F12

Summary

F12 (coagulation factor XII, HGNC:3530) is a protein-coding gene on chromosome 5q35.3, encoding Coagulation factor XII (P00748). Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin.

This gene encodes coagulation factor XII which circulates in blood as a zymogen. This single chain zymogen is converted to a two-chain serine protease with an heavy chain (alpha-factor XIIa) and a light chain. The heavy chain contains two fibronectin-type domains, two epidermal growth factor (EGF)-like domains, a kringle domain and a proline-rich domain, whereas the light chain contains only a catalytic domain. On activation, further cleavages takes place in the heavy chain, resulting in the production of beta-factor XIIa light chain and the alpha-factor XIIa light chain becomes beta-factor XIIa heavy chain. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then to beta-factor XIIa. The active factor XIIa participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. It activates coagulation factors VII and XI. Defects in this gene do not cause any clinical symptoms and the sole effect is that whole-blood clotting time is prolonged.

Source: NCBI Gene 2161 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital factor XII deficiency (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 24
• Clinical variants (ClinVar): 264 total — 8 pathogenic, 10 likely-pathogenic
• GTEx eGene: eQTL in 13 tissues, sQTL in 2 (q < 0.05)
• Phenotypes (HPO): 19
• Drug target: yes — 2 curated mechanism-of-action drugs; 3 molecules with ChEMBL bioactivity
• Approved drugs (ChEMBL mechanism of action): 2 — Bismuth Subgallate, Human C1-Esterase Inhibitor
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.29 (unconstrained)
• MANE Select transcript: NM_000505
• Interaction hub: 2,183 STRING partners (top 6% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3530
Approved symbol	F12
Name	coagulation factor XII
Location	5q35.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000131187
Ensembl biotype	protein_coding
OMIM	610619
Entrez	2161

Gene structure

Transcript identifiers

Ensembl transcripts: 54 — 33 nonsense_mediated_decay, 14 protein_coding, 6 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000253496

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

ENST00000253496, ENST00000502854, ENST00000503736, ENST00000504406, ENST00000510358, ENST00000514943, ENST00000696192, ENST00000696193, ENST00000696194, ENST00000696195, ENST00000696200, ENST00000696201, ENST00000898122, ENST00000898123, ENST00000898124, ENST00000898125, ENST00000898126, ENST00000898127, ENST00000898128, ENST00000898129, ENST00000991304, ENST00000991305, ENST00000991306, ENST00000991307, ENST00000991313, ENST00000991314, ENST00000991316, ENST00000991318, ENST00000991319, ENST00000991320, ENST00000991321, ENST00000991322, ENST00000991328, ENST00000991333, ENST00000991335, ENST00000991336, ENST00000991337, ENST00000991338, ENST00000991339, ENST00000991345, ENST00000991348, ENST00000991349, ENST00000991350, ENST00000991356, ENST00000991357, ENST00001054261, ENST00001054262, ENST00001054263, ENST00001107136, ENST00001107137, ENST00001107138, ENST00001107139, ENST00001121729, ENST00001136160

RefSeq mRNA: 1 — MANE Select: NM_000505 NM_000505

CCDS: CCDS34302

Canonical transcript exons

ENST00000253496 — 14 exons

Exon	Start	End
ENSE00003966402	177403481	177403617
ENSE00003966421	177403859	177404090
ENSE00003966422	177404196	177404413
ENSE00003966423	177402141	177402459
ENSE00003966424	177404499	177404664
ENSE00003966425	177405962	177406061
ENSE00003966429	177405735	177405805
ENSE00003966430	177405054	177405185
ENSE00003966431	177402550	177402698
ENSE00003966432	177409471	177409564
ENSE00003966433	177409046	177409103
ENSE00003966434	177404810	177404914
ENSE00003966435	177405323	177405433
ENSE00003966436	177403254	177403397

Expression profiles

Bgee: expression breadth ubiquitous, 191 present calls, max score 99.36.

FANTOM5 (CAGE): breadth broad, TPM avg 3.0033 / max 700.9392, expressed in 627 samples.

Highest expression (Bgee): lobe of liver, liver, gingival epithelium, gingiva, lower esophagus mucosa.

Genetic regulation across tissues (GTEx eQTL / sQTL)

F12 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 13 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

15 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Liver	eqtl	2.6e-38	+0.78	5:177409531:A:G
Esophagus Mucosa	eqtl	2.3e-08	-0.17	5:177387655:G:A
Brain Hypothalamus	eqtl	1.5e-07	-0.31	5:177404118:A:G
Cells Cultured fibroblasts	eqtl	1.7e-06	-0.27	5:177404118:A:G
Thyroid	eqtl	1.2e-04	-0.20	5:177404118:A:G
Lung	eqtl	7.5e-03	+0.23	5:177362718:G:T
Pituitary	eqtl	1.1e-02	-0.21	5:177404118:A:G
Pancreas	eqtl	1.6e-02	-0.24	5:177406414:G:A
Breast Mammary Tissue	eqtl	1.9e-02	+1.41	5:177508214:GC:G
Brain Frontal Cortex BA9	eqtl	3.1e-02	-0.91	5:176666822:T:C
Minor Salivary Gland	sqtl	3.2e-02	-2.18	5:176492323:G:A
Testis	eqtl	3.3e-02	+0.87	5:177404543:G:A
Cells EBV-transformed lymphocytes	eqtl	4.0e-02	-0.72	5:176740899:G:A
Pituitary	sqtl	4.3e-02	-1.77	5:176608967:G:A
Stomach	eqtl	4.4e-02	-0.21	5:177404118:A:G

