PROZ

Summary

PROZ (protein Z, vitamin K dependent plasma glycoprotein, HGNC:9460) is a protein-coding gene on chromosome 13q34, encoding Vitamin K-dependent protein Z (P22891). Appears to assist hemostasis by binding thrombin and promoting its association with phospholipid vesicles.

This gene encodes a liver vitamin K-dependent glycoprotein that is synthesized in the liver and secreted into the plasma. The encoded protein plays a role in regulating blood coagulation by complexing with protein Z-dependent protease inhibitor to directly inhibit activated factor X at the phospholipid surface. Deficiencies in this protein are associated with an increased risk of ischemic arterial diseases and fetal loss. Mutations in this gene are the cause of protein Z deficiency. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 8858 — RefSeq curated summary.

At a glance

• Gene–disease (curated): protein Z deficiency (Limited, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 50 total
• GTEx eGene: eQTL in 40 tissues, sQTL in 2 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.86 (unconstrained)
• MANE Select transcript: NM_003891
• Notable: 50 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9460
Approved symbol	PROZ
Name	protein Z, vitamin K dependent plasma glycoprotein
Location	13q34
Locus type	gene with protein product
Status	Approved
Aliases	PZ
Ensembl gene	ENSG00000126231
Ensembl biotype	protein_coding
OMIM	176895
Entrez	8858

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 19 protein_coding, 8 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000375547

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 5: 1

ENST00000375547, ENST00000342783, ENST00000493630, ENST00000906454, ENST00000906455, ENST00000906456, ENST00000906457, ENST00000906458, ENST00000906459, ENST00000906460, ENST00000906461, ENST00000906462, ENST00000906463, ENST00000906464, ENST00000906465, ENST00000906466, ENST00000906467, ENST00001005410, ENST00001005412, ENST00001005413, ENST00001005416, ENST00001005417, ENST00001005419, ENST00001005420, ENST00001005422, ENST00001109760, ENST00001120152, ENST00001131435

RefSeq mRNA: 2 — MANE Select: NM_003891 NM_001256134, NM_003891

CCDS: CCDS58300, CCDS9531

Canonical transcript exons

ENST00000375547 — 8 exons

Exon	Start	End
ENSE00000862541	113160014	113160177
ENSE00000862544	113160948	113160972
ENSE00000862547	113163009	113163122
ENSE00000862551	113164513	113164644
ENSE00000862556	113170413	113170530
ENSE00000862560	113171594	113172386
ENSE00003641744	113165053	113165120
ENSE00003842625	113158648	113158730

Expression profiles

Bgee: expression breadth ubiquitous, 155 present calls, max score 96.35.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2133 / max 87.1634, expressed in 25 samples.

Highest expression (Bgee): lobe of liver, liver, adult mammalian kidney, nephron tubule, kidney epithelium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PROZ is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 40 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 42 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	eqtl	2.1e-50	+0.70	13:113174098:C:T
Colon Transverse	eqtl	7.9e-39	+0.68	13:113174098:C:T
Spleen	eqtl	9.8e-30	+0.88	13:113168167:A:G
Stomach	eqtl	6.4e-29	-0.71	13:113167116:C:T
Testis	eqtl	3.5e-28	+0.60	13:113174098:C:T
Lung	eqtl	1.2e-26	+0.58	13:113192300:C:T
Pancreas	eqtl	3.8e-26	+0.77	13:113168167:A:G
Artery Tibial	eqtl	4.6e-25	+0.60	13:113167821:TCTTG:T
Whole Blood	eqtl	5.6e-25	+0.51	13:113182205:C:T
Cells Cultured fibroblasts	eqtl	2.8e-24	+0.59	13:113175036:C:T
Esophagus Mucosa	eqtl	4.9e-23	+0.58	13:113175036:C:T
Prostate	eqtl	5.3e-23	+0.65	13:113175036:C:T
Brain Cerebellum	eqtl	7.8e-23	+0.84	13:113174098:C:T
Pituitary	eqtl	2.7e-22	+0.66	13:113153960:C:G
Adipose Visceral Omentum	eqtl	9.2e-22	+0.63	13:113175036:C:T
Nerve Tibial	eqtl	1.1e-21	+0.58	13:113174098:C:T
Brain Cerebellar Hemisphere	eqtl	3.8e-20	-0.69	13:113175867:C:T
Skin Not Sun Exposed Suprapubic	eqtl	6.0e-19	+0.53	13:113174098:C:T
Adipose Subcutaneous	eqtl	3.3e-18	+0.48	13:113168167:A:G
Liver	eqtl	4.8e-18	+0.55	13:113146308:T:C

