PROC

Summary

PROC (protein C, inactivator of coagulation factors Va and VIIIa, HGNC:9451) is a protein-coding gene on chromosome 2q14.3, encoding Vitamin K-dependent protein C (P04070). Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids.

This gene encodes a vitamin K-dependent plasma glycoprotein. The encoded protein is cleaved to its activated form by the thrombin-thrombomodulin complex. This activated form contains a serine protease domain and functions in degradation of the activated forms of coagulation factors V and VIII. Mutations in this gene have been associated with thrombophilia due to protein C deficiency, neonatal purpura fulminans, and recurrent venous thrombosis.

Source: NCBI Gene 5624 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary thrombophilia due to congenital protein C deficiency (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 490 total — 38 pathogenic, 54 likely-pathogenic (top 7% of genes corpus-wide)
• GTEx eGene: eQTL in 23 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 27
• Drug target: yes — 2 curated mechanism-of-action drugs; 2 molecules with ChEMBL bioactivity
• Approved drugs (ChEMBL mechanism of action): 1 — Protein C Concentrate (Human)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.89 (unconstrained)
• MANE Select transcript: NM_000312

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9451
Approved symbol	PROC
Name	protein C, inactivator of coagulation factors Va and VIIIa
Location	2q14.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000115718
Ensembl biotype	protein_coding
OMIM	612283
Entrez	5624

Gene structure

Transcript identifiers

Ensembl transcripts: 125 — 81 protein_coding, 42 nonsense_mediated_decay, 2 retained_intron

MANE Select: ENST00000234071

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 1, TSL 3: 2, TSL 4: 5, TSL 5: 1

ENST00000234071, ENST00000402125, ENST00000409048, ENST00000419985, ENST00000427769, ENST00000429925, ENST00000431364, ENST00000442644, ENST00000464089, ENST00000474030, ENST00000883837, ENST00000883838, ENST00000883839, ENST00000883840, ENST00000883841, ENST00000883842, ENST00000883843, ENST00000883844, ENST00000883845, ENST00000883846, ENST00000883847, ENST00000883848, ENST00000883849, ENST00000883850, ENST00000883851, ENST00000883852, ENST00000883853, ENST00000883854, ENST00000883855, ENST00000883856, ENST00000883857, ENST00000883858, ENST00000883859, ENST00000883860, ENST00000883861, ENST00000883862, ENST00000883863, ENST00000883864, ENST00000883865, ENST00000883866, ENST00000883867, ENST00000883868, ENST00000883869, ENST00000883870, ENST00000883871, ENST00000883872, ENST00000883873, ENST00000883874, ENST00000883875, ENST00000883876, ENST00000883877, ENST00000883878, ENST00000883879, ENST00000883880, ENST00000883881, ENST00000883882, ENST00000883883, ENST00000883884, ENST00000883885, ENST00000883886, ENST00000883887, ENST00000883888, ENST00000883889, ENST00000883890, ENST00000883891, ENST00000883892, ENST00000883893, ENST00000883894, ENST00000883895, ENST00000883896, ENST00000883897, ENST00000883898, ENST00000883899, ENST00000883900, ENST00000883901, ENST00000883902, ENST00000883903, ENST00000883904, ENST00000973243, ENST00000990887, ENST00000990888, ENST00000990889, ENST00000990893, ENST00000990894, ENST00000990895, ENST00000990896, ENST00000990897, ENST00000990898, ENST00000990899, ENST00000990900, ENST00000990902, ENST00000990903, ENST00000990904, ENST00000990905, ENST00000990906, ENST00000990908, ENST00000990910, ENST00000990913, ENST00000990914, ENST00000990915, ENST00000990917, ENST00000990918, ENST00000990919, ENST00000990922, ENST00000990923, ENST00000990926, ENST00000990928, ENST00000990929, ENST00000990930, ENST00000990931, ENST00000990933, ENST00000990934, ENST00000990935, ENST00000990937, ENST00000990938, ENST00000990939, ENST00000990940, ENST00000990941, ENST00001119636, ENST00001119637, ENST00001119638, ENST00001119639, ENST00001119640, ENST00001119641, ENST00001144877

RefSeq mRNA: 12 — MANE Select: NM_000312 NM_000312, NM_001375602, NM_001375603, NM_001375604, NM_001375605, NM_001375606, NM_001375607, NM_001375608, NM_001375609, NM_001375610, NM_001375611, NM_001375613

CCDS: CCDS2145, CCDS92858

Canonical transcript exons

ENST00000234071 — 9 exons

Exon	Start	End
ENSE00000775729	127427105	127427222
ENSE00000775730	127426085	127426227
ENSE00000775732	127423034	127423171
ENSE00000857263	127419922	127420012
ENSE00001019181	127423274	127423408
ENSE00001853552	127428357	127429242
ENSE00003534324	127422917	127422941
ENSE00003618780	127421283	127421449
ENSE00003899562	127418427	127418492

Expression profiles

Bgee: expression breadth ubiquitous, 165 present calls, max score 99.31.

FANTOM5 (CAGE): breadth broad, TPM avg 2.9216 / max 797.7874, expressed in 338 samples.

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

Genetic regulation across tissues (GTEx eQTL / sQTL)

PROC is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 23 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 24 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Liver	sqtl	7.8e-72	+1.38	2:127419801:C:T
Colon Transverse	eqtl	3.9e-26	+0.45	2:127423658:GC:G
Brain Nucleus accumbens basal ganglia	eqtl	1.0e-15	-0.65	2:127422645:A:G
Testis	eqtl	4.6e-13	-0.66	2:127349894:T:C
Liver	eqtl	1.5e-09	-0.22	2:127417267:T:C
Small Intestine Terminal Ileum	eqtl	5.4e-09	+0.42	2:127432839:T:C
Skin Sun Exposed Lower leg	eqtl	1.2e-08	+0.32	2:127432839:T:C
Pituitary	eqtl	2.3e-08	+0.55	2:127423942:T:C
Brain Putamen basal ganglia	eqtl	2.4e-08	-0.56	2:127422262:G:A
Brain Caudate basal ganglia	eqtl	3.5e-08	-0.47	2:127422645:A:G
Brain Hypothalamus	eqtl	5.5e-07	+0.41	2:127423658:GC:G
Stomach	eqtl	9.9e-07	+0.24	2:127418299:G:A
Thyroid	eqtl	1.6e-06	+0.29	2:127433520:A:C
Esophagus Mucosa	eqtl	2.0e-04	+0.30	2:127423942:T:C
Pancreas	eqtl	2.4e-04	+0.40	2:127418286:C:T
Skin Not Sun Exposed Suprapubic	eqtl	6.8e-04	+0.23	2:127442291:G:A
Muscle Skeletal	eqtl	2.8e-03	-0.30	2:127491506:C:T
Colon Sigmoid	eqtl	1.7e-02	+0.28	2:126438371:G:C
Artery Tibial	eqtl	1.7e-02	+0.55	2:128047627:C:CAT
Brain Anterior cingulate cortex BA24	eqtl	2.0e-02	+1.22	2:127152004:C:G

FANTOM5 promoters

9 alternative TSS:

Promoter ID	TPM avg	Samples expressed
22422	1.5437	43
22429	0.8690	255
22424	0.2347	16
22430	0.1046	31
22428	0.0606	25
22425	0.0425	9
22423	0.0280	6
22427	0.0228	8
22426	0.0156	7

