PRRG4

Summary

PRRG4 (proline rich and Gla domain 4, HGNC:30799) is a protein-coding gene on chromosome 11p13, encoding Transmembrane gamma-carboxyglutamic acid protein 4 (Q9BZD6). May control axon guidance across the CNS.

Enables WW domain binding activity. Predicted to be involved in blood coagulation. Located in plasma membrane. Biomarker of cholangiocarcinoma.

Source: NCBI Gene 79056 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 28 total
• MANE Select transcript: NM_024081

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30799
Approved symbol	PRRG4
Name	proline rich and Gla domain 4
Location	11p13
Locus type	gene with protein product
Status	Approved
Aliases	TMG4
Ensembl gene	ENSG00000135378
Ensembl biotype	protein_coding
OMIM	611690
Entrez	79056

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000257836, ENST00000867854, ENST00000867855, ENST00000966885, ENST00000966886

RefSeq mRNA: 1 — MANE Select: NM_024081 NM_024081

CCDS: CCDS7881

Canonical transcript exons

ENST00000257836 — 6 exons

Exon	Start	End
ENSE00000918373	32830508	32830632
ENSE00000918374	32836658	32836821
ENSE00000918375	32838882	32838930
ENSE00000918376	32840107	32840239
ENSE00001004164	32829927	32830173
ENSE00001287840	32853296	32858120

Expression profiles

Bgee: expression breadth ubiquitous, 225 present calls, max score 97.77.

FANTOM5 (CAGE): breadth broad, TPM avg 3.8264 / max 130.9160, expressed in 797 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
113637	2.0362	368
113635	0.9945	394
113634	0.5980	307
113638	0.1122	71
113636	0.0856	48

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gingival epithelium	UBERON:0001949	97.77	gold quality
gingiva	UBERON:0001828	97.75	gold quality
esophagus squamous epithelium	UBERON:0006920	97.68	gold quality
penis	UBERON:0000989	96.75	gold quality
mammalian vulva	UBERON:0000997	95.87	gold quality
squamous epithelium	UBERON:0006914	95.19	gold quality
oral cavity	UBERON:0000167	95.10	gold quality
bronchial epithelial cell	CL:0002328	94.75	gold quality
epithelium of esophagus	UBERON:0001976	94.61	gold quality
palpebral conjunctiva	UBERON:0001812	94.33	gold quality
pharyngeal mucosa	UBERON:0000355	93.50	gold quality
upper leg skin	UBERON:0004262	92.56	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.50	gold quality
nipple	UBERON:0002030	92.23	gold quality
epithelium of bronchus	UBERON:0002031	91.41	gold quality
jejunal mucosa	UBERON:0000399	91.38	gold quality
bronchus	UBERON:0002185	91.01	gold quality
buccal mucosa cell	CL:0002336	90.74	gold quality
mucosa of sigmoid colon	UBERON:0004993	90.64	gold quality
colonic mucosa	UBERON:0000317	90.00	gold quality
skin of hip	UBERON:0001554	89.54	gold quality
nasal cavity mucosa	UBERON:0001826	89.43	gold quality
caput epididymis	UBERON:0004358	89.01	gold quality
nasal cavity epithelium	UBERON:0005384	88.81	gold quality
cervix epithelium	UBERON:0004801	88.22	gold quality
esophagus mucosa	UBERON:0002469	88.18	gold quality
seminal vesicle	UBERON:0000998	88.09	gold quality
renal medulla	UBERON:0000362	87.97	gold quality
lower esophagus mucosa	UBERON:0035834	87.89	gold quality
epithelium of nasopharynx	UBERON:0001951	87.42	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-89	no	68.66
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

214 targeting PRRG4, 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-3924	100.00	72.09	2394
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-12136	99.98	72.81	5713
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-5688	99.96	73.23	4504

Literature-anchored findings (GeneRIF, showing 4)

• Cellular localization and characterization of cytosolic binding partners for Gla domain-containing proteins PRRG4 and PRRG2. (PMID:23873930)
• the unique genotype identified in this study suggested that haploinsufficiencies of PAX6 or PRRG4 included in this region are candidate genes for severe developmental delay and autistic features characteristic of WAGR syndrome. (PMID:24357251)
• PRRG4 could re-localize hRobo1 from the cell surface, suggesting that PRRG4 is a functional homologue of Comm. Comm is required for axon guidance and synapse formation in the fly, so PRRG4 could contribute to the autistic symptoms of WAGR by disturbing either of these processes in the developing human brain. (PMID:28859078)
• PRRG4 promotes breast cancer metastasis through the recruitment of NEDD4 and downregulation of Robo1. (PMID:33037408)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	prrg4	ENSDARG00000030753
mus_musculus	Prrg4	ENSMUSG00000027171
rattus_norvegicus	Prrg4	ENSRNOG00000022710