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
136202	0.1382	20
136201	0.0545	13
136203	0.0206	1

Top tissues by expression

showing 100 of 291 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	96.35	gold quality
liver	UBERON:0002107	89.73	gold quality
adult mammalian kidney	UBERON:0000082	77.21	gold quality
nephron tubule	UBERON:0001231	75.55	silver quality
kidney epithelium	UBERON:0004819	70.97	silver quality
kidney	UBERON:0002113	70.69	gold quality
renal glomerulus	UBERON:0000074	69.29	silver quality
pancreatic ductal cell	CL:0002079	68.61	silver quality
metanephric glomerulus	UBERON:0004736	68.32	silver quality
cortex of kidney	UBERON:0001225	67.98	gold quality
mucosa of transverse colon	UBERON:0004991	67.78	gold quality
right testis	UBERON:0004534	65.82	gold quality
cerebellar hemisphere	UBERON:0002245	65.68	gold quality
right hemisphere of cerebellum	UBERON:0014890	65.38	gold quality
pituitary gland	UBERON:0000007	65.35	gold quality
cerebellar cortex	UBERON:0002129	65.27	gold quality
parotid gland	UBERON:0001831	64.41	gold quality
adenohypophysis	UBERON:0002196	64.25	gold quality
left testis	UBERON:0004533	64.25	gold quality
lower esophagus mucosa	UBERON:0035834	63.59	gold quality
metanephros	UBERON:0000081	63.40	gold quality
cerebellum	UBERON:0002037	63.20	gold quality
tibialis anterior	UBERON:0001385	61.89	silver quality
testis	UBERON:0000473	61.61	gold quality
metanephros cortex	UBERON:0010533	61.53	gold quality
body of pancreas	UBERON:0001150	60.16	gold quality
body of stomach	UBERON:0001161	59.34	gold quality
adult organism	UBERON:0007023	55.76	gold quality
ileal mucosa	UBERON:0000331	55.68	silver quality
granulocyte	CL:0000094	55.59	gold quality
stomach	UBERON:0000945	55.55	gold quality
spleen	UBERON:0002106	54.79	gold quality
fundus of stomach	UBERON:0001160	54.37	gold quality
vermiform appendix	UBERON:0001154	54.18	gold quality
rectum	UBERON:0001052	54.14	gold quality
right uterine tube	UBERON:0001302	54.09	gold quality
hindlimb stylopod muscle	UBERON:0004252	53.88	gold quality
small intestine Peyer’s patch	UBERON:0003454	53.85	gold quality
pancreas	UBERON:0001264	53.56	gold quality
upper leg skin	UBERON:0004262	53.52	silver quality
caecum	UBERON:0001153	53.04	gold quality
epithelial cell of pancreas	CL:0000083	52.69	gold quality
lymph node	UBERON:0000029	52.53	gold quality
right adrenal gland	UBERON:0001233	52.49	gold quality
adrenal tissue	UBERON:0018303	52.30	gold quality
left adrenal gland	UBERON:0001234	52.15	gold quality
left uterine tube	UBERON:0001303	52.00	gold quality
right adrenal gland cortex	UBERON:0035827	51.98	gold quality
small intestine	UBERON:0002108	51.95	gold quality
nasal cavity epithelium	UBERON:0005384	51.94	gold quality
transverse colon	UBERON:0001157	51.75	gold quality
left adrenal gland cortex	UBERON:0035825	51.49	gold quality
saliva-secreting gland	UBERON:0001044	51.34	gold quality
adrenal gland	UBERON:0002369	51.34	gold quality
deltoid	UBERON:0001476	51.32	gold quality
quadriceps femoris	UBERON:0001377	50.96	gold quality
blood	UBERON:0000178	50.86	gold quality
right lobe of thyroid gland	UBERON:0001119	50.83	gold quality
adrenal cortex	UBERON:0001235	50.78	gold quality
right coronary artery	UBERON:0001625	50.77	gold quality
smooth muscle tissue	UBERON:0001135	50.76	gold quality
muscle layer of sigmoid colon	UBERON:0035805	50.50	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
minor salivary gland	UBERON:0001830	50.29	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
right frontal lobe	UBERON:0002810	50.12	gold quality
prostate gland	UBERON:0002367	50.02	gold quality
intestine	UBERON:0000160	49.86	gold quality
vastus lateralis	UBERON:0001379	49.85	gold quality
thymus	UBERON:0002370	49.79	gold quality
Brodmann (1909) area 9	UBERON:0013540	49.67	gold quality
colon	UBERON:0001155	49.40	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
large intestine	UBERON:0000059	49.18	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
mouth mucosa	UBERON:0003729	49.14	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	49.04	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
heart left ventricle	UBERON:0002084	48.80	gold quality
duodenum	UBERON:0002114	48.73	gold quality
oviduct epithelium	UBERON:0004804	48.72	gold quality
oocyte	CL:0000023	48.66	gold quality
sigmoid colon	UBERON:0001159	48.63	gold quality
descending thoracic aorta	UBERON:0002345	48.60	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
lower esophagus muscularis layer	UBERON:0035833	48.55	gold quality
cardiac ventricle	UBERON:0002082	48.51	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
lower esophagus	UBERON:0013473	48.42	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
fallopian tube	UBERON:0003889	48.10	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.09