Top tissues by expression

showing 100 of 286 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.31	gold quality
liver	UBERON:0002107	97.81	gold quality
adult mammalian kidney	UBERON:0000082	80.41	gold quality
metanephros cortex	UBERON:0010533	76.08	gold quality
nephron tubule	UBERON:0001231	75.88	silver quality
kidney	UBERON:0002113	75.52	gold quality
kidney epithelium	UBERON:0004819	73.73	silver quality
cortex of kidney	UBERON:0001225	73.34	gold quality
triceps brachii	UBERON:0001509	73.19	gold quality
gluteal muscle	UBERON:0002000	73.06	gold quality
mucosa of transverse colon	UBERON:0004991	72.33	gold quality
pancreatic ductal cell	CL:0002079	71.93	silver quality
parotid gland	UBERON:0001831	71.56	gold quality
renal glomerulus	UBERON:0000074	71.03	silver quality
metanephric glomerulus	UBERON:0004736	69.10	silver quality
body of stomach	UBERON:0001161	68.28	gold quality
metanephros	UBERON:0000081	67.83	gold quality
granulocyte	CL:0000094	67.16	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	66.67	gold quality
lower esophagus mucosa	UBERON:0035834	65.88	gold quality
stomach	UBERON:0000945	65.76	gold quality
medial globus pallidus	UBERON:0002477	63.64	gold quality
fundus of stomach	UBERON:0001160	63.61	gold quality
transverse colon	UBERON:0001157	63.41	gold quality
nasal cavity epithelium	UBERON:0005384	63.19	gold quality
gall bladder	UBERON:0002110	63.09	gold quality
popliteal artery	UBERON:0002250	62.37	gold quality
tibial artery	UBERON:0007610	62.32	gold quality
descending thoracic aorta	UBERON:0002345	62.28	gold quality
small intestine Peyer’s patch	UBERON:0003454	61.94	gold quality
vena cava	UBERON:0004087	61.92	gold quality
heart right ventricle	UBERON:0002080	61.66	gold quality
right coronary artery	UBERON:0001625	61.64	gold quality
aorta	UBERON:0000947	61.60	gold quality
globus pallidus	UBERON:0001875	61.52	gold quality
blood	UBERON:0000178	61.26	gold quality
renal medulla	UBERON:0000362	60.92	silver quality
thoracic aorta	UBERON:0001515	60.68	gold quality
muscle layer of sigmoid colon	UBERON:0035805	60.64	gold quality
ascending aorta	UBERON:0001496	60.61	gold quality
gastrocnemius	UBERON:0001388	60.41	gold quality
small intestine	UBERON:0002108	60.41	gold quality
amygdala	UBERON:0001876	60.35	gold quality
lymph node	UBERON:0000029	60.18	gold quality
endocervix	UBERON:0000458	59.74	gold quality
hypothalamus	UBERON:0001898	59.64	gold quality
left coronary artery	UBERON:0001626	59.53	gold quality
muscle of leg	UBERON:0001383	59.52	gold quality
coronary artery	UBERON:0001621	59.34	gold quality
colon	UBERON:0001155	59.26	gold quality
nucleus accumbens	UBERON:0001882	59.20	gold quality
intestine	UBERON:0000160	59.05	gold quality
islet of Langerhans	UBERON:0000006	58.85	gold quality
large intestine	UBERON:0000059	58.64	gold quality
right hemisphere of cerebellum	UBERON:0014890	58.55	gold quality
body of uterus	UBERON:0009853	58.42	gold quality
cerebellar hemisphere	UBERON:0002245	58.31	gold quality
cingulate cortex	UBERON:0003027	58.30	gold quality
muscle organ	UBERON:0001630	58.10	gold quality
substantia nigra	UBERON:0002038	58.10	gold quality
anterior cingulate cortex	UBERON:0009835	57.96	gold quality
cerebellar cortex	UBERON:0002129	57.91	gold quality
Brodmann (1909) area 9	UBERON:0013540	57.76	gold quality
endothelial cell	CL:0000115	57.73	gold quality
spleen	UBERON:0002106	57.67	gold quality
right lobe of thyroid gland	UBERON:0001119	57.55	gold quality
midbrain	UBERON:0001891	57.53	gold quality
pons	UBERON:0000988	57.50	gold quality
cerebellum	UBERON:0002037	57.48	gold quality
sigmoid colon	UBERON:0001159	57.43	gold quality
nasal cavity mucosa	UBERON:0001826	57.38	gold quality
caudate nucleus	UBERON:0001873	57.37	gold quality
leukocyte	CL:0000738	57.35	gold quality
left lobe of thyroid gland	UBERON:0001120	57.29	gold quality
lower esophagus	UBERON:0013473	57.24	gold quality
lower esophagus muscularis layer	UBERON:0035833	57.21	gold quality
prefrontal cortex	UBERON:0000451	56.90	gold quality
bone marrow cell	CL:0002092	56.86	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	56.85	gold quality
right frontal lobe	UBERON:0002810	56.83	gold quality
putamen	UBERON:0001874	56.64	gold quality
monocyte	CL:0000576	56.55	gold quality
colonic epithelium	UBERON:0000397	56.52	gold quality
rectum	UBERON:0001052	56.50	gold quality
mononuclear cell	CL:0000842	56.49	gold quality
thyroid gland	UBERON:0002046	56.47	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	56.38	gold quality
spinal cord	UBERON:0002240	56.32	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	56.14	gold quality
left uterine tube	UBERON:0001303	55.99	gold quality
myocardium	UBERON:0002349	55.89	gold quality
pancreas	UBERON:0001264	55.87	gold quality
duodenum	UBERON:0002114	55.60	gold quality
uterine cervix	UBERON:0000002	55.58	gold quality
gingival epithelium	UBERON:0001949	55.56	gold quality
frontal cortex	UBERON:0001870	55.53	gold quality
buccal mucosa cell	CL:0002336	55.46	gold quality
central nervous system	UBERON:0001017	55.44	gold quality
brain	UBERON:0000955	55.41	gold quality
body of pancreas	UBERON:0001150	55.38	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-9467	yes	13.77
E-MTAB-5061	no	3.18
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enriched

39 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	250.8	not detected
Kidney	tissue	10.9	not detected
Nucleus accumbens	tissue	2.3
Locus coeruleus	tissue	2.3
Stomach 1	tissue	2.1	not detected
Hippocampus	tissue	1.9	not detected
Postcentral gyrus	tissue	1.5
Bone marrow	tissue	1.0	not detected
Choroid plexus	tissue	0.8
Colon	tissue	0.7	not detected
Duodenum	tissue	0.7	not detected
Skin 1	tissue	0.6	not detected
Lymph node	tissue	0.6	not detected
Rectum	tissue	0.6	not detected
Gallbladder	tissue	0.6	not detected
Small intestine	tissue	0.5	not detected
Thymus	tissue	0.5
Pituitary gland	tissue	0.3
Tonsil	tissue	0.3	not detected
Vagina	tissue	0.2	not detected
Skeletal muscle	tissue	0.2	not detected
Urinary bladder	tissue	0.2	not detected
Lung	tissue	0.2	not detected
Spleen	tissue	0.2	not detected
Fallopian tube	tissue	0.2	not detected
Cervix	tissue	0.1	not detected
Heart muscle	tissue	0.1	not detected
Cerebral cortex	tissue	0.1	not detected
Retina	tissue	0.1
Seminal vesicle	tissue	0.1	not detected
Salivary gland	tissue	0.1	not detected
Endometrium 1	tissue	0.1	not detected
Epididymis	tissue	0.1	not detected
Medulla oblongata	tissue	0.1
Placenta	tissue	0.1	not detected
Thyroid gland	tissue	0.1	not detected
Prostate	tissue	0.1	not detected
Appendix	tissue	0.1	not detected
Insular cortex	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 183; highest nTPM — Gigantocellular reticular nuclei, pars (4.6), Superior olive (4.4), Lateral lemniscal nuclei (4.2), Medial periolivary nuclei (4.2), Subcoeruleus area (4.2).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXM1, HNF1A, NFIA, NFIC, ONECUT1, SMAD6, SP1

miRNA regulators (miRDB)

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

13 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-4317	98.49	67.09	987
HSA-MIR-6834-3P	98.16	65.77	551
HSA-MIR-6502-5P	98.09	66.73	495
HSA-MIR-1301-5P	98.09	66.62	495
HSA-MIR-3907	96.76	65.04	662
HSA-MIR-3059-3P	96.71	67.08	606
HSA-MIR-552-3P	96.68	64.12	1026
HSA-MIR-4653-3P	96.26	67.03	725
HSA-MIR-764	94.16	64.85	656

Functional genomics

gnomAD constraint: pLI 2.19e-05, LOEUF 0.894, missense Z 1.62 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000234071 — one region, missense o/e 0.84.

Literature-anchored findings (GeneRIF, showing 40)