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
65090	1.4809	15
65088	0.8596	422
65087	0.3978	238
65086	0.1260	59
65089	0.0906	23
65091	0.0483	8

Top tissues by expression

showing 100 of 284 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.36	gold quality
liver	UBERON:0002107	98.71	gold quality
gingival epithelium	UBERON:0001949	92.35	gold quality
gingiva	UBERON:0001828	90.22	gold quality
lower esophagus mucosa	UBERON:0035834	88.25	gold quality
mucosa of transverse colon	UBERON:0004991	88.09	gold quality
cervix squamous epithelium	UBERON:0006922	87.70	silver quality
squamous epithelium	UBERON:0006914	84.61	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.10	gold quality
esophagus mucosa	UBERON:0002469	83.77	gold quality
endothelial cell	CL:0000115	83.75	gold quality
middle temporal gyrus	UBERON:0002771	83.42	gold quality
epithelium of esophagus	UBERON:0001976	81.02	gold quality
tongue squamous epithelium	UBERON:0006919	80.99	silver quality
nucleus accumbens	UBERON:0001882	80.69	gold quality
esophagus squamous epithelium	UBERON:0006920	80.68	gold quality
cervix epithelium	UBERON:0004801	79.03	silver quality
caudate nucleus	UBERON:0001873	78.45	gold quality
putamen	UBERON:0001874	77.59	gold quality
Brodmann (1909) area 23	UBERON:0013554	77.02	gold quality
pancreatic ductal cell	CL:0002079	76.97	silver quality
prefrontal cortex	UBERON:0000451	76.96	gold quality
oral cavity	UBERON:0000167	76.92	gold quality
mammalian vulva	UBERON:0000997	76.74	gold quality
skin of abdomen	UBERON:0001416	76.68	gold quality
skin of leg	UBERON:0001511	76.11	gold quality
Brodmann (1909) area 9	UBERON:0013540	75.82	gold quality
zone of skin	UBERON:0000014	75.44	gold quality
right frontal lobe	UBERON:0002810	75.31	gold quality
cingulate cortex	UBERON:0003027	74.96	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	74.64	gold quality
anterior cingulate cortex	UBERON:0009835	74.63	gold quality
frontal cortex	UBERON:0001870	74.27	gold quality
neocortex	UBERON:0001950	73.85	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	73.59	gold quality
telencephalon	UBERON:0001893	73.55	gold quality
cerebral cortex	UBERON:0000956	73.12	gold quality
duodenum	UBERON:0002114	73.07	gold quality
amygdala	UBERON:0001876	72.20	gold quality
blood	UBERON:0000178	71.99	gold quality
forebrain	UBERON:0001890	71.98	gold quality
vagina	UBERON:0000996	71.81	gold quality
jejunal mucosa	UBERON:0000399	71.63	gold quality
Ammon’s horn	UBERON:0001954	71.56	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	70.94	gold quality
colonic mucosa	UBERON:0000317	70.87	gold quality
temporal lobe	UBERON:0001871	70.63	gold quality
transverse colon	UBERON:0001157	70.19	gold quality
penis	UBERON:0000989	70.00	gold quality
cortical plate	UBERON:0005343	69.26	gold quality
tendon of biceps brachii	UBERON:0008188	69.01	gold quality
primary visual cortex	UBERON:0002436	68.96	gold quality
entorhinal cortex	UBERON:0002728	68.96	silver quality
mucosa of sigmoid colon	UBERON:0004993	68.81	silver quality
adult mammalian kidney	UBERON:0000082	68.68	gold quality
Brodmann (1909) area 46	UBERON:0006483	68.58	silver quality
pharyngeal mucosa	UBERON:0000355	68.44	silver quality
brain	UBERON:0000955	67.94	gold quality
granulocyte	CL:0000094	67.90	gold quality
central nervous system	UBERON:0001017	67.47	gold quality
bone marrow	UBERON:0002371	67.36	gold quality
stromal cell of endometrium	CL:0002255	67.35	gold quality
esophagus	UBERON:0001043	67.35	gold quality
superior frontal gyrus	UBERON:0002661	66.67	gold quality
small intestine Peyer’s patch	UBERON:0003454	66.62	gold quality
small intestine	UBERON:0002108	66.57	gold quality
oviduct epithelium	UBERON:0004804	66.51	silver quality
hair follicle	UBERON:0002073	66.49	gold quality
hypothalamus	UBERON:0001898	66.44	gold quality
trabecular bone tissue	UBERON:0002483	66.39	gold quality
skin of hip	UBERON:0001554	66.10	gold quality
biceps brachii	UBERON:0001507	66.06	gold quality
germinal epithelium of ovary	UBERON:0001304	65.86	gold quality
upper leg skin	UBERON:0004262	65.67	gold quality
monocyte	CL:0000576	65.58	gold quality
leukocyte	CL:0000738	65.39	gold quality
occipital lobe	UBERON:0002021	65.35	gold quality
mononuclear cell	CL:0000842	65.30	gold quality
olfactory bulb	UBERON:0002264	65.00	gold quality
type B pancreatic cell	CL:0000169	64.92	gold quality
cartilage tissue	UBERON:0002418	64.85	gold quality
mouth mucosa	UBERON:0003729	64.64	gold quality
superficial temporal artery	UBERON:0001614	64.60	gold quality
intestine	UBERON:0000160	64.35	gold quality
large intestine	UBERON:0000059	64.15	gold quality
colon	UBERON:0001155	64.12	gold quality
jejunum	UBERON:0002115	63.89	silver quality
mucosa of urinary bladder	UBERON:0001259	63.75	gold quality
nasal cavity epithelium	UBERON:0005384	63.63	gold quality
tibia	UBERON:0000979	63.53	gold quality
body of pancreas	UBERON:0001150	63.31	gold quality
uterine cervix	UBERON:0000002	63.16	gold quality
orbitofrontal cortex	UBERON:0004167	62.74	gold quality
nipple	UBERON:0002030	62.33	silver quality
nasal cavity mucosa	UBERON:0001826	62.20	gold quality
postcentral gyrus	UBERON:0002581	62.12	silver quality
kidney	UBERON:0002113	62.10	gold quality
cortex of kidney	UBERON:0001225	61.84	gold quality
pituitary gland	UBERON:0000007	61.57	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	61.57	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.55
E-HCAD-13	no	3.05