HPA expression

RNA tissue specificity: Tissue enriched

30 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	48.8	medium
Kidney	tissue	13.4	not detected
Pituitary gland	tissue	1.2
Choroid plexus	tissue	1.2
Retrosplenial cortex	tissue	1.1
Putamen	tissue	1.0
Postcentral gyrus	tissue	1.0
Nucleus accumbens	tissue	0.8
Testis	tissue	0.7	not detected
Medulla oblongata	tissue	0.6
Hippocampus	tissue	0.6	not detected
Skin 1	tissue	0.5	not detected
Substantia nigra	tissue	0.5
Locus coeruleus	tissue	0.5
Pancreas	tissue	0.3	not detected
Spinal cord	tissue	0.3
Adrenal gland	tissue	0.3	not detected
Appendix	tissue	0.3	not detected
Lymph node	tissue	0.2	not detected
Stomach 1	tissue	0.2	not detected
Salivary gland	tissue	0.2	not detected
Duodenum	tissue	0.2	not detected
Heart muscle	tissue	0.1	not detected
Retina	tissue	0.1
Vagina	tissue	0.1	not detected
Colon	tissue	0.1	not detected
Spleen	tissue	0.1	not detected
Small intestine	tissue	0.1	not detected
Gallbladder	tissue	0.1	not detected
Bone marrow	tissue	0.1	not detected

Brain sub-regions (HPA Brain Atlas): detected in 184; highest nTPM — Flocculonodular lobe (2.7), Vermis (2.6), Cerebellar cortex (2.4), Parietal operculum (1.4), Precentral gyrus (1.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF4A, SP1

miRNA regulators (miRDB)

Targeting PROZ by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

18 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-3660	99.68	67.33	1149
HSA-MIR-4526	99.68	67.07	1136
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-3972	97.19	66.46	808
HSA-MIR-3974	96.56	66.22	928
HSA-MIR-423-3P	95.99	67.75	62
HSA-MIR-4513	95.04	67.06	727
HSA-MIR-6855-3P	95.04	66.57	725

Functional genomics

gnomAD constraint: pLI 1.96e-18, LOEUF 1.86, missense Z -0.242 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000375547 — one region, missense o/e 1.02.