• A heterozygous G–>T transversion at position 1388 of the protein C (PC) gene which predicted the substitution of Arg(-1) to a Leu (PC(R-1L)) was identified in a thrombophilic patient. This shifts the propeptidase cleavage site by one amino acid. (PMID:11686318)
• The combined effect of aprotinin and extracorporeal circulation resulted in lowered APC ratios for Factor V Leiden blood. Increased risk of perioperative thrombosis in cardiac surgical patients heterozygous for the F5L mutation is predicted. (PMID:11761087)
• Contribution of basic residues of the 70-80-loop to heparin binding and anticoagulant function of activated protein C. (PMID:11994010)
• X-ray crystallography of Activated Protein C (PMID:12029084)
• protease activated receptor 1 (PAR1) is the target for endothelial cell protein C receptor (EPCR)-dependent activated protein C (APC) signaling, suggesting a role for this receptor cascade in protection from sepsis (PMID:12052963)
• identifies FVa binding site in the positive exosite of APC that is primarily involved in binding and cleaving at Arg(506) on FVa (PMID:12063259)
• In this population-based study, a low protein C level has been determined to be associated with an increased incidence of venous thromboembolism. (PMID:12067914)
• APC is able to cleave at Arg506 and at Arg679 in FVa Cambridge and FVa Hong Kong. (PMID:12091344)
• Activated protein C cleaves factor Va more efficiently on endothelium than on platelet surfaces. (PMID:12091346)
• Molecular biological basis and diagnosis of hereditary defects (review) (PMID:12193972)
• APC inhibited both the binding of NF-kB to target sites and the degradation of I kappa B alpha, and inhibited both the binding of activator protein-1 (AP-1) to target sites and the activation of mitogen-activated protein kinase pathways. (PMID:12195699)
• activation of protein C by thrombin and inactivation of plasma FVa by APC are not impaired in human volunteers with acute hyperhomocysteinemia. (PMID:12200374)
• thrombomodulin-dependent activation of protein C is regulated by Smad6 and Smad7 (PMID:12407115)
• Smoking-induced vascular endothelium injury reduces activated protein C in a cigarette smoke dose-dependent manner, leading to activated protein C deficiency hypercoagulability. (PMID:12482406)
• The ability of activated protein C to upregulate the production of MCP-1 is most likely by increasing the stability of MCP-1-mRNA rather than by transcriptional activation via NF-KB (PMID:12540965)
• Data show that activated protein C directly prevents apoptosis in hypoxic human brain endothelium through transcriptionally dependent inhibition of tumor suppressor protein p53. (PMID:12563316)
• Interactions within thrombin that involve autolytic loop-2 and the Na(+)-binding site impair thrombin action on protein C, yet the activity of the mutant meizothrombins for protein C was increased to >10 times that of alpha-thrombin (PMID:12588872)
• physiologically relevant concentrations of PF4 stimulate thrombin-dependent activated protein C generation in cultured vascular endothelial cells (PMID:12609838)
• mAb identifies binding site on PROC involved in APC-mediated inactivation of factor Va; binding is phospholipid-independent and calcium-dependent. (PMID:12871399)
• seven newly found mutations in PROC are described; one with 4% PROC activity is a novel mutation in the promoter region, located in the HNF-1 site and associated with the Y226H heterozygous mutation (PMID:12960605)
• REVIEW OF the physiology of the protein C pathway with special emphasis on pediatric venous thromboembolism as well as acquired disturbances of protein C pathway during sepsis (PMID:14517747)
• activated protein C inactivates factor Va in the absence of arginine cleavage sites (PMID:14660667)
• The cleavage and inactivation of PAI-1 by generated thrombin is proposed to be responsible for the shortening of clot lysis time by Ca2+ and for coagulation-associated over-expression of fibrinolysis, which was suppressed by aPC. (PMID:14675098)
• free APC, APC-PCI and APC-alpha1AT generation is reduced in newborn compared to adult plasma with or without endothelium, likely due to reduced plasma PC levels. Endothelium enhances APC generation, regardless of plasma type. (PMID:14961149)
• Poor susceptibility to APC and impaired APC cofactor activity contributed equally to FV(Leiden)-associated APC resistance, whereas FV(R2)-associated APC resistance was entirely due to the reduced APC cofactor activity of FV(R2). (PMID:14976057)
• R147W mutation is a significant thrombotic risk factor and is the most common defect of PROC gene in Taiwanese patients with protein C deficiency (PMID:15114590)
• individuals carrying the 4600AG EPCR genotype have high sEPCR levels but do not have an increased risk of thrombosis, whereas individuals carrying the 4678CC genotype have higher APC levels and lower risk of venous thromboembolism (PMID:15116250)
• Review. TM, APC, & EPCR impact coagulation, inflammation, fibrinolysis, & cell proliferation. We review the functions of this complex multimolecular system & how its components maintain homeostasis under hypercoagulable &/or proinflammatory conditions. (PMID:15178554)
• Activated protein C (APC) and MMP-2 are coordinately up-regulated and tightly bound in rheumatoid arthritis (RA) synovial fluid and colocalized in synovia. APC may modulate MMP-2 activity in RA. (PMID:15248212)
• face 1 was necessary for efficient phospholipid binding but face 2 residues were not strictly required for phospholipid binding and were involved in the interaction with activated protein C (PMID:15308562)
• No significant differences exist between survivors and nonsurvivors of sepsis with respect to baseline protein C levels. (PMID:15319291)
• Results provide insights into the importance of the activated protein C (APC)-phospholipid interaction for the APC-mediated cleavages at Arg-306 and Arg-506 in coagulation factor Va. (PMID:15337738)
• Exposure of human umbilical vein endothelial cells or monocytes to activated protein C (6.25-100 nM) results in the release of endothelial protein C receptor-containing microparticles. (PMID:15486064)
• A new antiinflammatory mechanism of APC-dependent gene regulation occurs in human coronary artery endothelial cells. APC downregulates genes related to inflammation, most pronounced under intermediate or mild inflammatory conditions. (PMID:15505101)
• mechanism of thrombomodulin action is to kinetically facilitate the productive encounter of thrombin and protein C and to allosterically change the conformation of the activation peptide of protein C for optimal presentation to the thrombin active site (PMID:15582990)
• protein C binding to sEPCR and phospholipids is broadly dependent on correct Gla domain folding, but can be selectively influenced by judicious mutation (PMID:15634335)
• analysis of PAR1 cleavage and signaling in response to activated protein C and thrombin (PMID:15665002)
• APC anticoagulant activity in plasma and factor Va inactivation as a result of cleavages at R506 and R306 by APC is markedly enhanced by cholesterol in phospholipid vesicles (PMID:15670041)
• PC interactions with thrombin and thrombomodulin are likely contribute in a secondary or minor way to protein substrate affinity (PMID:15705565)
• endothelial protein C receptor ligation and sphingosine 1-phosphate receptor transactivation results in endothelial cell cytoskeletal rearrangement and barrier protection through activated protein C (PMID:15710622)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	proca	ENSDARG00000038258
danio_rerio	proca	ENSDARG00000093079
rattus_norvegicus	Proc	ENSRNOG00000014376
drosophila_melanogaster	CG9672	FBGN0030777

Paralogs (1): PROZ (ENSG00000126231)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:97771) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 14 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal suckling behavior	1
focal hepatic necrosis	1
liver inflammation	1
intracranial hemorrhage	1
abnormal innate immunity	1
abnormal blood coagulation	1
liver degeneration	1
liver fibrosis	1
bruising	1
neonatal lethality, complete penetrance	1
perinatal lethality, complete penetrance	1
abnormal cardiac thrombosis	1
abnormal lung thrombosis	1
abnormal brain 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
Pan paniscus	Q2F9P4	98.7%	Diamond
Hoplocephalus stephensii	P83370	97.6%	Diamond
Tachypleus tridentatus	P28175	97.2%	Diamond
Carcinoscorpius rotundicauda	Q26422	97.2%	Diamond
Bos taurus	P00741	96.8%	Diamond
Ovis aries	P16291	96.8%	Diamond
Macaca fascicularis	Q4R577	96.3%	Diamond
Macaca mulatta	Q28520	96.0%	Diamond
Mus musculus	Q8CFG9	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
Cavia porcellus	P16295	75.8%	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
MIR4783	ncRNA	100616187
MAP3K2	protein-coding	10746
MAP3K2-DT	ncRNA	100506922
MYO7B	protein-coding	4648
IWS1	protein-coding	55677
ERCC3	protein-coding	2071

Protein

Protein identifiers

Vitamin K-dependent protein C — P04070 (reviewed: P04070)

Alternative names: Anticoagulant protein C, Autoprothrombin IIA, Blood coagulation factor XIV

All UniProt accessions (7): E7END6, E7ENR9, E7EU72, E7EVH6, P04070, F2Z2A0, H7BYX9

UniProt curated annotations — full annotation on UniProt →

Function. Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids. Exerts a protective effect on the endothelial cell barrier function.

Subunit / interactions. Synthesized as a single chain precursor, which is cleaved into a light chain and a heavy chain held together by a disulfide bond. The enzyme is then activated by thrombin, which cleaves a tetradecapeptide from the amino end of the heavy chain; this reaction, which occurs at the surface of endothelial cells, is strongly promoted by thrombomodulin. Interacts (activated) with iripin-8, a serine protease inhibitor from Ixodes ricinus saliva.

Subcellular location. Secreted. Golgi apparatus. Endoplasmic reticulum.

Tissue specificity. Plasma; synthesized in the liver.

Post-translational modifications. Carboxylated by vitamin K-dependent GGCX to form gamma-carboxyglutamate; these residues are essential for the binding of calcium. N- and O-glycosylated. Partial (70%) N-glycosylation of Asn-371 with an atypical N-X-C site produces a higher molecular weight form referred to as alpha. The lower molecular weight form, not N-glycosylated at Asn-371, is beta. O-glycosylated with core 1 or possibly core 8 glycans. The iron and 2-oxoglutarate dependent 3-hydroxylation of aspartate and asparagine is (R) stereospecific within EGF domains. May be phosphorylated on a Ser or Thr in a region (AA 25-30) of the propeptide.

Disease relevance. Thrombophilia due to protein C deficiency, autosomal dominant (THPH3) [MIM:176860] A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. Individuals with decreased amounts of protein C are classically referred to as having type I protein C deficiency and those with normal amounts of a functionally defective protein as having type II deficiency. The disease is caused by variants affecting the gene represented in this entry. Thrombophilia due to protein C deficiency, autosomal recessive (THPH4) [MIM:612304] A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. It results in a thrombotic condition that can manifest as a severe neonatal disorder or as a milder disorder with late-onset thrombophilia. The severe form leads to neonatal death through massive neonatal venous thrombosis. Often associated with ecchymotic skin lesions which can turn necrotic called purpura fulminans, this disorder is very rare. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Calcium also binds, with stronger affinity to another site, beyond the GLA domain. This GLA-independent binding site is necessary for the recognition of the thrombin-thrombomodulin complex.

Similarity. Belongs to the peptidase S1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P04070-1	1	yes
P04070-2	2

RefSeq proteins (12): NP_000303, NP_001362531, NP_001362532, NP_001362533, NP_001362534, NP_001362535, NP_001362536, NP_001362537, NP_001362538, NP_001362539, NP_001362540, NP_001362542 (=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
IPR001314	Peptidase_S1A	Family
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
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR018114	TRYPSIN_HIS	Active_site
IPR033116	TRYPSIN_SER	Active_site
IPR035972	GLA-like_dom_SF	Homologous_superfamily
IPR043504
IPR050442	Peptidase_S1_coag_factors	Family

Pfam: PF00089, PF00594, PF14670

Enzyme classification (BRENDA)

• EC 3.4.21.69 — activated protein C (thrombin-activated peptidase) (BRENDA: 5 organisms, 241 substrates, 99 inhibitors, 42 Km, 24 kcat entries)

Substrate kinetics (BRENDA)

17 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
S-2288	0.39–1.723	8
S-2366	0.0009–0.001	5
SPECTROZYME PCA	0.131–0.177	5
SPPCA	0.234–0.258	3
FACTOR VIIIA	0.0001	2
NALPHA-BENZOYL-L-ARGININE 4-NITROANILIDE	0.43–0.9	2
BENZYLOXYCARBONYL-VAL-GLY-ARG	0.528	1
D-ILE-PRO-ARG	0.606	1
D-PHE-PIPECOLYL-ARG	0.373	1
D-PRO-PHE-ARG	0.505	1
D-VAL-CYCLOHEXYL-ALA-ARG	0.259	1
D-VAL-LEU-ARG	0.345	1
FACTOR VA	—	1
FACTOR VAR506Q	0.0002	1
MEMBRANE-BOUND FACTOR VA	—	1

UniProt features (184 total): sequence variant 93, strand 27, helix 14, disulfide bond 12, modified residue 11, glycosylation site 5, turn 4, domain 4, active site 3, chain 3, sequence conflict 2, splice variant 2, signal peptide 1, propeptide 1, site 1, peptide 1

Structure

Experimental structures (PDB)

12 structures by resolution:

PDB	Title	Method	Resolution (Å)
1LQV	Crystal structure of the Endothelial protein C receptor with phospholipid in the groove …	X-RAY DIFFRACTION	1.6
3JTC	Importance of Mg2+ in the Ca2+-Dependent Folding of the gamma-Carboxyglutamic Acid …	X-RAY DIFFRACTION	1.6
4DT7	Crystal structure of thrombin bound to the activation domain QEDQVDPRLIDGKMTRRGDS of …	X-RAY DIFFRACTION	1.9
6M3B	hAPC-c25k23 Fab complex	X-RAY DIFFRACTION	2.2
1AUT	Human activated protein C	X-RAY DIFFRACTION	2.8
3F6U	Crystal structure of human Activated Protein C (APC) complexed with PPACK	X-RAY DIFFRACTION	2.8
9MOV	Cryo-EM structure of factor Va bound to activated protein C	ELECTRON MICROSCOPY	3
9MOT	Cryo-EM structure of factor Va bound to activated protein C	ELECTRON MICROSCOPY	3.15
8JRV	Cryo-EM structure of the glucagon receptor bound to glucagon and beta-arrestin 1	ELECTRON MICROSCOPY	3.3
9BVM	Vitamin K-dependent gamma-carboxylase with protein C propeptide and glutamate-rich region …	ELECTRON MICROSCOPY	3.4
8JRU	Cryo-EM structure of the glucagon receptor bound to beta-arrestin 1 in ligand-free state	ELECTRON MICROSCOPY	3.5
6M3C	hAPC-h1573 Fab complex	X-RAY DIFFRACTION	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04070-F1	82.35	0.58

Antibody-complex structures (SAbDab)

2 antibodies co-crystallized with this protein: 6M3B, 6M3C

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Serine-type peptidases, Predicted secreted proteins, Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers, Candidate cardiovascular disease genes, Disease related genes, FDA approved drug targets, Biotech drugs, Small molecule drugs, Human disease related genes

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH approved

Functional residue map

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

Catalytic / active sites (4)

Position	Role
253	charge relay system
299	charge relay system
402	charge relay system
211–212	cleavage; by thrombin

Post-translational modifications (11)

Type	Positions
4-carboxyglutamate	48, 49, 56, 58, 61, 62, 67, 68, 71
(3r)-3-hydroxyaspartate	113
Phosphoserine	347

Disulfide bonds (12)

Type	Positions
Disulfide bond	59–64, 92–111, 101–106, 105–120, 122–131, 140–151, 147–160, 162–175, 238–254, 373–387, 398–426
Interchain (between light and heavy chains)	183–319

Glycosylation sites (5)

Type	Positions
O-linked (galnac…) threonine	19
N-linked (glcnac…) asparagine	139, 290, 355, 371

Function

Pathways and Gene Ontology

Reactome pathways

11 curated (TAS) of 19; 2 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

19 pathways:

ID	Pathway	Evidence
R-HSA-9930479	Defective cleavage of FV variant at R334 ⚕	curated
R-HSA-9930449	Defective cleavage of FV variant at a.a.534 ⚕	curated
R-HSA-9769743	Amplification and propagation of coagulation cascade	curated
R-HSA-202733	Cell surface interactions at the vascular wall	curated
R-HSA-9769733	Fibrin formation	curated
R-HSA-159740	Gamma-carboxylation of protein precursors	curated
R-HSA-8957275	Post-translational protein phosphorylation	curated
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	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-109582	Hemostasis	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-597592	Post-translational protein modification	—
R-HSA-140837		—
R-HSA-140875		—
R-HSA-140877		—

MSigDB gene sets: 202 (showing top): MODULE_172, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_COAGULATION, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GNF2_GSTM1, PEREZ_TP63_TARGETS, GNF2_HPN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GOBP_REGULATION_OF_ENDOTHELIAL_CELL_DIFFERENTIATION, MODULE_16, FOXD3_01, GOBP_NEGATIVE_REGULATION_OF_COAGULATION

GO Biological Process (8): proteolysis (GO:0006508), blood coagulation (GO:0007596), negative regulation of blood coagulation (GO:0030195), negative regulation of apoptotic process (GO:0043066), negative regulation of inflammatory response (GO:0050728), negative regulation of coagulation (GO:0050819), positive regulation of establishment of endothelial barrier (GO:1903142), hemostasis (GO:0007599)

GO Molecular Function (7): serine-type endopeptidase activity (GO:0004252), calcium ion binding (GO:0005509), endopeptidase activity (GO:0004175), protein binding (GO:0005515), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (5): extracellular region (GO:0005576), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), Golgi apparatus (GO:0005794), Golgi lumen (GO:0005796)

Reactome top-level categories

7 top-level categories:

Category	Pathways
Gamma-carboxylation, transport, and amino-terminal cleavage of proteins	3
Coagulation pathway	3
Metabolism of proteins	2
Post-translational protein modification	2
Defective FV causes thrombophilia	2
Hemostasis	1
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1

GO top-level categories

38 GO namespaces:

Category	Terms
coagulation	2
peptidase activity	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
intracellular organelle lumen	2
protein metabolic process	1
hemostasis	1
wound healing	1
blood coagulation	1
regulation of blood coagulation	1
negative regulation of coagulation	1
negative regulation of wound healing	1
negative regulation of hemostasis	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
regulation of coagulation	1
negative regulation of multicellular organismal process	1
establishment of endothelial barrier	1
positive regulation of endothelial cell development	1
regulation of establishment of endothelial barrier	1
regulation of body fluid levels	1
endopeptidase activity	1
serine-type peptidase activity	1
metal ion binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
serine hydrolase activity	1
catalytic activity	1
cellular anatomical structure	1
endoplasmic reticulum	1
Golgi apparatus	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 7 of 21 annotations. The rest are phylogenetic / computational / electronic (IEA).

7 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of apoptotic process	BP	mutant phenotype
negative regulation of coagulation	BP	mutant phenotype
negative regulation of inflammatory response	BP	mutant phenotype
positive regulation of establishment of endothelial barrier	BP	mutant phenotype
Golgi apparatus	CC	direct assay
endoplasmic reticulum	CC	direct assay
serine-type endopeptidase activity	MF	mutant phenotype

Protein interactions and networks

STRING

showing 15 of 966 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PROC	THBD	P07204	820
PROC	F3	P13726	814
PROC	PGA4	P00790	806
PROC	PGA4	P00790	805
PROC	PGA4	P00790	789
PROC	SERPINC1	P01008	748
PROC	SPINK1	P00995	662
PROC	PROCR	Q9UNN8	651
PROC	TFPI	P10646	628
PROC	CPB2	Q96IY4	595
PROC	F8	P00451	593
PROC	F13B	P05160	593
PROC	F2R	P25116	577
PROC	CPB1	P15086	497
PROC	VWF	P04275	481

IntAct

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

7 partners by confidence:

Partner	Interaction type	MIscore	Records
CYSRT1	physical association	0.560	3
MMP15	physical association	0.400	2
MATR3	physical association	0.400	1
CSNK2B	physical association	0.370	1
TK1	physical association	0.370	1
PROS1	association	0.350	1
WNT5A	association	0.350	1

BioGRID (21 interactions; top human partners by supporting records): EPHA6 (Affinity Capture-MS; 2 records), NPB (Affinity Capture-MS; 2 records), PDF (Affinity Capture-MS; 2 records), SERPINA5 (Reconstituted Complex; 2 records), WNT5A (Affinity Capture-MS; 2 records), CSNK2B (Two-hybrid), CYSRT1 (Two-hybrid), H3F3A (Affinity Capture-MS), KLK1 (Reconstituted Complex), MATR3 (Cross-Linking-MS (XL-MS)), PARP12 (Proximity Label-MS), PF4 (Reconstituted Complex), PROCR (Reconstituted Complex), PROS1 (Affinity Capture-MS), TK1 (Two-hybrid)

SIGNOR signaling

showing 4 of 8 signaling interactions:

A	Effect	B	Mechanism
Thrombin-Thrombomodulin	“up-regulates activity”	PROC	cleavage
PROC	“down-regulates activity”	F7	cleavage
PROC	“down-regulates activity”	F5	cleavage
GGCX	“up-regulates activity”	PROC	carboxylation

Ligand–receptor pairs (CellPhoneDB) (1)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

1 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
PROCR	ligand

Disease & clinical

Genetic variants

Variant evidence for PROC: 490 ClinVar records (92 pathogenic / likely pathogenic); 1 PharmGKB clinical annotation; 5 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	38
Likely pathogenic	54
Uncertain significance	190
Likely benign	109
Benign	18

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 92 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
839161	NM_000312.4(PROC):c.595C>T (p.Arg199Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
677	NM_000312.4(PROC):c.1015G>A (p.Val339Met)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
579309	NM_000312.4(PROC):c.1019C>T (p.Thr340Met)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
1389677	NM_000312.4(PROC):c.445dup (p.His149fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
1074000	NM_000312.4(PROC):c.520C>T (p.Gln174Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
1427775	NM_000312.4(PROC):c.1218G>A (p.Met406Ile)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
838069	NM_000312.4(PROC):c.326_330dup (p.Cys111fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1992373	NM_000312.4(PROC):c.94C>T (p.Arg32Cys)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
161333	NM_000312.4(PROC):c.125G>A (p.Arg42His)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	4
627072	NM_000312.4(PROC):c.440G>A (p.Cys147Tyr)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	4
469122	NM_000312.4(PROC):c.352T>C (p.Phe118Leu)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
546154	NM_000312.4(PROC):c.1216A>G (p.Met406Val)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
627329	NM_000312.4(PROC):c.532G>C (p.Ala178Pro)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
627365	NM_000312.4(PROC):c.715G>A (p.Gly239Arg)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
1067579	NM_000312.4(PROC):c.1099G>A (p.Val367Met)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2

Per-variant reference — Sugi Variant

Explore PROC’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 888):