HPA expression

RNA tissue specificity: Tissue enriched

33 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	210.2	not detected
Caudate putamen	tissue	1.6
Cerebellum	tissue	0.8	not detected
Vagina	tissue	0.7	not detected
Putamen	tissue	0.6
Pituitary gland	tissue	0.5
Cerebral cortex	tissue	0.5	not detected
Frontal cortex	tissue	0.5
Basal ganglia	tissue	0.5	not detected
Occipital cortex	tissue	0.5
Spinal cord	tissue	0.4
Pons	tissue	0.3
Medulla oblongata	tissue	0.3
Superior colliculi	tissue	0.3
Septum	tissue	0.3
Somatosensory cortex	tissue	0.3
Midbrain	tissue	0.2
Thalamus	tissue	0.2
Substantia nigra	tissue	0.2
Bone marrow	tissue	0.2	not detected
Hippocampal formation	tissue	0.2
Periaqueductal gray	tissue	0.2
Prefrontal cortex	tissue	0.1
Motor cortex	tissue	0.1
Hypothalamus	tissue	0.1
Duodenum	tissue	0.1	not detected
Corpus callosum	tissue	0.1
Entorhinal cortex	tissue	0.1
Ventral forebrain	tissue	0.1
Retrosplenial and cingulate cortex	tissue	0.1
Olfactory bulb	tissue	0.1
Temporal cortex	tissue	0.1
Insular cortex	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 8; highest nTPM — Ventral spinal cord (0.4), Dorsal spinal cord (0.3), Hippocampus, CA1 (0.3), Dorsal hippocampus (0.2), Ventral hippocampus (0.2).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EPAS1, ESR1, HNF4A, SMAD3, SPI1, VSX2

miRNA regulators (miRDB)

Targeting F12 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

14 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-637	97.91	64.05	1517
HSA-MIR-5581-5P	97.91	66.50	965

Functional genomics

gnomAD constraint: pLI 2.94e-26, LOEUF 1.29, missense Z -0.227 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000253496 — one region, missense o/e 0.97.

Literature-anchored findings (GeneRIF, showing 40)