Literature-anchored findings (GeneRIF, showing 40)

• Weak regulation of protein Z biosynthesis by inflammatory cytokines indicates that it is not a negative acute-phase protein. Plasma PZ concentration is genetically controlled. (PMID:11858503)
• case control studies in humans indicating that diminution of protein Z in factor V Leiden patients aggravates thromboembolic risk (PMID:12297123)
• Low plasma protein Z values were significantly associated with ischemic stroke except in diabetic subjects and females (PMID:12490280)
• enhanced immune-complex formation with protein Z may play a role in unexplained embryo losses (PMID:12623836)
• Blood levels of protein Z measured within 7 days of acute stroke were significantly higher in cases than in controls (geometric mean, 1.46 versus 1.16 microg/mL; P<0.0001, consistent with its importance in ischemic stroke or as an acute phase reactant (PMID:12970515)
• There is a positive correlation between the disease duration and protein Z levels in patients with Behcet’s disease (PMID:14507116)
• PZ levels below 565 ng/mL were associated with ACS (PMID:14652653)
• The A allele of an intron F polymorphism of the PZ gene appears to be a novel protective genetic marker for the risk of cerebral ischemia in young adults. In the context of juvenile stroke, high PZ plasma levels may represent a prothrombotic condition (PMID:14671240)
• protein Z deficiency could be also a risk factor for acute coronary syndromes, early fetal losses, and increased the arterial risk in antiphospholipid syndrome–REVIEW (PMID:15314579)
• Coexpression of E30Q with wild-type protein Z interfered with the secretion of the wild type (PMID:15626740)
• decreased PZ and PS levels are additional risk factors for adverse pregnancy outcome (PMID:15748239)
• data show a progressive increase in protein Z levels with gestational age in normal pregnancies and a return to normal levels around 6 to 12 weeks postpartum (PMID:15841316)
• protein Z may have a role in development of ischemic stroke as shown in polymorphism analysis (PMID:15879328)
• data does not support the hypothesis that protein Z is prothrombotic and the 79A allele is protective for ischemic stroke [letter] (PMID:16120837)
• case control studies indicate that low protein Z level may be another risk factor for retinal vessel occlusion in patients without traditional risk factors for these disorders (PMID:16191090)
• rare alleles of polymorphisms encoding the protein z gene are not significantly associated with ACS (PMID:16807661)
• Linkage analysis for three coagulation factors clustering on chromosome 13q34: factor VII, factor X and protein Z. (PMID:17403098)
• proposed structural model (PMID:17456189)
• A high rate of protein Z deficiency is observed in patients with preeclampsia and fetal demise. (PMID:17701666)
• HNF-4alpha plays a crucial role in human PZ gene expression in hepatocytic cells, and Sp1 is also important (PMID:17958743)
• association between low protein Z levels and the occurrence of PAD. (PMID:18000618)
• The isolated presence of the PZ intron F 79A allele as well as the combination with known thrombophilic risk factors was protective against RPL between the 8th and 12th weeks of gestation. (PMID:18177644)
• Protein Z levels were reduced in patients with chronic kidney disease, and not elevated in patients on haemodialysis (PMID:18180611)
• Intron F G79A polymorphism of PZ gene does not contribute to meaningful diagnostic investigation of thrombophilia in cancer patients (PMID:18246466)
• G79A polymorphism of the PZ gene was shown to be a new independent risk factor for cerebral venous thrombosis (PMID:18677630)
• The median maternal plasma protein Z concentration was significantly lower in patients with pyelonephritis during pregnancy than in patients with normal pregnancies. (PMID:18828054)
• Low PZ levels, but not intron F G79A polymorphism, are associated with unexplained pregnancy loss. (PMID:19026439)
• the ATG haplotype of the protein Zgene is a genetic marker for symptomatic stroke/thromboembolism in white German children (PMID:19050305)
• The frequency of intron F G79A polymorphism of protein Z gene was higher in patients than controls, and carrying 79 AA genotype could be a risk factor for severe sepsis and septic shock. (PMID:19124455)
• Haplotypic or genotypic combinations of three protein Z polymorphisms influence protein Z plasma level. (PMID:19132212)
• Protein Z g-42a variant and the risk of pregnancy-related venous thromboembolism in a cohort of Italian patients. (PMID:19185907)
• the difference observed in secretion patterns of protein Z and factor X was mainly based on the structure of their gamma-carboxyglutamic acid domains. (PMID:19188667)
• plasma level is not a key player in the pathophysiology of premature coronary artery disease; rare genotypes of PZ gene were found to be associated with premature coronary artery disease (PMID:19572077)
• The distribution of allele and genotype frequencies of Protein Z A-13G and G79A polymorphisms did not differ significantly between Behcets disease patients and controls; no associations between thrombotic events protein Z gene polymorphisms (PMID:19796528)
• PROTEIN A AND PZI WERE FOUND IN KIDNEY TUBULES BY IMMUNOHISTOCHEMISTRY (PMID:20024489)
• Results of this meta-analysis are consistent with a role for protein Z deficiency in thrombotic diseases, including arterial thrombosis, pregnancy complications and venous thromboembolism. (PMID:20076855)
• Premature newborns suffering from respiratory distress syndrome showed decreased serum protein Z levels than normal preterm control newborns with further increase in its pattern after recovery. (PMID:20180321)
• the roles of PZ plasma level and PZ gene polymorphisms remain debated with conflicting results in arterial, venous, or placental thrombosis (PMID:20416992)
• Data show that mutation of four ZPI contact residues eliminated PZ binding and membrane-dependent PZ acceleration of fXa inhibition. (PMID:20427285)
• Low PZ levels are associated with the pathobiology of HELLP syndrome. (PMID:20460354)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	proza	ENSDARG00000037783
danio_rerio	prozb	ENSDARG00000076900
mus_musculus	Proz	ENSMUSG00000031445
rattus_norvegicus	Proz	ENSRNOG00000019700
drosophila_melanogaster	CG32834	FBGN0052834
drosophila_melanogaster	CG34043	FBGN0054043