Position(s)	Effect	Δscore	Sites
2:127421424	donor_gain	1.0000
2:127426194	donor_gain	1.0000
2:127428355–127428356	acceptor_loss	1.0000	5
2:127423128	donor_gain	0.9900
2:127423409–127423410	donor_loss	0.9900	5
2:127426099	acceptor_gain	0.9900
2:127427103–127427104	acceptor_loss	0.9900	6
2:127427193	donor_gain	0.9900
2:127428356	acceptor_loss	0.9900
2:127418493–127418494	donor_loss	0.9800	6

AlphaMissense

900 missense substitutions predicted likely pathogenic (of 3,068 scored), across 212 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
D299	8	0.989	0.997
D401	8	0.980	0.992
H253	8	0.965	0.982
D396	8	0.962	0.989
S421	8	0.953	0.997
S402	8	0.939	0.987
M385	8	0.836	0.922
C387	7	0.995	0.999
C254	7	0.994	0.997
C373	7	0.992	0.998
W342	7	0.990	0.998
C426	7	0.989	0.996
C398	7	0.988	0.995
C238	7	0.984	0.994
C319	7	0.984	0.989
C140	7	0.979	0.989
C151	7	0.976	0.989
C147	7	0.974	0.991
W444	7	0.972	0.996
W225	7	0.969	0.996

HPA cancer prognostics

RNA cancer specificity: Cancer enriched (Liver Hepatocellular Carcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (validation)	favorable	0.000935

Disease associations

OMIM: gene MIM:612283 | disease phenotypes: MIM:176860, MIM:612304

GenCC curated gene-disease

3 curated gene-disease records:

Disease	Classification	Inheritance	Records
thrombophilia due to protein C deficiency, autosomal dominant	Definitive	Autosomal dominant	4
hereditary thrombophilia due to congenital protein C deficiency	Definitive	Semidominant	2
thrombophilia due to protein C deficiency, autosomal recessive	Strong	Autosomal recessive	3

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
hereditary thrombophilia due to congenital protein C deficiency	Definitive	SD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (3 panels, 2 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

3 panels:

Panel	Rating
Inherited bleeding disorders	green
Thrombophilia with a likely monogenic cause	green
Fetal anomalies	amber

Mondo (4): thrombophilia due to protein C deficiency, autosomal dominant (MONDO:0008316), thrombophilia due to protein C deficiency, autosomal recessive (MONDO:0012860), hereditary thrombophilia due to congenital protein C deficiency (MONDO:0019145), cerebral palsy (MONDO:0006497)

Orphanet (1): Severe hereditary thrombophilia due to congenital protein C deficiency (Orphanet:745)

HPO phenotypes

27 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000478	Abnormality of the eye
HP:0000707	Abnormality of the nervous system
HP:0000963	Thin skin
HP:0000979	Purpura
HP:0001000	Abnormal skin pigmentation
HP:0001038	Warfarin-induced skin necrosis
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0002204	Pulmonary embolism
HP:0002625	Deep venous thrombosis
HP:0002638	Superficial thrombophlebitis
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003623	Neonatal onset
HP:0004850	Recurrent deep vein thrombosis
HP:0004936	Venous thrombosis
HP:0005293	Venous insufficiency
HP:0005305	Cerebral venous thrombosis
HP:0005543	Reduced protein C activity
HP:0007902	Vitreous hemorrhage
HP:0008065	Aplasia/Hypoplasia of the skin
HP:0100021	Cerebral palsy
HP:0100659	Abnormal cerebral vascular morphology
HP:0100724	Hypercoagulability
HP:0100758	Gangrene

GWAS associations

5 associations:

Study	Trait	p-value
GCST006119_6	Protein C levels	2e-42
GCST000780_2	Protein C levels	4e-36
GCST006585_2180	Blood protein levels	5e-13
GCST002686_1	Protein C levels	2e-12
GCST006585_2832	Blood protein levels	2e-12

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004633	protein C measurement

MeSH disease descriptors

4 disease descriptors:

Descriptor	Name	Tree numbers
D002547	Cerebral Palsy	C10.228.140.140.254
D020151	Protein C Deficiency	C15.378.100.100.690; C15.378.147.880; C15.378.925.795; C16.320.099.690
C535424	Congenital thrombotic disease, due to Protein C deficiency *(supp.)*
C567353	Thrombophilia, Hereditary, Due To Protein C Deficiency, Autosomal Recessive *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4444 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the PROC protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

2 curated-mechanism drugs:

Drug	Modality	Max phase
PROTEIN C CONCENTRATE (HUMAN)	Unknown	4
PROTHROMBIN COMPLEX CONCENTRATE	Protein	3

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 19,099 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

2 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL266349	MELAGATRAN	4	5,456
CHEMBL48361	DABIGATRAN	3	13,643

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

1 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs1799808	Dosage	3	phenprocoumon

PharmGKB variants

1 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1799808	PROC	3	1.75	1	phenprocoumon

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs1799808	phenprocoumon	Dosage, Metabolism/PK	Genotype CC is associated with increased dose of phenprocoumon as compared to genotypes CT + TT.	PMID:21110013

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — S1: Chymotrypsin

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 37 [PMID: 24418773]	Inhibition	7.4	pKi

Binding affinities (BindingDB)

242 measured of 320 human assays (344 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL3956096	KI	0.06 nM
N-(4-chloro-2-(5-chloropyridin-2-ylcarbamoyl)phenyl)-4-(N,N-dimethylcarbamimidoyl)-2-fluorobenzamide	KI	0.06 nM
CHEMBL3900166	KI	0.14 nM
1-[3-(Aminomethyl)phenyl]-N-[3-fluoro-2-(methylsulfonyl)-[1,1-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide	KI	0.15 nM
5-chloro-N-(5-chloropyridin-2-yl)-2-(4-((2-iminooxazolidin-3-yl)methyl)benzamido)benzamide	IC50	0.2 nM
CHEMBL3984725	KI	0.22 nM
CHEMBL3898956	KI	0.24 nM
5-Chloro-N-(5-chloro-pyridin-2-yl)-2-(4-{[methyl-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-amino]-methyl}-benzoylamino)-benzamide	IC50	0.3 nM
(2R)-N-[(3-aminobenzene)sulfonyl]-2-[(4-carbamimidoyl-3-hydroxyphenyl)amino]-2-(3,5-diethoxy-2-fluorophenyl)acetamide	KI	0.35 nM
(2R,3R)-2-(3-Carbamimidoyl-benzyl)-3-[(3’-carbamoyl-biphenyl-4-carbonyl)-amino]-butyric acid methyl ester	KI	0.5 nM
(R)-5-Guanidino-2-phenylmethanesulfonylamino-pentanoic acid {[(R)-4-guanidino-1-(thiazole-2-carbonyl)-butylcarbamoyl]-methyl}-amide	IC50	0.5 nM
5-chloro-N-(5-chloro-pyridin-2-yl)-2-[4-(N,N-dimethyl-carbamimidoyl)-benzoylamino]-benzamide	IC50	0.5 nM
2-[4-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-yl]-N-[4-guanidino-1-(thiazole-2-carbonyl)-butyl]-acetamide	IC50	0.51 nM
CHEMBL3898371	KI	0.55 nM
4-hydroxy-3-{[(3S)-2-oxo-3-{thieno[3,2-b]pyridine-2-sulfonamido}pyrrolidin-1-yl]methyl}benzene-1-carboximidamide	KI	0.7 nM
5-Chloro-N-(5-chloro-pyridin-2-yl)-2-[4-(N,N’-dimethyl-guanidinomethyl)-benzoylamino]-benzamide	IC50	0.7 nM
N-(2-(5-chloropyridin-2-ylcarbamoyl)-4-methoxyphenyl)-4-(N,N-dimethylcarbamimidoyl)-2-fluorobenzamide	IC50	0.7 nM
CHEMBL3967204	KI	0.72 nM
2-[4-(5-Chloro-naphthalene-2-sulfonyl)-2-oxo-piperazin-1-yl]-N-[4-guanidino-1-(thiazole-2-carbonyl)-butyl]-acetamide	IC50	0.79 nM
{4-[4-Chloro-2-(5-chloro-pyridin-2-ylcarbamoyl)-phenylcarbamoyl]-benzyl}-trimethyl-ammonium	IC50	0.8 nM
5-Chloro-N-(5-chloro-pyridin-2-yl)-2-[4-(N,N’,N’’-trimethyl-guanidinomethyl)-benzoylamino]-benzamide	IC50	0.8 nM
5-Chloro-N-(5-chloro-pyridin-2-yl)-2-[4-(N’,N’-dimethyl-hydrazinomethyl)-benzoylamino]-benzamide	IC50	0.9 nM
2-{4-[(Acetimidoyl-methyl-amino)-methyl]-benzoylamino}-5-chloro-N-(5-chloro-pyridin-2-yl)-benzamide	IC50	0.9 nM
5-Chloro-N-(5-chloro-pyridin-2-yl)-2-{4-[(N-methyl-guanidino)-methyl]-benzoylamino}-benzamide	IC50	1 nM
2-[4-({[2-(Acetimidoyl-methyl-amino)-ethyl]-methyl-amino}-methyl)-benzoylamino]-5-chloro-N-(5-chloro-pyridin-2-yl)-benzamide	IC50	1.1 nM
5-Chloro-N-(5-chloro-pyridin-2-yl)-2-[4-(2-dimethylamino-4,5-dihydro-imidazol-1-ylmethyl)-benzoylamino]-benzamide	IC50	1.3 nM
5-Chloro-N-(5-chloro-pyridin-2-yl)-2-(4-guanidinomethyl-benzoylamino)-benzamide	IC50	1.4 nM
3-[(S)-3-(5-Chloro-thieno[3,2-b]pyridine-2-sulfonylamino)-2-oxo-pyrrolidin-1-ylmethyl]-4-hydroxy-benzamidine	KI	1.5 nM
5-Chloro-N-(5-chloro-pyridin-2-yl)-2-(4-{[(4,5-dihydro-oxazol-2-yl)-methyl-amino]-methyl}-benzoylamino)-benzamide	IC50	1.5 nM
5-Chloro-N-(5-chloro-pyridin-2-yl)-2-[4-(2-imino-imidazolidin-1-ylmethyl)-benzoylamino]-benzamide	IC50	1.5 nM
N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide	IC50	1.5 nM
4-Hydroxy-3-[(S)-2-oxo-3-(thieno[2,3-c]pyridine-2-sulfonylamino)-pyrrolidin-1-ylmethyl]-benzamidine	KI	2 nM
3-[(S)-3-(4-Chloro-thieno[3,2-c]pyridine-2-sulfonylamino)-2-oxo-pyrrolidin-1-ylmethyl]-4-hydroxy-benzamidine	KI	2 nM
N-[4-Guanidino-1-(thiazole-2-carbonyl)-butyl]-2-[2-oxo-4-(quinoline-8-sulfonyl)-piperazin-1-yl]-acetamide	IC50	2 nM
2-[4-(4-Chloro-benzenesulfonyl)-2-oxo-piperazin-1-yl]-N-[(R)-4-guanidino-1-(thiazole-2-carbonyl)-butyl]-acetamide	IC50	2 nM
2-(3-Methanesulfonyl-naphthalen-2-yl)-5-methyl-2H-pyrazole-3-carboxylic acid [2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-amide	IC50	2 nM
2-(3-Fluoro-naphthalen-2-yl)-5-methyl-2H-pyrazole-3-carboxylic acid (2’-aminomethyl-3-fluoro-biphenyl-4-yl)-amide	IC50	2 nM
2-(6-Chloro-naphthalen-2-yl)-5-methyl-2H-pyrazole-3-carboxylic acid (2’-dimethylaminomethyl-3-fluoro-biphenyl-4-yl)-amide	IC50	2 nM
5-Chloro-N-(5-chloro-pyridin-2-yl)-2-[4-({methyl-[2-(N-methyl-guanidino)-ethyl]-amino}-methyl)-benzoylamino]-benzamide	IC50	2 nM
5-Chloro-N-(5-chloro-pyridin-2-yl)-2-(4-{[(4,5-dihydro-1H-imidazol-2-yl)-methyl-amino]-methyl}-benzoylamino)-benzamide	IC50	2 nM
(2R)-2-(5-CHLORO-2-THIENYL)-N-{(3S)-1-[(1S)-1-METHYL-2-MORPHOLIN-4-YL-2-OXOETHYL]-2-OXOPYRROLIDIN-3-YL}PROPENE-1-SULFONAMIDE	KI	2 nM
CHEMBL2153381	IC50	2.1 nM
1-{4-[4-Chloro-2-(5-chloro-pyridin-2-ylcarbamoyl)-phenylcarbamoyl]-benzyl}-1-methyl-pyrrolidinium	IC50	2.3 nM
CHEMBL2153377	IC50	2.7 nM
4-hydroxy-3-{[(3S)-3-[(7-methoxynaphthalene-2-)sulfonamido]-2-oxopyrrolidin-1-yl]methyl}benzene-1-carboximidamide	KI	3 nM
4-Amino-3-[(S)-3-(5-chloro-thieno[3,2-b]pyridine-2-sulfonylamino)-2-oxo-pyrrolidin-1-ylmethyl]-benzamidine	KI	3 nM
4-Hydroxy-3-[(S)-2-oxo-3-(thieno[3,2-c]pyridine-2-sulfonylamino)-pyrrolidin-1-ylmethyl]-benzamidine	KI	3 nM
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl}-benzamidine	IC50	3 nM
(S)-2-(3-Carbamimidoyl-benzoyl)-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (2’-sulfamoyl-biphenyl-4-yl)-amide	IC50	3 nM
1-(4-Amino-quinazolin-7-ylmethyl)-4-(6-chloro-1H-benzoimidazole-2-sulfonyl)-piperazin-2-one	KI	3 nM