• 2 unrelated factor XII-deficient Japanese families had 2 new mutations: a heterozygous Q421K with reduced FXII activity and a severe homozygous mutation (R123P). (PMID:11776307)
• Heat shock protein 90 catalyzes activation of the prekallikrein-kininogen complex in the absence of factor XII. (PMID:11792853)
• linkage mapping; quantitative-trait locus in the human factor XII gene influences both plasma factor XII levels and susceptibility to thrombotic disease (PMID:11805911)
• The TT genotype of the FXII 46C>T polymorphism is associated with a high risk of CHD in men with high cholesterol. (PMID:12208481)
• This supports the hypothesis that binding to endothelial cells protects the activated FXII against inactivation by its major endogenous inhibitor. Hence, the function of FXII may be localized at cellular surfaces. (PMID:12492481)
• A homozygous substitution of G to C at 10587 (cDNA position 1458) in the FXII gene results in a Trp to Cys substitution in the catalytic domain. Reduced secretion of FXII protein was due to incorrect folding caused by the introduction of Cys486. (PMID:12876626)
• factor XII binds to lung & dermal microvascular endothelial cells and astrocytes in a saturable and Zn(+2) dependent manner, which may serve to concentrate proteins binding to high molecular weight kininogen. (PMID:14597972)
• the 46C–>T polymorphism itself is an independent risk factor for venous thrombosis in the Spanish population (PMID:15116249)
• The role played by FXII deficiency in the pathogenesis of venous thrombosis is minor, if any. (PMID:15306750)
• similar FXIIa levels in acute or chronic phases of coronary atherosclerosis suggests that the initial arterial denudation and acute-phase response associated to acute coronary syndromes are not major determinants for prolonged FXII activation (PMID:15567455)
• An amino acid substitution in F12 was discovered and characterized in an elderly Japanese male. (PMID:15617741)
• allele-specific dosage-dependent effect of the 46T-allele on plasma FXII levels (PMID:15748262)
• cross-reacting material is present in approximately 5% of homozygote patients. More precisely, seven of 145 patients. Only in one case, the was antigen level normal (FXII (PMID:16015420)
• Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency (PMID:16170239)
• results suggest that HK interferes with the binding of FXII to sulfatides and thereby the autoactivation of FXII. The binding of activated FXII to the ECM suggests that FXIIa may be a modulator of cellular adhesion, migration and vascularization. (PMID:16493494)
• Two different missense mutations were identified in exactly the same position within exon 9 of the F12 gene in patient with angioedema. (PMID:16638441)
• homozygosity for the C46T polymorphism of the F12 gene may have a role in venous thrombosis during the first pregnancy/puerperium in previously asymptomatic women (PMID:17408404)
• Factor XII impairs arterial thrombus formation but is not associated with excessive bleeding.Factor XII selectively contributes to thrombus formation in occlusive disease but not in normal hemostasis. (PMID:17605651)
• study reports hereditary angioedema with normal C1 inhibitor gene in a family associated with the p.Thr328Lys mutation in the F12 gene (PMID:17825897)
• No significant differences are observed in genotype and mutant allele frequencies of the FXII C46T polymorphism between mouth caner patients and healthy controls. (PMID:17982641)
• Lower FXII activity represents an independent risk for CHD and ACS. This is not the case for FXIIa levels or the FXII 46C>T variation. (PMID:18021303)
• Identified 15 genetic variants; the deficiency was caused by 5281delG in exon 9 of Patient 1; the 6306delG in exon 12 and deletion of 23 bp in intron 8 of Patient 2, and a G-8C transversion in Patient 3 (PMID:18024408)
• The TT genotype of the functional factor XII C46T gene polymorphism may be a new independent risk factor for cerebral venous thrombosis (CVT). (PMID:18180442)
• Used synthetic peptides in inhibition and direct binding studies to identify the antigenic binding site of autoantibodies to FXII in patients with recurrent pregnancy loss. (PMID:18278180)
• Sulfated galactan from the red alga Botryocladia occidentalis induces factor XII activation. (PMID:18327401)
• The dimeric structure of FXI is essential for normal proteolytic activation of FXI by FXIIa, thrombin, or FXIa either in solution or on an anionic surface but not for FIX activation by FXIa in solution. (PMID:18441012)
• A novel mutation in a patient with congenital coagulation factor XII deficiency. (PMID:18710647)
• factor XII is activated by misfolded proteins in humans, leading to kallikrein formation without initiating coagulation (PMID:18725990)
• thrombin is activated by prothrombinase and interacts with sufficiently poor affinity with F12 so that it is rapidly released from its site of production to participate in its numerous hemostatic functions (PMID:18765660)
• FXIIa, but not FXII, binds in a Zn2+-independent manner to immobilized FN through the type I repeat modules. (PMID:18793325)
• factor XII deficiency: a report of three new mutations exon 13 (Q501STOP), exon 14 (P547L) and -13C>T promoter region in three compound heterozygotes (PMID:18832903)
• These results support that the mentioned mutation in factor XII gene causes hereditary angioedema type III. (PMID:19178407)
• missense mutation in F12 is present in 3 affected females of a family with estrogen-dependent inherited angioedema; affected females have polymorphisms associated with lower levels of APP & ACE; study suggests multiple genes may contribute to this disease (PMID:19178938)
• The F12 46C –> T gene polymorphism is not related to CAD in the studied population. (PMID:19204433)
• Includes the study of a polymorphic upstream ORF in this gene, and shows that it functions to reduce protein levels by ~50%. (PMID:19372376)
• 1st report of molecular genotype of hemophilia A in the Saudi population: the intron 22 inversion was seen in 10 patients; 5 point mutations (1 new:R593P) & a new deletion/insertion involving different exons were detected. (PMID:19448530)
• Contrary to the results of a recently published study, no indication that the Thr309Lys mutation causes a ‘gain-of-function’ of FXIIa was observed in this investigation. (PMID:19474702)
• Thirty-five female patients with hereditary angioedema and the factor XII mutations p.Thr309Lys and p.Thr309Arg who came from 13 unrelated families were studied, but no difference between mutation p.Thr309Arg and p.Thr309Lys was found (PMID:19477491)
• A common functional polymorphism in the promoter of the FXII gene (F12-4C>T) is not associated with peripheral arterial disease. (PMID:19625260)
• there is an important subtype of hereditary angioedema (HAE), designated type III HAE, which is associated with pathogenic mutations in the F12 gene. (PMID:19647418)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	f9a	ENSDARG00000010097
mus_musculus	F12	ENSMUSG00000021492
rattus_norvegicus	F12	ENSRNOG00000015139