Paralogs (1): PROC (ENSG00000115718)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1860488) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 2 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased susceptibility to induced morbidity/mortality	1
increased susceptibility to induced thrombosis	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pan troglodytes	Q95ND7	99.8%	Diamond
Pongo abelii	Q5RCB6	99.5%	Diamond
Tropidechis carinatus	P81428	99.3%	Diamond
Notechis scutatus scutatus	P82807	99.3%	Diamond
Hoplocephalus stephensii	P83370	97.6%	Diamond
Bos taurus	P00741	96.8%	Diamond
Ovis aries	P16291	96.8%	Diamond
Macaca mulatta	Q28520	96.0%	Diamond
Oxyuranus microlepidotus	Q58L95	95.1%	Diamond
Oxyuranus scutellatus	Q58L96	95.1%	Diamond
Pseudonaja textilis	Q1L659	93.6%	Diamond
Capra hircus	Q28315	92.7%	Diamond
Cryptophis nigrescens	B5G6G5	89.2%	Diamond
Canis lupus familiaris	P19540	88.5%	Diamond
Felis catus	Q6SA95	88.5%	Diamond
Oryctolagus cuniculus	Q28661	86.3%	Diamond
Sus scrofa	P16293	86.1%	Diamond
Pseudechis porphyriacus	Q58L93	86.1%	Diamond
Demansia vestigiata	A6MFK7	85.8%	Diamond
Equus caballus	Q28380	84.7%	Diamond
Macaca nemestrina	Q28858	79.4%	Diamond
Gallus gallus	Q804X6	58.1%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR8075	ncRNA	102465874
LAMP1	protein-coding	3916
PCID2	protein-coding	55795
GRTP1	protein-coding	79774
CUL4A	protein-coding	8451
F10	protein-coding	2159
F10-AS2	protein-coding	102724474

Protein

Protein identifiers

Vitamin K-dependent protein Z — P22891 (reviewed: P22891)

All UniProt accessions (1): P22891

UniProt curated annotations — full annotation on UniProt →

Function. Appears to assist hemostasis by binding thrombin and promoting its association with phospholipid vesicles. Inhibits activity of the coagulation protease factor Xa in the presence of SERPINA10, calcium and phospholipids.

Subunit / interactions. Interacts with SERPINA10.

Subcellular location. Secreted.

Tissue specificity. Plasma.

Post-translational modifications. The iron and 2-oxoglutarate dependent 3-hydroxylation of aspartate and asparagine is (R) stereospecific within EGF domains.