ChEMBL bioactivities

129 potent at pChembl≥5 of 179 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.34	Ki	0.46	nM	CHEMBL4471466
9.21	Ki	0.61	nM	CHEMBL2016865
8.72	Ki	1.9	nM	CHEMBL4638245
8.29	Ki	5.1	nM	CHEMBL2016866
7.57	Ki	27	nM	CHEMBL3660179
7.41	Ki	39	nM	CHEMBL2315240
7.41	Ki	39	nM	CHEMBL3898956
7.40	Ki	40	nM	CHEMBL3115901
7.39	Ki	41	nM	CHEMBL3594313
7.32	Ki	48	nM	CHEMBL2016869
7.22	Ki	60	nM	CHEMBL3660177
7.16	Ki	70	nM	CHEMBL3898371
7.14	Ki	73	nM	CHEMBL3127463
7.05	Ki	90	nM	CHEMBL2016871
7.00	Ki	100	nM	CHEMBL3115900
7.00	Ki	100	nM	CHEMBL3115904
7.00	IC50	100	nM	CHEMBL211973
6.89	IC50	130	nM	CHEMBL3115901
6.81	Ki	155	nM	CHEMBL3956096
6.76	Ki	175	nM	CHEMBL3967204
6.72	Ki	190	nM	CHEMBL3902498
6.70	Ki	200	nM	CHEMBL3115897
6.68	Ki	210	nM	CHEMBL3660187
6.66	Ki	220	nM	CHEMBL3934882
6.65	Ki	223	nM	CHEMBL2016870
6.60	IC50	250	nM	CHEMBL215639
6.60	Ki	250	nM	CHEMBL3660188
6.58	IC50	260	nM	CHEMBL3115900
6.52	Ki	300	nM	CHEMBL3115903
6.52	Ki	300	nM	CHEMBL3115899
6.52	Ki	300	nM	CHEMBL3115898
6.52	Ki	300	nM	CHEMBL3115894
6.51	Ki	310	nM	CHEMBL3660171
6.47	Ki	340	nM	CHEMBL3984725
6.46	IC50	350	nM	CHEMBL425613
6.40	Ki	400	nM	CHEMBL3115893
6.40	Ki	400	nM	CHEMBL3660173
6.38	Ki	420	nM	CHEMBL2315242
6.37	IC50	430	nM	CHEMBL215357
6.33	IC50	470	nM	CHEMBL3115904
6.30	Ki	500	nM	CHEMBL3115905
6.30	Ki	500	nM	CHEMBL215295
6.26	Ki	555	nM	CHEMBL3660186
6.25	Ki	564	nM	CHEMBL2016868
6.24	Ki	570	nM	CHEMBL3660190
6.22	Ki	600	nM	CHEMBL3660191
6.17	IC50	670	nM	CHEMBL3115897
6.15	IC50	710	nM	CHEMBL212789
6.14	Ki	725	nM	CHEMBL3900166
6.12	IC50	750	nM	CHEMBL380157