Paralogs (16): F7 (ENSG00000057593), F11 (ENSG00000088926), F9 (ENSG00000101981), HGFAC (ENSG00000109758), F10 (ENSG00000126218), KLK10 (ENSG00000129451), C1RL (ENSG00000139178), C1R (ENSG00000159403), KLKB1 (ENSG00000164344), C1S (ENSG00000182326), PRSS55 (ENSG00000184647), CFD (ENSG00000197766), CFI (ENSG00000205403), PRSS51 (ENSG00000253649), HP (ENSG00000257017), HPR (ENSG00000261701)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1891012) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 4 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal response to CNS ischemic injury	1
decreased cerebral infarct size	1
abnormal bradykinin level	1
increased partial thromboplastin time	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
Pongo abelii	Q5R8J0	97.9%	Diamond
Oryctolagus cuniculus	P50757	95.2%	Diamond
Bos taurus	Q9GLE5	95.1%	Diamond
Equus caballus	Q28377	94.4%	Diamond
Macaca mulatta	P12545	93.1%	Diamond
Mesocricetus auratus	Q9ESM7	92.7%	Diamond
Papio cynocephalus	P16227	92.6%	Diamond
Notophthalmus viridescens	Q91400	91.7%	Diamond
Xenopus laevis	Q91740	91.7%	Diamond
Desmodus rotundus	P15638	89.9%	Diamond
Canis lupus familiaris	P80009	89.7%	Diamond
Gallus gallus	P11722	88.9%	Diamond
Sus scrofa	Q8SQ23	82.8%	Diamond
Cavia porcellus	Q04962	73.2%	Diamond
Streptomyces glaucescens	Q54179	71.3%	Diamond
Phytophthora infestans	B1AC90	67.4%	Diamond
Drosophila melanogaster	Q9VWU1	66.9%	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
RGS14	protein-coding	10636
LMAN2	protein-coding	10960
PFN3	protein-coding	345456
SLC34A1	protein-coding	6569
DBN1	protein-coding	1627
GRK6	protein-coding	2870
PRR7-AS1	ncRNA	340037
PRR7	protein-coding	80758
PDLIM7	protein-coding	9260

Protein

Protein identifiers

Coagulation factor XII — P00748 (reviewed: P00748)

Alternative names: Hageman factor

All UniProt accessions (5): A0A8Q3WL25, A0A8Q3WL28, A0A8Q3WL35, A0A8Q3WL37, P00748

UniProt curated annotations — full annotation on UniProt →

Function. Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then trypsin cleaves it to beta-factor XIIa. Alpha-factor XIIa activates factor XI to factor XIa.

Subunit / interactions. Interacts with HRG; the interaction, which is enhanced in the presence of zinc ions and inhibited by heparin-binding, inhibits factor XII autoactivation and contact-initiated coagulation. Interacts (inactive and activated) with D7L2, an anticoagulant protein from Anopheles gambiae. Interacts (activated) with iripin-8, a serine protease inhibitor from Ixodes ricinus saliva. Interacts (inactive and activated) (via amino acids 1-77) with triafestin-1 and triafestin-2, anticoagulant proteins from Triatoma infestans. Interacts (inactive and activated) (via amino acids 1-77) with short form salivary protein D7R1, an anticoagulant protein from Anopheles stephensi. Interacts (inactive and activated) (via fibronectin type II domain) with haemaphysalin, an anticoagulant protein from Haemaphysalis longicornis.

Subcellular location. Secreted.

Post-translational modifications. Factor XII is activated by kallikrein in alpha-factor XIIa, which is further converted by trypsin into beta-factor XIIa. Alpha-factor XIIa is composed of an NH2-terminal heavy chain, called coagulation factor XIIa heavy chain, and a COOH-terminal light chain, called coagulation factor XIIa light chain, connected by a disulfide bond. Beta-factor XIIa is composed of 2 chains linked by a disulfide bond, an N-terminal nonapeptide, called beta-factor XIIa part 1, and coagulation factor XIIa light chain, also known in this context as beta-factor XIIa part 2. O- and N-glycosylated. The O-linked polysaccharides were not identified, but are probably the mucin type linked to GalNAc.

Disease relevance. Factor XII deficiency (FA12D) [MIM:234000] An asymptomatic anomaly of in vitro blood coagulation. Its diagnosis is based on finding a low plasma activity of the factor in coagulating assays. It is usually only accidentally discovered through pre-operative blood tests. Factor XII deficiency is divided into two categories, a cross-reacting material (CRM)-negative group (negative F12 antigen detection) and a CRM-positive group (positive F12 antigen detection). The disease is caused by variants affecting the gene represented in this entry. Angioedema, hereditary, 3 (HAE3) [MIM:610618] A hereditary angioedema occurring only in women. Hereditary angioedema is an autosomal dominant disorder characterized by episodic local swelling involving subcutaneous or submucous tissue of the upper respiratory and gastrointestinal tracts, face, extremities, and genitalia. Hereditary angioedema type 3 differs from types 1 and 2 in that both concentration and function of C1 esterase inhibitor are normal. Hereditary angioedema type 3 is precipitated or worsened by high estrogen levels (e.g., during pregnancy or treatment with oral contraceptives). The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activity is promoted in the presence of negatively charged surfaces.

Similarity. Belongs to the peptidase S1 family.