Similarity. Belongs to the peptidase S1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P22891-1	1	yes
P22891-2	2

RefSeq proteins (2): NP_001243063, NP_003882* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000294	GLA_domain	Domain
IPR000742	EGF	Domain
IPR001254	Trypsin_dom	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR012224	Pept_S1A_FX	Family
IPR017857	Coagulation_fac-like_Gla_dom	Homologous_superfamily
IPR035972	GLA-like_dom_SF	Homologous_superfamily
IPR043504
IPR050442	Peptidase_S1_coag_factors	Family

Pfam: PF00008, PF00089, PF00594, PF14670

UniProt features (74 total): strand 24, modified residue 14, disulfide bond 9, helix 7, glycosylation site 6, domain 4, turn 4, sequence variant 2, signal peptide 1, propeptide 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures by resolution:

PDB	Title	Method	Resolution (Å)
3F1S	Crystal structure of Protein Z complexed with protein Z-dependent inhibitor	X-RAY DIFFRACTION	2.3
3H5C	X-Ray Structure of Protein Z-Protein Z Inhibitor Complex	X-RAY DIFFRACTION	3.26

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22891-F1	85.39	0.59

Human Protein Atlas

Protein class: Enzymes, Peptidases, Serine-type peptidases, Predicted secreted proteins, Plasma proteins, Candidate cardiovascular disease genes

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH supported

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 (14)

Type	Positions
4-carboxyglutamate	55, 57, 60, 61, 66, 67, 70, 73, 75, 80, 47, 48, 51
(3r)-3-hydroxyaspartate	104

Disulfide bonds (9)

Type	Positions
Disulfide bond	58–63, 91–102, 96–111, 113–122, 129–141, 137–150, 152–165, 203–219, 327–341

Glycosylation sites (6)

Type	Positions
O-linked (glc…) serine	93
N-linked (glcnac…) asparagine	99, 225, 233, 306, 332

Function

Pathways and Gene Ontology

Reactome pathways

4 curated (TAS) of 8; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

8 pathways:

ID	Pathway	Evidence
R-HSA-159740	Gamma-carboxylation of protein precursors	curated
R-HSA-9769739	Regulation of clotting cascade	curated
R-HSA-159782	Removal of aminoterminal propeptides from gamma-carboxylated proteins	curated
R-HSA-159763	Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus	curated
R-HSA-163841	Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	—
R-HSA-159854	Gamma-carboxylation, transport, and amino-terminal cleavage of proteins	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-597592	Post-translational protein modification	—

MSigDB gene sets: 74 (showing top): MODULE_172, GOBP_WOUND_HEALING, REACTOME_GAMMA_CARBOXYLATION_TRANSPORT_AND_AMINO_TERMINAL_CLEAVAGE_OF_PROTEINS, MODULE_109, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, chr13q34, MODULE_113, GOBP_HEMOSTASIS, MODULE_209, GOBP_REGULATION_OF_BODY_FLUID_LEVELS, GOCC_ENDOPLASMIC_RETICULUM_LUMEN, MODULE_107, GOBP_PROTEOLYSIS, GOCC_GOLGI_LUMEN, GOMF_PEPTIDASE_ACTIVITY

GO Biological Process (3): proteolysis (GO:0006508), blood coagulation (GO:0007596), hemostasis (GO:0007599)

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

GO Cellular Component (4): endoplasmic reticulum lumen (GO:0005788), Golgi lumen (GO:0005796), extracellular exosome (GO:0070062), extracellular region (GO:0005576)

Reactome top-level categories

5 top-level categories:

Category	Pathways
Gamma-carboxylation, transport, and amino-terminal cleavage of proteins	3
Coagulation pathway	1
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1
Post-translational protein modification	1
Metabolism of proteins	1

GO top-level categories

14 GO namespaces:

Category	Terms
intracellular organelle lumen	2
protein metabolic process	1
hemostasis	1
wound healing	1
coagulation	1
regulation of body fluid levels	1
endopeptidase activity	1
serine-type peptidase activity	1
metal ion binding	1
binding	1
endoplasmic reticulum	1
Golgi apparatus	1
extracellular vesicle	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 1 of 11 annotations. The rest are phylogenetic / computational / electronic (IEA).