PubChem BioAssay actives

107 with measured affinity, of 468 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-[[(2R)-1-[[(2S)-3-[3-(aminomethyl)phenyl]-1-[(4-carbamimidoylphenyl)methylamino]-1-oxopropan-2-yl]amino]-1-oxo-5-phenylpentan-2-yl]sulfamoylmethyl]benzoic acid	1558649: Inhibition of activated protein kinase C (unknown origin)	ki	0.0005	uM
3-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-3-[3-[(diaminomethylideneamino)methyl]phenyl]-1-oxopropan-2-yl]amino]-1-oxo-5-phenylpentan-2-yl]sulfamoylmethyl]benzoic acid	656104: Inhibition of activated protein C by dixon plot method	ki	0.0006	uM
methyl N-[(10R,14S)-14-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-2,3-dihydropyridin-1-yl]-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.02,7]nonadeca-1(19),2(7),3,5,15,17-hexaen-5-yl]carbamate	1657779: Inhibition of human activated protein C using pyro-Glu-Pro-Arg-pNA(para-nitroaniline) substrate by spectrophotometry	ki	0.0019	uM
(7S,10R)-10-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-4,9,13-trioxo-3,8,14-triazabicyclo[14.3.1]icosa-1(19),16(20),17-triene-7-carboxamide	656104: Inhibition of activated protein C by dixon plot method	ki	0.0051	uM
(11S,14R)-14-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-3,13,22-trioxo-1,4,12,21,24-pentazatetracyclo[22.2.2.15,9.116,20]triaconta-5,7,9(30),16(29),17,19-hexaene-11-carboxamide;2,2,2-trifluoroacetic acid	724897: Inhibition of human activated protein C using H-D-Lys(Cbz)-Pro-Arg-pNA as substrate after 5 to 10 mins by micro plate reader analysis	ki	0.0390	uM
(5R,11R)-11-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-16-cyclopropylsulfonyl-7-(2,2-difluoroethoxy)-5,13-dimethyl-2,13-diazatricyclo[13.3.1.16,10]icosa-1(19),6,8,10(20),15,17-hexaene-3,12-dione	1331378: Inhibition of activated protein C (unknown origin)	ki	0.0390	uM
2-[[(2R)-1-[[(2S)-3-(4-aminophenyl)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxopropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.0400	uM
4-[[(2R)-7-ethylsulfonyl-3,12-dioxo-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(19),6,8,10(21),16(20),17-hexaen-2-yl]amino]benzenecarboximidamide	1235265: Inhibition of human APC measured for 30 mins	ki	0.0410	uM
(12S,15R)-15-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-3,14,24-trioxo-1,4,13,23,26-pentazatetracyclo[24.2.2.16,10.117,21]dotriaconta-6,8,10(32),17(31),18,20-hexaene-12-carboxamide	656104: Inhibition of activated protein C by dixon plot method	ki	0.0480	uM
1-[(2R,15R)-2-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-4,15,17-trimethyl-3,12-dioxo-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10(21),16,19-hexaen-7-yl]cyclopropane-1-carboxylic acid	1316615: Inhibition of activated protein C (unknown origin) at 37 degC by chromogenic substrate assay	ki	0.0700	uM
2-[3-(6-carbamimidoyl-4-methyl-4-phenyl-2,3-dihydro-1H-quinolin-2-yl)-5-(3-methylbutanoylamino)phenyl]-5-carbamoylbenzoic acid	1074188: Binding affinity to human activated protein C assessed as release of p-nitroaniline after 10 to 120 mins by spectrophotometric analysis	ki	0.0730	uM
(2R)-N-(3-aminophenyl)sulfonyl-2-(4-carbamimidoyl-3-hydroxyanilino)-2-(3,5-diethoxy-2-fluorophenyl)acetamide	1797275: Serine Protease Inhibition Assay from Article 10.1074/jbc.M409068200: “A selective, slow binding inhibitor of factor VIIa binds to a nonstandard active site conformation and attenuates thrombus formation in vivo.”	ki	0.0870	uM
(13S,16R)-16-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-15-oxo-2,7-dioxa-14-azatricyclo[16.2.2.28,11]tetracosa-1(21),4,8,10,18(22),19,23-heptaene-13-carboxamide	656104: Inhibition of activated protein C by dixon plot method	ki	0.0900	uM
2-[[(2R)-1-[[2-[(4-carbamimidoylphenyl)methylcarbamoyl]-1,3-dihydroinden-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	268973: Inhibition of human aPC	ic50	0.1000	uM
2-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.1000	uM
2-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.1000	uM
1-[(2R,15R)-2-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-4,15,17-trimethyl-3,12-dioxo-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10(21),16,19-hexaen-7-yl]cyclohexane-1-carboxylic acid	1316615: Inhibition of activated protein C (unknown origin) at 37 degC by chromogenic substrate assay	ki	0.1550	uM
(2R,15R)-2-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-4,15,17-trimethyl-7-[1-(2H-tetrazol-5-yl)cyclopropyl]-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10(21),16,19-hexaene-3,12-dione	1316615: Inhibition of activated protein C (unknown origin) at 37 degC by chromogenic substrate assay	ki	0.1750	uM
(2R,15R)-2-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-7-cyclopropylsulfonyl-4,15,17-trimethyl-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10(21),16,19-hexaene-3,12-dione	1315785: Inhibition of human activated protein C using pyroGlu-Pro-Arg-pNA as substrate assessed as release of pNA after 10 to 120 mins by spectrophotometric method	ki	0.1900	uM
2-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.2000	uM
(2R,15R)-2-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-7-cyclopropyl-4,15,17-trimethyl-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10(21),16,19-hexaene-3,12-dione	1316615: Inhibition of activated protein C (unknown origin) at 37 degC by chromogenic substrate assay	ki	0.2200	uM
(21S,24R)-24-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-4,12,23-trioxo-3,13,22-triazatetracyclo[24.3.1.16,10.115,19]dotriaconta-1(29),6(32),7,9,15,17,19(31),26(30),27-nonaene-21-carboxamide	656104: Inhibition of activated protein C by dixon plot method	ki	0.2230	uM
2-[[(2R)-1-[[2-[(4-carbamimidoylphenyl)methylcarbamoyl]-1,3-dihydrocyclopenta[a]naphthalen-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]acetic acid	268973: Inhibition of human aPC	ic50	0.2500	uM
2-[[(2R)-1-[[3-[4-(aminomethyl)phenyl]-1-[(4-carbamimidoylphenyl)methylamino]-1-oxopropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.3000	uM
2-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-3-naphthalen-1-yl-1-oxopropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.3000	uM
2-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.3000	uM
2-[[(2R)-1-[[1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.3000	uM
1-[(2R,15R)-2-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-4,15,17-trimethyl-3,12-dioxo-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10(21),16,19-hexaen-7-yl]cyclopentane-1-carboxylic acid	1316615: Inhibition of activated protein C (unknown origin) at 37 degC by chromogenic substrate assay	ki	0.3400	uM
2-[[(2R)-1-[[(1S)-2-[(4-carbamimidoylphenyl)methylamino]-1-(2,3-dihydro-1H-inden-2-yl)-2-oxoethyl]amino]-3-methyl-1-oxobutan-2-yl]amino]acetic acid	268973: Inhibition of human aPC	ic50	0.3500	uM
2-[[(2R)-1-[[1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-3-piperidin-4-ylpropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.4000	uM
(18R,21S)-18-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-3,10,19-trioxo-2,5,8,11,20-pentazatetracyclo[21.2.2.25,8.112,16]triaconta-1(26),12,14,16(28),23(27),24-hexaene-21-carboxamide;2,2,2-trifluoroacetic acid	724897: Inhibition of human activated protein C using H-D-Lys(Cbz)-Pro-Arg-pNA as substrate after 5 to 10 mins by micro plate reader analysis	ki	0.4200	uM
2-[[(2R)-1-[[2-[(4-carbamimidoylphenyl)methylcarbamoyl]-1,3-dihydrophenalen-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]acetic acid	268973: Inhibition of human aPC	ic50	0.4300	uM
(2S)-2-[[(2R)-2-amino-2-cyclohexylacetyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-5-(diaminomethylideneamino)pentanamide	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.5000	uM
2-[[(1R)-2-[[2-[(4-carbamimidoylphenyl)methylcarbamoyl]-1,3-dihydroinden-2-yl]amino]-1-cyclohexyl-2-oxoethyl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.5000	uM
(12S,15R)-15-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-3,14,24-trioxo-4,13,23-triazatetracyclo[24.2.2.16,10.117,21]dotriaconta-1(29),6,8,10(32),17(31),18,20,26(30),27-nonaene-12-carboxamide	656104: Inhibition of activated protein C by dixon plot method	ki	0.5640	uM
2-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-3-phenylpropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]acetic acid	268973: Inhibition of human aPC	ic50	0.7100	uM
1-[(2R,15R)-2-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-4,15,17-trimethyl-3,12-dioxo-13-oxa-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10(21),16,19-hexaen-7-yl]cyclobutane-1-carboxylic acid	1316615: Inhibition of activated protein C (unknown origin) at 37 degC by chromogenic substrate assay	ki	0.7250	uM
2-[[(2R)-1-[[2-[(4-carbamimidoylphenyl)methylcarbamoyl]-1,3-dihydroinden-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]acetic acid	268973: Inhibition of human aPC	ic50	0.7500	uM
2-[[(2R)-1-[[2-[(4-carbamimidoylphenyl)methylcarbamoyl]-1,3-dihydroinden-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]acetic acid	268973: Inhibition of human aPC	ic50	0.8000	uM
3-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]propanoic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.8000	uM
(2R)-2-[(1-aminoisoquinolin-6-yl)amino]-7-ethylsulfonyl-17-methyl-4,11-diazatricyclo[14.2.2.16,10]henicosa-1(18),6,8,10(21),16,19-hexaene-3,12-dione	1235265: Inhibition of human APC measured for 30 mins	ki	0.8300	uM
(20S,23R)-23-(benzylsulfonylamino)-N-[(4-carbamimidoylphenyl)methyl]-3,12,22-trioxo-2,6,9,13,21-pentazatetracyclo[23.2.2.26,9.114,18]dotriaconta-1(28),14,16,18(30),25(29),26-hexaene-20-carboxamide;2,2,2-trifluoroacetic acid	724897: Inhibition of human activated protein C using H-D-Lys(Cbz)-Pro-Arg-pNA as substrate after 5 to 10 mins by micro plate reader analysis	ki	0.8800	uM
2-[[(2R)-2-amino-3-cyclohexylpropanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.9000	uM
2-[[(2R)-1-[[(1S)-2-[(4-carbamimidoylphenyl)methylamino]-2-oxo-1-piperidin-4-ylethyl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	0.9000	uM
2-[[(2R)-1-[[6-[(4-carbamimidoylphenyl)methylcarbamoyl]-5,7-dihydrocyclopenta[b]pyridin-6-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]acetic acid	268973: Inhibition of human aPC	ic50	1.0700	uM
2-[[(2R)-1-[[1-[(4-carbamimidoylphenyl)methylamino]-3-(4-cyanophenyl)-1-oxopropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid	1069315: Competitive inhibition of human APC using S-2366 as substrate	ki	1.1000	uM
2-[[(2R)-1-[[2-[(4-carbamimidoylphenyl)methylcarbamoyl]-1,3-dihydroinden-2-yl]amino]-4-methyl-1-oxohexan-2-yl]amino]acetic acid	268973: Inhibition of human aPC	ic50	1.1200	uM
(11R)-11-[(1-amino-4-fluoroisoquinolin-6-yl)amino]-16-cyclopropylsulfonyl-7-(2,2-difluoroethoxy)-13-methyl-2,13-diazatricyclo[13.3.1.16,10]icosa-1(19),6,8,10(20),15,17-hexaene-3,12-dione	1331378: Inhibition of activated protein C (unknown origin)	ki	1.2000	uM
3-[[(3S)-3-[(7-methoxynaphthalen-2-yl)sulfonylamino]-2-oxopyrrolidin-1-yl]methyl]benzenecarboximidamide	30725: Compound was evaluated for the inhibition of activated protein C (aPC)	ki	1.2000	uM
2-[[(1R)-2-[(2S)-2-[(4-carbamimidoylphenyl)methylcarbamoyl]azetidin-1-yl]-1-cyclohexyl-2-oxoethyl]amino]acetic acid	1069326: Inhibition of human APC using S-2366 as substrate preincubated for 300 seconds followed by substrate addition measured after 40 mins by spectrophotometric analysis	ic50	1.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
ethinyl estradiol-desogestrel combination	affects activity, decreases expression, increases activity, increases expression	8
Ethinyl Estradiol	increases expression, affects cotreatment, increases activity, affects expression, affects binding	7
Gestodene	increases expression, decreases activity, decreases expression, affects cotreatment, affects expression (+1 more)	6
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	5
Cyclosporine	decreases expression, increases expression, affects expression	4
Aflatoxin B1	affects expression, decreases expression, decreases methylation	4
Benzo(a)pyrene	affects methylation, decreases expression	3
Contraceptives, Oral	affects activity, decreases expression, affects response to substance	3
Levonorgestrel	increases activity, increases expression, affects cotreatment	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
Air Pollutants	decreases expression, increases abundance, increases expression	2
Estradiol	increases expression, decreases expression, affects cotreatment	2
Warfarin	affects response to substance, increases response to substance	2
aristolochic acid I	increases expression	1
testosterone enanthate	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
terbufos	increases methylation	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
norgestimate	affects cotreatment, increases expression	1
sodium arsenite	decreases expression	1
tetrabromobisphenol A	decreases expression	1
dienogest	affects cotreatment, increases activity	1
cupric chloride	decreases reaction, affects binding, decreases activity	1
zinc sulfide	decreases expression, affects cotreatment	1
CycloProvera	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
CMF protocol	decreases expression	1
brequinar	decreases expression	1