RefSeq proteins (1): NP_000496* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000001	Kringle	Domain
IPR000083	Fibronectin_type1	Domain
IPR000562	FN_type2_dom	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
IPR013806	Kringle-like	Homologous_superfamily
IPR014394	Coagulation_fac_XII/HGFA	Family
IPR018056	Kringle_CS	Conserved_site
IPR018114	TRYPSIN_HIS	Active_site
IPR033116	TRYPSIN_SER	Active_site
IPR036943	FN_type2_sf	Homologous_superfamily
IPR038178	Kringle_sf	Homologous_superfamily
IPR043504
IPR050127	Serine_Proteases_S1	Family

Pfam: PF00008, PF00039, PF00040, PF00051, PF00089

Enzyme classification (BRENDA)

• EC 3.4.21.38 — coagulation factor XIIa (BRENDA: 7 organisms, 78 substrates, 137 inhibitors, 36 Km, 35 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
D-PRO-PHE-ARG-4-NITROANILIDE	0.021–0.2	6
PREKALLIKREIN	0.0008–0.0017	2
S-2302	0.1–2.7	2
BENZYLOXYCARBONYL-ALA-ARG-SCH2C6H5	0.012	1
BENZYLOXYCARBONYL-ALA-ARG-SCH2CH(CH3)2	0.034	1
BENZYLOXYCARBONYL-ALA-GLY-ARG-4-NITROANILIDE	3.9	1
BENZYLOXYCARBONYL-ALA-PHE-ARG-4-NITROANILIDE	1.5	1
BENZYLOXYCARBONYL-ARG-SCH2CH(CH3)2	0.103	1
BENZYLOXYCARBONYL-ASN-GLY-ARG-4-NITROANILIDE	2.7	1
BENZYLOXYCARBONYL-ASN-PHE-ARG-4-NITROANILIDE	0.66	1
BENZYLOXYCARBONYL-GLU-ARG-SCH2CH(CH3)2	0.15	1
BENZYLOXYCARBONYL-GLY-ARG-SCH2CH(CH3)2	0.036	1
BENZYLOXYCARBONYL-LYS-ARG-SCH2CH(CH3)2	0.054	1
BENZYLOXYCARBONYL-LYS-GLY-ARG-4-NITROANILIDE	0.7	1
BENZYLOXYCARBONYL-LYS-PHE-ARG-4-NITROANILIDE	0.16	1

UniProt features (121 total): strand 36, disulfide bond 20, sequence variant 17, helix 14, glycosylation site 9, turn 7, domain 6, chain 3, active site 3, compositionally biased region 2, sequence conflict 2, signal peptide 1, region of interest 1

Structure

Experimental structures (PDB)

17 structures by resolution:

PDB	Title	Method	Resolution (Å)
7PRJ	Factor XII Fibronectin type II (FXII FnII) domain	X-RAY DIFFRACTION	1.2
6X0T	Structure of human plasma factor XIIa in complex with …	X-RAY DIFFRACTION	1.39
4BDX	The structure of the FnI-EGF tandem domain of coagulation factor XII	X-RAY DIFFRACTION	1.62
7PRK	Factor XII Fibronectin type II (FXII FnII) domain	X-RAY DIFFRACTION	1.64
6X0S	Structure of human plasma factor XIIa in complex with …	X-RAY DIFFRACTION	1.9
7FBP	FXIIa-cMCoFx1 complex	X-RAY DIFFRACTION	1.99
4XDE	Coagulation Factor XII protease domain crystal structure	X-RAY DIFFRACTION	2.14
6B74	Structures of the two-chain human plasma Factor XIIa co-crystallized with potent …	X-RAY DIFFRACTION	2.32
6B77	Structures of the two-chain human plasma factor XIIa co-crystallized with potent …	X-RAY DIFFRACTION	2.37
4XE4	Coagulation Factor XII protease domain crystal structure	X-RAY DIFFRACTION	2.4
4BDW	The structure of the FnI-EGF tandem domain of coagulation factor XII in complex with …	X-RAY DIFFRACTION	2.5
6GT6	Crystal structure of recombinant coagulation factor beta-XIIa	X-RAY DIFFRACTION	2.54
8R8D	Cryo-EM structure of coagulation factor beta-XIIa in complex with the garadacimab Fab …	ELECTRON MICROSCOPY	2.6
6L63	Human Coagulation Factor XIIa (FXIIa) bound with the macrocyclic peptide F3 containing …	X-RAY DIFFRACTION	3
6SZW	Asymmetric complex of Factor XII and kininogen with gC1qR/C1QBP/P32 is governed by …	X-RAY DIFFRACTION	3.14
8OS5	Crystal structure of the Factor XII heavy chain reveals an interlocking dimer with a FnII …	X-RAY DIFFRACTION	3.4
6QF7	Crystal structures of the recombinant beta-Factor XIIa protease with bound Thr-Arg and …	X-RAY DIFFRACTION	4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P00748-F1	76.47	0.41

Antibody-complex structures (SAbDab)

2 antibodies co-crystallized with this protein: 8R8D, GARADACIMAB

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Serine-type peptidases, Predicted secreted proteins, Plasma proteins, Candidate cardiovascular disease genes, Disease related genes, FDA approved drug targets, Biotech 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 (3)