Paralogs (3): PRRG3 (ENSG00000130032), PRRG1 (ENSG00000130962), OVCH2 (ENSG00000183378)

Protein

Protein identifiers

Transmembrane gamma-carboxyglutamic acid protein 4 — Q9BZD6 (reviewed: Q9BZD6)

Alternative names: Proline-rich gamma-carboxyglutamic acid protein 4

All UniProt accessions (2): A0A0S2Z5N9, Q9BZD6

UniProt curated annotations — full annotation on UniProt →

Function. May control axon guidance across the CNS. Prevents the delivery of ROBO1 at the cell surface and down-regulates its expression.

Subunit / interactions. Interacts (via cytoplasmic domain) with WW domain-containing proteins MAGI1, MAGI3, NEDD4, NEDD4L, WWTR1/TAZ and YAP1.

Subcellular location. Endoplasmic reticulum-Golgi intermediate compartment membrane. Cell membrane.

Tissue specificity. Widely expressed with highest levels in kidney.

Post-translational modifications. Gamma-carboxyglutamate residues are formed by vitamin K dependent carboxylation. These residues are essential for the binding of calcium.

Similarity. Belongs to the commissureless family.

RefSeq proteins (1): NP_076986* (*=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 (17 total): sequence variant 3, modified residue 2, mutagenesis site 2, topological domain 2, short sequence motif 2, signal peptide 1, propeptide 1, disulfide bond 1, chain 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BZD6-F1	67.04	0.14

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 (2): 163, 72

Disulfide bonds (1): 69–74

Mutagenesis-validated functional residues (2):

Position	Phenotype
189	reduced binding to magi1, magi3, nedd4, nedd4l, wwtr1 and yap1.
207	reduced binding to magi1. no effect on binding to magi3, nedd4, nedd4l, wwtr1 or yap1.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 169 (showing top): RACCACAR_AML_Q6, NFKB_Q6, GOBP_WOUND_HEALING, RICKMAN_METASTASIS_DN, CHARAFE_BREAST_CANCER_BASAL_VS_MESENCHYMAL_UP, BILD_E2F3_ONCOGENIC_SIGNATURE, TGIF_01, TGANTCA_AP1_C, GOBP_HEMOSTASIS, AML1_01, GOBP_REGULATION_OF_BODY_FLUID_LEVELS, MYB_Q5_01, LIU_SOX4_TARGETS_DN, CHARAFE_BREAST_CANCER_LUMINAL_VS_MESENCHYMAL_UP, ZHENG_BOUND_BY_FOXP3

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

GO Molecular Function (4): serine-type endopeptidase activity (GO:0004252), calcium ion binding (GO:0005509), WW domain binding (GO:0050699), protein binding (GO:0005515)

GO Cellular Component (5): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), membrane (GO:0016020), endoplasmic reticulum-Golgi intermediate compartment membrane (GO:0033116), extracellular region (GO:0005576)

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
protein domain specific binding	1
binding	1
membrane	1
cell periphery	1
endoplasmic reticulum-Golgi intermediate compartment	1
bounding membrane of organelle	1

Protein interactions and networks

STRING

514 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRRG4	CCDC73	Q6ZRK6	605
PRRG4	TCP11L1	Q9NUJ3	584
PRRG4	VNN1	O95497	572
PRRG4	CLEC4D	Q8WXI8	572
PRRG4	QSER1	Q2KHR3	561
PRRG4	ANXA3	P12429	507
PRRG4	SRC	P12931	493
PRRG4	DEPDC7	Q96QD5	476
PRRG4	TNFAIP6	P98066	446
PRRG4	SDR16C5	Q8N3Y7	441
PRRG4	UCMA	Q8WVF2	436
PRRG4	GGCX	P38435	431
PRRG4	EIF3M	Q7L2H7	427
PRRG4	NDFIP1	Q9BT67	421
PRRG4	RAB3GAP2	Q9H2M9	421

IntAct

54 interactions, top by confidence:

A	B	Type	Score
PRRG4	YAP1	psi-mi:“MI:0407”(direct interaction)	0.820
PRRG4	NEDD4	psi-mi:“MI:0407”(direct interaction)	0.820
PRRG4	NEDD4	psi-mi:“MI:0915”(physical association)	0.820
NEDD4	PRRG4	psi-mi:“MI:0407”(direct interaction)	0.820
YAP1	PRRG4	psi-mi:“MI:0407”(direct interaction)	0.820
PRRG4	YAP1	psi-mi:“MI:0915”(physical association)	0.820
PRRG4	NEDD4L	psi-mi:“MI:0407”(direct interaction)	0.660
PRRG4	NEDD4L	psi-mi:“MI:0915”(physical association)	0.660
PRRG4	WWTR1	psi-mi:“MI:0407”(direct interaction)	0.600
PRRG4	WWTR1	psi-mi:“MI:0915”(physical association)	0.600
PRRG4	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.590
PRRG4	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.540
PRRG4	MAGI3	psi-mi:“MI:0915”(physical association)	0.540
PRRG4	Magi1	psi-mi:“MI:0915”(physical association)	0.520
PRRG4	YAP1	psi-mi:“MI:0915”(physical association)	0.520
PRRG4	LYN	psi-mi:“MI:0407”(direct interaction)	0.440
PRRG4	OSTF1	psi-mi:“MI:0407”(direct interaction)	0.440
PRRG4	GRB2	psi-mi:“MI:0407”(direct interaction)	0.440
PRRG4	ARHGEF7	psi-mi:“MI:0407”(direct interaction)	0.440
PRRG4	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
PRRG4	WWP1	psi-mi:“MI:0407”(direct interaction)	0.440
PRRG4	HECW1	psi-mi:“MI:0407”(direct interaction)	0.440
PRRG4	ITCH	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (55): STXBP4 (Affinity Capture-MS), YAP1 (Affinity Capture-MS), YAP1 (Affinity Capture-MS), STXBP4 (Affinity Capture-MS), PRRG4 (Two-hybrid), PRRG4 (Two-hybrid), MAGI3 (Reconstituted Complex), YAP1 (Reconstituted Complex), WWTR1 (Reconstituted Complex), NEDD4L (Reconstituted Complex), NEDD4 (Reconstituted Complex), LYN (Reconstituted Complex), OSTF1 (Reconstituted Complex), GRB2 (Reconstituted Complex), ARHGEF7 (Reconstituted Complex)

ESM2 similar proteins: A0A1B0GRQ0, A0A1B0GSZ0, A0A1B0GVT2, A0A590UK83, A0PK05, A2VDU1, A2VE22, A4QNL6, A5D7B5, A5D992, O43609, O75324, P0DKX4, P29414, P61807, P61808, Q0VFM5, Q15053, Q16655, Q17Q87, Q1L0X2, Q2KIK3, Q2TBG9, Q3MHM8, Q498C7, Q4V921, Q58CU5, Q5RBD8, Q5RF07, Q5RGQ8, Q64448, Q6UWT2, Q80ZU4, Q8BGN6, Q8BUM6, Q8C3K5, Q8C817, Q8K1D8, Q8N6S5, Q91VT8

Diamond homologs: A6MFK7, A6MFK8, A7Z070, B5G6G5, O14668, O14669, O19045, O88947, P00734, P00735, P00740, P00741, P00742, P00743, P00744, P00745, P07224, P07225, P08709, P16293, P16294, P16296, P18292, P19221, P19540, P22457, P22891, P25155, P31394, P33587, P53813, P70375, P81428, P82807, P83370, P98118, P98139, Q08761, Q14393, Q19AZ8

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 35 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
FCERI mediated Ca+2 mobilization	5	57.6×	3e-06
Signaling by SCF-KIT	5	40.0×	1e-05
FCGR3A-mediated phagocytosis	6	36.2×	2e-06
PIP3 activates AKT signaling	5	10.8×	1e-03
Signaling by Receptor Tyrosine Kinases	5	8.3×	3e-03
Antigen processing: Ubiquitination & Proteasome degradation	5	6.0×	9e-03
Adaptive Immune System	6	5.8×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	6	74.3×	9e-08
cell surface receptor protein tyrosine kinase signaling pathway	5	25.6×	1e-04
adaptive immune response	7	17.4×	3e-05
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	6	13.8×	2e-04
ubiquitin-dependent protein catabolic process	5	10.9×	2e-03
protein ubiquitination	7	8.5×	6e-04
intracellular signal transduction	6	6.7×	4e-03
negative regulation of apoptotic process	6	6.1×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	15
Likely benign	3
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

750 predictions. Top by Δscore:

Variant	Effect	Δscore
11:32830506:A:AG	acceptor_gain	1.0000
11:32830507:G:GA	acceptor_gain	1.0000
11:32830507:GTTT:G	acceptor_gain	1.0000
11:32836656:A:AG	acceptor_gain	1.0000
11:32836657:G:GG	acceptor_gain	1.0000
11:32836657:GT:G	acceptor_gain	1.0000
11:32836786:G:GT	donor_gain	1.0000
11:32836818:AACGG:A	donor_loss	1.0000
11:32836819:ACGGT:A	donor_loss	1.0000
11:32836820:CGGT:C	donor_loss	1.0000
11:32836821:GGT:G	donor_loss	1.0000
11:32836822:G:GG	donor_gain	1.0000
11:32836823:T:G	donor_loss	1.0000
11:32840105:A:G	acceptor_gain	1.0000
11:32830171:CAGG:C	donor_loss	0.9900
11:32830172:AGGT:A	donor_loss	0.9900
11:32830173:GGTAC:G	donor_loss	0.9900
11:32830174:G:A	donor_loss	0.9900
11:32830175:T:A	donor_loss	0.9900
11:32830506:AGTTT:A	acceptor_gain	0.9900
11:32830507:GT:G	acceptor_gain	0.9900
11:32830507:GTT:G	acceptor_gain	0.9900
11:32830507:GTTTG:G	acceptor_gain	0.9900
11:32830630:AAGGT:A	donor_loss	0.9900
11:32830631:AGG:A	donor_loss	0.9900
11:32830632:GGT:G	donor_loss	0.9900
11:32830633:G:GA	donor_loss	0.9900
11:32830634:T:A	donor_loss	0.9900
11:32836657:GTGT:G	acceptor_gain	0.9900
11:32836814:A:G	donor_gain	0.9900

AlphaMissense

1456 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:32836759:T:A	C69S	0.989
11:32836760:G:C	C69S	0.989
11:32836774:T:A	C74S	0.988
11:32836775:G:C	C74S	0.988
11:32838893:G:C	W93C	0.980
11:32838893:G:T	W93C	0.980
11:32836775:G:A	C74Y	0.973
11:32836759:T:C	C69R	0.968
11:32838888:T:C	F92L	0.968
11:32838890:T:A	F92L	0.968
11:32838890:T:G	F92L	0.968
11:32836774:T:C	C74R	0.966
11:32836776:C:G	C74W	0.964
11:32836760:G:A	C69Y	0.963
11:32836761:C:G	C69W	0.963
11:32836775:G:T	C74F	0.959
11:32836760:G:T	C69F	0.958
11:32836789:G:C	A79P	0.953
11:32836758:G:C	E68D	0.948
11:32836758:G:T	E68D	0.948
11:32838891:T:A	W93R	0.935
11:32838891:T:C	W93R	0.935
11:32836660:T:C	F36L	0.933
11:32836662:T:A	F36L	0.933
11:32836662:T:G	F36L	0.933
11:32836787:A:G	E78G	0.933
11:32838889:T:G	F92C	0.932
11:32840163:G:A	G125R	0.929
11:32840163:G:C	G125R	0.929
11:32836755:A:C	R67S	0.926

dbSNP variants (sampled 300 via entrez): RS1000025177 (11:32845946 C>T), RS1000068152 (11:32831198 T>C), RS1000264218 (11:32837651 G>A), RS1000378397 (11:32830728 G>A), RS1000471726 (11:32830433 G>A,T), RS1000534737 (11:32853073 C>T), RS1000546434 (11:32839805 T>A), RS1000808321 (11:32831898 A>G), RS1000909202 (11:32838500 T>C), RS1001000602 (11:32839446 G>A,C), RS1001013723 (11:32853802 T>C), RS1001245907 (11:32846298 T>C), RS1001320796 (11:32838709 T>C), RS1001456218 (11:32858583 A>G), RS1001506300 (11:32831519 C>A,G,T)

Disease associations

OMIM: gene MIM:611690 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000490_4	Parkinson’s disease (age of onset)	5.000000e-07
GCST90002400_634	Plateletcrit	8.000000e-18
GCST90002402_344	Platelet count	8.000000e-13

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset
EFO:0007985	platelet crit
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases methylation	4
sodium arsenite	decreases expression	2
entinostat	affects cotreatment, increases expression	2
Acetaminophen	decreases expression, affects response to substance	2
Ethanol	increases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
trichostatin A	increases expression	1
sulforaphane	decreases expression	1
nickel sulfate	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
14-deoxy-11,12-didehydroandrographolide	decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
incobotulinumtoxinA	decreases expression	1
NSC 689534	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Zoledronic Acid	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Copper	affects binding, decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Estradiol	decreases expression, affects cotreatment	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1

Clinical trials (associated diseases)

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