1 experimentally-supported GO terms:

GO term	NS	Evidence
extracellular exosome	CC	high-throughput assay

Protein interactions and networks

STRING

showing 15 of 734 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PROZ	SERPINA10	Q9UK55	919
PROZ	CTSG	P08311	555
PROZ	F13B	P05160	529
PROZ	PLAT	P00750	517
PROZ	ELANE	P08246	487
PROZ	DEFB124	Q8NES8	456
PROZ	CHST13	Q8NET6	435
PROZ	FCN3	O75636	421
PROZ	SERPIND1	P05546	416
PROZ	OR5M11	Q96RB7	412
PROZ	FGG	P02679	410
PROZ	F8W876	F8W876	397
PROZ	F12	P00748	386
PROZ	SERPINC1	P01008	385
PROZ	HRG	P04196	382

IntAct

Human interaction partners of PROZ in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

5 partners by confidence:

Partner	Interaction type	MIscore	Records
SERPINA10	direct interaction	0.650	7
OR52W1	physical association	0.400	1
IDE	association	0.350	1
IP6K3	association	0.350	1
MAP2K7	association	0.350	1

BioGRID (58 interactions; top human partners by supporting records): CDC6 (Affinity Capture-MS; 2 records), DNAJB9 (Affinity Capture-MS; 2 records), EGFL7 (Affinity Capture-MS; 2 records), ETV3 (Affinity Capture-MS; 2 records), FOXF2 (Affinity Capture-MS; 2 records), FOXG1 (Affinity Capture-MS; 2 records), GNL3L (Affinity Capture-MS; 2 records), HSPA5 (Affinity Capture-MS; 2 records), INTS6 (Affinity Capture-MS; 2 records), IP6K3 (Affinity Capture-MS; 2 records), KANK2 (Affinity Capture-MS; 2 records), MAP2K7 (Affinity Capture-MS; 2 records), MELK (Affinity Capture-MS; 2 records), MLF1 (Affinity Capture-MS; 2 records), OR52W1 (Affinity Capture-MS; 2 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
GGCX	“up-regulates activity”	PROZ	carboxylation

Disease & clinical

Genetic variants

Variant evidence for PROZ: 50 ClinVar records (0 pathogenic / likely pathogenic); 4 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	8
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 29 predictions of 736):

Position(s)	Effect	Δscore	Sites
13:113170412	acceptor_loss	1.0000	3
13:113171592–113171593	acceptor_loss	1.0000	5
13:113158731–113158732	donor_loss	0.9900	3
13:113160012–113160013	acceptor_loss	0.9900	6
13:113165039	acceptor_gain	0.9900
13:113165046	acceptor_gain	0.9900
13:113170410	acceptor_gain	0.9900
13:113170411	acceptor_loss	0.9900	3
13:113170531–113170532	donor_loss	0.9900	5
13:113171593	acceptor_loss	0.9900

AlphaMissense

590 missense substitutions predicted likely pathogenic (of 2,611 scored), across 155 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
N260	8	0.760	0.937
C63	7	0.971	0.986
C58	7	0.970	0.991
F366	7	0.966	0.991
C111	7	0.964	0.979
C122	7	0.963	0.986
C152	7	0.963	0.981
C96	7	0.960	0.982
C137	7	0.956	0.983
C141	7	0.956	0.978
C102	7	0.955	0.983
C281	7	0.954	0.977
C129	7	0.949	0.982
C203	7	0.949	0.970
C219	7	0.948	0.979
C150	7	0.947	0.973
C165	7	0.943	0.980
C113	7	0.937	0.960
F72	7	0.936	0.973
C91	7	0.936	0.968

HPA cancer prognostics

RNA cancer specificity: Cancer enriched (Liver Hepatocellular Carcinoma)

Disease associations

OMIM: gene MIM:176895 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
protein Z deficiency	Limited	Unknown

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (1 panels, 0 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

1 panels:

Panel	Rating
Thrombophilia with a likely monogenic cause	amber

Mondo (1): protein Z deficiency (MONDO:0013532)

GWAS associations

4 associations:

Study	Trait	p-value
GCST000082_1	Factor VII	5e-16
GCST90002406_571	Reticulocyte fraction of red cells	1e-9
GCST008103_61	Bipolar disorder	1e-6
GCST005721_3	Food allergy (parent-of-origin effect)	4e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0004619	factor VII measurement
EFO:0005939	parental genotype effect measurement
EFO:0007016	food allergy measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
methyleugenol	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Rosiglitazone	decreases expression	1
Arsenic	affects methylation	1
Catechin	affects cotreatment, decreases expression	1
Cisplatin	decreases expression	1
Malathion	decreases expression	1
N-Nitrosopyrrolidine	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Valproic Acid	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Permethrin	decreases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.