Position	Role
412	charge relay system
461	charge relay system
563	charge relay system

Disulfide bonds (20)

Type	Positions
Disulfide bond	47–73, 61–88, 98–110, 104–119, 121–130, 135–163, 161–170, 178–189, 183–198, 200–209, 217–295, 238–277, 266–290, 359–486, 397–413, 405–475, 436–439, 500–569, 532–548, 559–590

Glycosylation sites (9)

Type	Positions
O-linked (fuc) threonine	109
N-linked (glcnac…) asparagine	249, 433
O-linked (galnac…) threonine	299, 305, 328, 329, 337
O-linked (galnac…) serine	308

Function

Pathways and Gene Ontology

Reactome pathways

6 curated (TAS) of 12; 5 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

12 pathways:

ID	Pathway	Evidence
R-HSA-9936900	Aggregated β-amyloid induces FXII autocatalysis ⚕	curated
R-HSA-9657689	Defective SERPING1 causes hereditary angioedema ⚕	curated
R-HSA-9657688	Defective factor XII causes hereditary angioedema ⚕	curated
R-HSA-9970672	FXIIa activates plasma kallikrein-kinin system	curated
R-HSA-9935598	FXIIa, PKa-dependent activation of coagulation pathway	curated
R-HSA-9855719	Regulation of FXIIa and plasma kallikrein activity	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-9671793	Diseases of hemostasis ⚕	—
R-HSA-109582	Hemostasis	—
R-HSA-140837		—
R-HSA-140877		—
R-HSA-9651496		—

MSigDB gene sets: 239 (showing top): MODULE_172, GOBP_POSITIVE_REGULATION_OF_PROTEIN_MATURATION, GOBP_PROTEIN_ACTIVATION_CASCADE, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_COAGULATION, GNF2_GSTM1, GNF2_HPN, GOBP_POSITIVE_REGULATION_OF_COAGULATION, GOBP_REGULATION_OF_ACUTE_INFLAMMATORY_RESPONSE, SHAFFER_IRF4_TARGETS_IN_PLASMA_CELL_VS_MATURE_B_LYMPHOCYTE, GOBP_NEGATIVE_REGULATION_OF_COAGULATION, GOBP_WOUND_HEALING, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS

GO Biological Process (15): plasma kallikrein-kinin cascade (GO:0002353), Factor XII activation (GO:0002542), blood coagulation (GO:0007596), blood coagulation, intrinsic pathway (GO:0007597), positive regulation of plasminogen activation (GO:0010756), protein processing (GO:0016485), protein autoprocessing (GO:0016540), positive regulation of blood coagulation (GO:0030194), zymogen activation (GO:0031638), fibrinolysis (GO:0042730), innate immune response (GO:0045087), response to misfolded protein (GO:0051788), positive regulation of fibrinolysis (GO:0051919), proteolysis (GO:0006508), hemostasis (GO:0007599)

GO Molecular Function (7): serine-type endopeptidase activity (GO:0004252), calcium ion binding (GO:0005509), misfolded protein binding (GO:0051787), 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), rough endoplasmic reticulum (GO:0005791), plasma membrane (GO:0005886), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062)

Reactome top-level categories

5 top-level categories:

Category	Pathways
Defects of contact activation system and kallikrein-kinin system	3
FXIIa activates plasma kallikrein-kinin system	1
Regulation of clotting cascade	1
Innate Immune System	1
Disease	1

GO top-level categories

45 GO namespaces:

Category	Terms
positive regulation of protein processing	2
protein processing	2
negative regulation of blood coagulation	2
kinin cascade	1
plasma kallikrein-kinin cascade	1
activation of plasma proteins involved in acute inflammatory response	1
regulation of acute inflammatory response	1
hemostasis	1
wound healing	1
coagulation	1
protein activation cascade	1
blood coagulation, fibrin clot formation	1
regulation of plasminogen activation	1
plasminogen activation	1
proteolysis	1
protein maturation	1
blood coagulation	1
regulation of blood coagulation	1
positive regulation of coagulation	1
positive regulation of wound healing	1
positive regulation of hemostasis	1
immune response	1
defense response to symbiont	1
response to topologically incorrect protein	1
fibrinolysis	1
positive regulation of biological process	1
regulation of fibrinolysis	1
protein metabolic process	1
regulation of body fluid levels	1
endopeptidase activity	1
serine-type peptidase activity	1
metal ion binding	1
protein binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
serine hydrolase activity	1
catalytic activity	1
cellular anatomical structure	1
endoplasmic reticulum	1
membrane	1
cell periphery	1
external encapsulating structure	1
extracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 12 of 28 annotations. The rest are phylogenetic / computational / electronic (IEA).

