region 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9BVP	ELECTRON MICROSCOPY	3.3
9BVQ	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14669-F1	72.84	0.28

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): 70

Disulfide bonds (1): 67–72

Mutagenesis-validated functional residues (11):

Position	Phenotype
31	abolishes gamma-carboxylation.
49	impairs propeptide removal.
173	no effect on interaction with yap1.
174	no effect on interaction with yap1.
175	abolishes interaction with yap1.
176	abolishes interaction with yap1.
177	abolishes interaction with yap1.
178	abolishes interaction with yap1.
179	significantly impairs interaction with yap1.
180	significantly impairs interaction with yap1.
195	significantly impairs interaction with yap1.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 115 (showing top): AREB6_01, CAGCTG_AP4_Q5, GOBP_WOUND_HEALING, BROWNE_HCMV_INFECTION_48HR_DN, CYTAGCAAY_UNKNOWN, SANSOM_APC_TARGETS_DN, GOBP_HEMOSTASIS, GOBP_REGULATION_OF_BODY_FLUID_LEVELS, GOBP_PROTEOLYSIS, GOMF_PEPTIDASE_ACTIVITY, MZF1_02, HEB_Q6, HOFFMANN_LARGE_TO_SMALL_PRE_BII_LYMPHOCYTE_DN, MIKKELSEN_MCV6_LCP_WITH_H3K4ME3, MIKKELSEN_MEF_LCP_WITH_H3K4ME3

GO Biological Process (2): proteolysis (GO:0006508), blood coagulation (GO:0007596)

GO Molecular Function (3): serine-type endopeptidase activity (GO:0004252), calcium ion binding (GO:0005509), protein binding (GO:0005515)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), extracellular region (GO:0005576), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein metabolic process	1
hemostasis	1
wound healing	1
coagulation	1
endopeptidase activity	1
serine-type peptidase activity	1
metal ion binding	1
binding	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

374 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRRG2	GGCX	P38435	873
PRRG2	YAP1	P46937	861
PRRG2	PRR12	Q9ULL5	598
PRRG2	NOSIP	Q9Y314	523
PRRG2	UCMA	Q8WVF2	521
PRRG2	LATS1	O95835	520
PRRG2	RCN3	Q96D15	495
PRRG2	LRRC20	Q8TCA0	491
PRRG2	TP53AIP1	Q9HCN2	490
PRRG2	ERBB4	Q15303	483
PRRG2	NEDD4	P46934	475
PRRG2	LATS2	Q9NRM7	424
PRRG2	BCL2L12	Q9HB09	420
PRRG2	SHISA4	Q96DD7	409
PRRG2	CSN1S1	P47710	408

IntAct

13 interactions, top by confidence:

A	B	Type	Score
PRRG2	YAP1	psi-mi:“MI:0915”(physical association)	0.660
YAP1	PRRG2	psi-mi:“MI:0407”(direct interaction)	0.660
CRK	PRRG2	psi-mi:“MI:0915”(physical association)	0.490
PRRG2	NEDD4L	psi-mi:“MI:0915”(physical association)	0.400
PRRG2	WWTR1	psi-mi:“MI:0915”(physical association)	0.400
PRRG2	YAP1	psi-mi:“MI:0915”(physical association)	0.400
PRRG2	Magi1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (11): FATE1 (Two-hybrid), PRRG2 (Reconstituted Complex), PRRG2 (Two-hybrid), PRRG2 (Two-hybrid), FATE1 (Two-hybrid), FAM221A (Two-hybrid), NEDD4L (Reconstituted Complex), Magi1 (Reconstituted Complex), YAP1 (Reconstituted Complex), WWTR1 (Reconstituted Complex), PRRG2 (Affinity Capture-Luminescence)

ESM2 similar proteins: A0A1B0GU29, A6NLX4, A6QNY1, A9CBA0, B7ZWI3, O14669, O88472, P14784, P16297, P25918, P26896, Q0VFL4, Q13651, Q32M26, Q38J84, Q38J85, Q3SYS8, Q58CT8, Q5BK39, Q5EAA5, Q5HZE8, Q5NCP0, Q5RCL0, Q64322, Q68DV7, Q6AXS2, Q6AXU5, Q6NUJ2, Q6UWV7, Q86UW2, Q8BHB3, Q8BLR5, Q8BSU2, Q8C353, Q8C708, Q8K1T1, Q8MII8, Q8N6P7, Q8NET5, Q8R182

Diamond homologs: A6MFK7, A6MFK8, A7Z070, B5G6G5, O14668, O14669, O19045, O88947, P00734, P00735, P00740, P00741, P00742, P00743, P00744, P00745, P04070, P07224, P07225, P08709, P16293, P16294, P16296, P18292, P19221, P19540, P22457, P22891, P25155, P31394, P33587, P53813, P70375, P81428, P82807, P83370, P98118, P98139, Q08761, Q14393

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	23
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1193 predictions. Top by Δscore:

Variant	Effect	Δscore
19:49581482:G:C	donor_loss	1.0000
19:49583896:A:AG	acceptor_gain	1.0000
19:49583897:C:G	acceptor_gain	1.0000
19:49588631:GA:G	donor_gain	1.0000
19:49588633:G:GG	donor_gain	1.0000
19:49581477:GGCAG:G	donor_gain	0.9900
19:49581478:GCAG:G	donor_gain	0.9900
19:49581478:GCAGG:G	donor_gain	0.9900
19:49581482:G:GG	donor_gain	0.9900
19:49581483:T:A	donor_loss	0.9900
19:49583527:T:G	acceptor_gain	0.9900
19:49583533:T:A	acceptor_gain	0.9900
19:49583534:G:A	acceptor_gain	0.9900
19:49583690:G:GT	donor_gain	0.9900
19:49588486:C:G	acceptor_gain	0.9900
19:49588491:CTGCA:C	acceptor_loss	0.9900
19:49588492:TGCA:T	acceptor_loss	0.9900
19:49588493:GCA:G	acceptor_loss	0.9900
19:49588494:CAGG:C	acceptor_loss	0.9900
19:49588495:AG:A	acceptor_gain	0.9900
19:49588495:AGGG:A	acceptor_loss	0.9900
19:49588496:GG:G	acceptor_gain	0.9900
19:49588496:GGGC:G	acceptor_gain	0.9900
19:49588628:CAAGA:C	donor_gain	0.9900
19:49588629:AAGA:A	donor_gain	0.9900
19:49588630:AGA:A	donor_gain	0.9900
19:49588631:GAG:G	donor_gain	0.9900
19:49588632:AG:A	donor_loss	0.9900
19:49588633:G:C	donor_loss	0.9900
19:49588634:T:A	donor_loss	0.9900

AlphaMissense

1280 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:49583924:G:C	W91C	0.996
19:49583924:G:T	W91C	0.996
19:49583655:T:A	C67S	0.994
19:49583656:G:C	C67S	0.994
19:49583670:T:A	C72S	0.994
19:49583671:G:C	C72S	0.994
19:49583650:G:C	R65P	0.991
19:49583655:T:C	C67R	0.990
19:49583670:T:C	C72R	0.989
19:49583919:T:C	F90L	0.988
19:49583921:T:A	F90L	0.988
19:49583921:T:G	F90L	0.988
19:49583657:T:G	C67W	0.987
19:49583672:T:G	C72W	0.987
19:49583920:T:C	F90S	0.984
19:49583920:T:G	F90C	0.984
19:49583671:G:A	C72Y	0.982
19:49583656:G:A	C67Y	0.980
19:49583654:G:C	E66D	0.978
19:49583654:G:T	E66D	0.978
19:49583685:G:C	A77P	0.974
19:49588544:G:C	G117R	0.973
19:49583671:G:T	C72F	0.972
19:49583922:T:A	W91R	0.970
19:49583922:T:C	W91R	0.970
19:49583653:A:T	E66V	0.969
19:49583678:G:C	W74C	0.969
19:49583678:G:T	W74C	0.969
19:49583656:G:T	C67F	0.968
19:49583923:G:C	W91S	0.966

dbSNP variants (sampled 300 via entrez): RS1000082702 (19:49590226 G>A), RS1000261389 (19:49586299 G>A,C), RS1000332089 (19:49580610 C>T), RS1000861328 (19:49589281 C>T), RS1000883726 (19:49578734 C>T), RS1001090826 (19:49590870 G>C), RS1001490907 (19:49588912 C>T), RS1001810395 (19:49579922 C>G), RS1001827679 (19:49587876 C>T), RS1002104443 (19:49585935 C>T), RS1002157983 (19:49590342 G>A), RS1002169525 (19:49590209 G>C), RS1002384241 (19:49581888 C>T), RS1002388407 (19:49582250 A>AAC), RS1002655230 (19:49584642 T>G)

Disease associations

OMIM: gene MIM:604429 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002539_91	Schizophrenia	5.000000e-08
GCST004601_194	Red blood cell count	8.000000e-12
GCST004604_44	Hematocrit	1.000000e-10
GCST006803_99	Schizophrenia	4.000000e-11
GCST007201_263	Schizophrenia	2.000000e-08
GCST007201_404	Schizophrenia	7.000000e-07
GCST010083_298	Hemoglobin levels	3.000000e-13
GCST011368_5	Iron status biomarkers (total iron binding capacity)	2.000000e-14
GCST90002383_293	Hematocrit	1.000000e-18
GCST90002384_467	Hemoglobin	4.000000e-21
GCST90002403_308	Red blood cell count	1.000000e-22

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004305	erythrocyte count
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0006334	total iron binding capacity

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	increases abundance, increases expression	2
CGP 52608	increases reaction, affects binding	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	increases expression, increases abundance	1
Cisplatin	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Phthalic Acids	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	1
Thiram	decreases expression	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

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