ChEMBL screening assays

117 unique, capped per target: 117 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1008037	Binding	Inhibition of activated protein C	Design, structure-activity relationships, X-ray crystal structure, and energetic contributions of a critical P1 pharmacophore: 3-chloroindole-7-yl-based factor Xa inhibitors. — *J Med Chem*

Clinical trials (associated diseases)

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

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00154830	Phase 4	COMPLETED	Alterations of Functional Activities and Leg Stiffness After Hamstring Lengthening in Cerebral Palsy Children
NCT00432055	Phase 4	COMPLETED	Effects of Botulinum Toxin Type A in Adults With Cerebral Palsy
NCT00549471	Phase 4	TERMINATED	Improvement After Botulinum Toxin Injections to the Arms in Children With Cerebral Palsy
NCT00752934	Phase 4	TERMINATED	Does Oral Baclofen Improve Care and Comfort in Spastic Children in Nursing Homes?
NCT00964639	Phase 4	COMPLETED	Postoperative Pain in Children With Cerebral Palsy After Pelvic and Femoral Osteotomies
NCT01386255	Phase 4	WITHDRAWN	Placebo Controlled Study of Baclofen for GERD in Children With Cerebral Palsy
NCT02546999	Phase 4	COMPLETED	Does Botulinum Toxin A Make Walking Easier in Children With Cerebral Palsy?
NCT02633241	Phase 4	COMPLETED	A Pilot Study of Dexmedetomidine-Propofol in Children Undergoing Magnetic Resonance Imaging
NCT03117322	Phase 4	COMPLETED	Synbiotic, Prebiotics and Probiotics in Children With Cerebral Palsy and Constipation
NCT03648658	Phase 4	UNKNOWN	Paracetamol Study in Patients With Low Muscle Mass
NCT04074265	Phase 4	COMPLETED	Peri-operative Use of a Pain Injection in Pediatric Patients With Cerebral Palsy
NCT04273737	Phase 4	TERMINATED	Amantadine in Treating Cognitive & Motor Impairments in Adolescents and Adults With Cerebral Palsy
NCT04523935	Phase 4	COMPLETED	Excessive Crying in Children With Cerebral Palsy and Communication Deficits
NCT05887765	Phase 4	COMPLETED	Effect of Systematic Dexamethasone on the Duration of Popliteal Nerve Block for Anesthesia After Pediatric Ankle Surgery
NCT06176430	Phase 4	UNKNOWN	Comparison of Twice Weekly Versus Daily Iron Therapy in Treating Anemia in Children With Cerebral Palsy
NCT06189781	Phase 4	RECRUITING	Pain Injection Versus Epidural Anesthesia for Hip Surgery in Pediatric Patients With Cerebral Palsy
NCT00014989	Phase 3	COMPLETED	Beneficial Effects of Antenatal Magnesium Sulfate (BEAM Trial)
NCT00065949	Phase 3	UNKNOWN	Magnesium Sulfate to Prevent Brain Injury in Premature Infants
NCT00367068	Phase 3	COMPLETED	Dutch National ITB Study in Children With Cerebral Palsy
NCT00491894	Phase 3	COMPLETED	Safety and Efficacy Study of Oral Glycopyrrolate Liquid for the Treatment of Pathologic (Chronic Moderate to Severe) Drooling in Pediatric Patients 3 to 18 Years of Age With Cerebral Palsy or Other Neurologic Conditions
NCT00632528	Phase 3	COMPLETED	MEOPA to Improve Physical Therapy Results After Multilevel Surgery
NCT00822029	Phase 3	TERMINATED	Use of Oral Bisphosphonates in the Treatment of Osteoporosis of Non-walking Children With Cerebral Palsy
NCT00922077	Phase 3	COMPLETED	Individualized Neurodevelopmental Treatment
NCT01249417	Phase 3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Study
NCT01251380	Phase 3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Follow-on Study
NCT01437644	Phase 3	COMPLETED	The Post-Operative Pain in Cerebral Palsy (POPPIES) Trial
NCT01492608	Phase 3	COMPLETED	Magnesium Sulphate for Preterm Birth (MASP Study)
NCT01603602	Phase 3	COMPLETED	BOTOX® Treatment in Pediatric Upper Limb Spasticity
NCT01603615	Phase 3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Upper Limb Spasticity
NCT01603628	Phase 3	COMPLETED	BOTOX® Treatment in Pediatric Lower Limb Spasticity
NCT01603641	Phase 3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Lower Limb Spasticity
NCT01633736	Phase 3	UNKNOWN	Targeted Hip Strength Training in Children With Cerebral Palsy (CP)
NCT01898520	Phase 3	COMPLETED	A Safety, Efficacy and Tolerability Study of Sativex for the Treatment of Spasticity in Children Aged 8 to 18 Years
NCT01929434	Phase 3	COMPLETED	Efficacy of Stem Cell Transplantation Compared to Rehabilitation Treatment of Patients With Cerebral Paralysis
NCT02002884	Phase 3	COMPLETED	Dose-response Study of Efficacy and Safety of Botulinum Toxin Type A to Treat Spasticity of the Arm(s) or of Arm(s) and Leg(s) in Cerebral Palsy
NCT02270736	Phase 3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02839785	Phase 3	TERMINATED	Analgesia and Physiotherapy in Children With Cerebral Palsy (ANTALKINECP)
NCT03110341	Phase 3	UNKNOWN	Effect of Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome
NCT03302871	Phase 3	COMPLETED	Integrated Management Enhances Functional Gains in Children With Cerebral Palsy Treated by BoNT-A
NCT03306212	Phase 3	COMPLETED	Efficacy of Intermittent Serial Casting on Spastic Wrist Flexion Deformity
NCT03469999	Phase 3	COMPLETED	Effect of Dysport Injections on Energy Expenditure and Walking Efficiency in Children With Cerebral Palsy
NCT03472261	Phase 3	COMPLETED	Integrated Management of Pronation Deformity in Cerebral Palsy
NCT03616067	Phase 3	TERMINATED	Evaluation of the Efficacy of the Injection of Botulinum Toxin A vs Scopolamine Patches in the Treatment of Drooling in Children With Cerebral Palsy
NCT05206513	Phase 3	COMPLETED	Study to Assess the Efficacy, Safety, and Tolerability of Valbenazine for the Treatment of Dyskinesia Due to Cerebral Palsy
NCT06128616	Phase 3	UNKNOWN	Efficacy of Extracorporeal Shock Wave Therapy in Children With Cerebral Palsy
NCT06840158	Phase 3	COMPLETED	Double-blind Comparative Randomized Multicenter
NCT07524972	Phase 3	RECRUITING	Antenatal Magnesium Sulphate in High-Risk Preterm Patients
NCT07672158	Phase 3	NOT_YET_RECRUITING	Tranexamic Acid to Reduce Blood Loss After Varus Derotation Osteotomy
NCT00060957	Phase 2	COMPLETED	Botulinum Toxin (BOTOX) for Cerebral Palsy
NCT00061139	Phase 2	UNKNOWN	Constraint-Based Therapy to Improve Motor Function in Children With Cerebral Palsy
NCT00114075	Phase 2	COMPLETED	Effects of Walking Analysis on Surgical Outcomes
NCT00221247	Phase 2	COMPLETED	Acupuncture as Complementary Therapy for Cerebral Palsy
NCT00221611	Phase 2	COMPLETED	Intrathecal Administration of Baclofen (ITB) to Cerebral Palsy Patients With Therapy-Resistant Spasticity
NCT00295295	Phase 2	COMPLETED	Vibration Intervention to Improve Bone and Muscle in Children With Cerebral Palsy
NCT00413946	Phase 2	COMPLETED	Does Erythropoietin Improve Outcome in Very Preterm Infants?
NCT00455637	Phase 2	TERMINATED	Which is the Best Dose of Dysport in Helping With Hip Pain for Children With Cerebral Palsy?
NCT00467207	Phase 2	COMPLETED	Intensive Strength Training in Children With Cerebral Palsy - Effect on Hand Function
NCT01028833	Phase 2	COMPLETED	Effects of Power Mobility on Young Children With Severe Motor Impairments
NCT01115998	Phase 2	COMPLETED	Effect of Power Wheelchairs on the Development and Function of Young Children With Severe Physical Disabilities
NCT01147653	Phase 2	COMPLETED	A Randomized Study of Autologous Umbilical Cord Blood Reinfusion in Children With Cerebral Palsy

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PROC across ~30M SureChEMBL compounds — explore on Sugi Predict.