12 experimentally-supported GO terms:

GO term	NS	Evidence
Factor XII activation	BP	direct assay
plasma kallikrein-kinin cascade	BP	direct assay
positive regulation of blood coagulation	BP	direct assay
positive regulation of fibrinolysis	BP	direct assay
positive regulation of plasminogen activation	BP	direct assay
protein autoprocessing	BP	direct assay
protein processing	BP	direct assay
response to misfolded protein	BP	direct assay
zymogen activation	BP	direct assay
extracellular exosome	CC	high-throughput assay
extracellular matrix	CC	high-throughput assay
serine-type endopeptidase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,183 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
F12	SERPING1	P05155	919
F12	KNG1	P01042	801
F12	F3	P13726	580
F12	TPPP	O94811	517
F12	F13A1	P00488	516
F12	F8	P00451	495
F12	ATP5PF	P18859	492
F12	SERPINC1	P01008	481
F12	ALB	P02768	464
F12	F5	P12259	437
F12	FOXH1	O75593	435
F12	TFPI	P10646	411
F12	C9	P02748	399
F12	BDKRB2	P30411	393
F12	SERPIND1	P05546	389

IntAct

Human interaction partners of F12 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

8 partners by confidence:

Partner	Interaction type	MIscore	Records
APP	physical association	0.560	3
LAMP2	physical association	0.560	3
HSPA8	association	0.530	2
KNG1	direct interaction	0.440	2
C1QBP	direct interaction	0.440	1
N	direct interaction	0.440	1
S	direct interaction	0.440	1
GP1BA	proximity	0.270	1

BioGRID (82 interactions; top human partners by supporting records): HIF1A (Affinity Capture-Western; 4 records), EPAS1 (Affinity Capture-Western; 3 records), ANKRD40 (Affinity Capture-MS; 2 records), GP1BA (Co-localization; 2 records), HSPA8 (Affinity Capture-MS; 2 records), NF1 (Affinity Capture-Western; 2 records), ACAD10 (Affinity Capture-MS), ACSF2 (Affinity Capture-MS), AGO2 (Affinity Capture-RNA), AMBRA1 (Affinity Capture-MS), ARHGEF4 (Affinity Capture-MS), ATXN2 (Affinity Capture-MS), BAG3 (Affinity Capture-MS), BAG5 (Affinity Capture-MS), CDC42EP1 (Affinity Capture-MS)

SIGNOR signaling

14 signaling interactions:

A	Effect	B	Mechanism
ESR1	“up-regulates quantity by expression”	F12	“transcriptional regulation”
HNF4A	“down-regulates quantity by repression”	F12	“transcriptional regulation”
F12	“up-regulates activity”	“GPIb-IX-V complex”	binding
SERPINA1	“down-regulates activity”	F12	binding
SERPINE1	“down-regulates activity”	F12	binding
SERPING1	“down-regulates activity”	F12	binding
F12	“up-regulates activity”	KLKB1	cleavage
F12	“up-regulates activity”	F11	cleavage
KLKB1	“up-regulates activity”	F12	cleavage
“Blood vessel damage”	up-regulates	F12
MMP13	“down-regulates quantity by destabilization”	F12	cleavage
MMP14	“down-regulates quantity by destabilization”	F12	cleavage
MMP12	“down-regulates quantity by destabilization”	F12	cleavage
SERPINC1	“down-regulates activity”	F12	cleavage

Disease & clinical

Genetic variants

Variant evidence for F12: 264 ClinVar records (18 pathogenic / likely pathogenic); 1 PharmGKB clinical annotation; 24 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	10
Uncertain significance	119
Likely benign	62
Benign	13

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 18 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
1169	NM_000505.4(F12):c.983C>A (p.Thr328Lys)	Pathogenic	criteria provided, multiple submitters, no conflicts	14
2572132	NM_000505.4(F12):c.1517del (p.Gly506fs)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
1170	NM_000505.4(F12):c.983C>G (p.Thr328Arg)	Pathogenic	criteria provided, single submitter	3
3066136	NM_000505.4(F12):c.1570del (p.Val524fs)	Pathogenic	criteria provided, single submitter	1
3381898	NM_000505.4(F12):c.303_304del (p.His101fs)	Pathogenic	criteria provided, single submitter	1
4085814	NM_000505.4(F12):c.800+2T>C	Pathogenic	criteria provided, single submitter	1
4770174	NM_000505.4(F12):c.1532-1G>A	Pathogenic	criteria provided, single submitter	1
1473234	NM_000505.4(F12):c.800+1G>A	Likely pathogenic	criteria provided, single submitter	1
2671919	NM_000505.4(F12):c.415C>T (p.Gln139Ter)	Likely pathogenic	criteria provided, single submitter	1
3381899	NM_000505.4(F12):c.1561G>A (p.Glu521Lys)	Likely pathogenic	criteria provided, single submitter	1
3779632	NM_000505.4(F12):c.1375C>T (p.Gln459Ter)	Likely pathogenic	criteria provided, single submitter	1
3779633	NM_000505.4(F12):c.1681-1G>C	Likely pathogenic	criteria provided, single submitter	1
4081386	NM_000505.4(F12):c.800+1G>C	Likely pathogenic	criteria provided, single submitter	1
4086125	NM_000505.4(F12):c.312C>A (p.Cys104Ter)	Likely pathogenic	criteria provided, single submitter	1
4849475	NM_000505.4(F12):c.1158C>A (p.Tyr386Ter)	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore F12’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; 22 predictions of 1,020):

Position(s)	Effect	Δscore	Sites
5:177403479–177403480	donor_loss	1.0000	3
5:177403497	donor_gain	1.0000
5:177403618–177403619	acceptor_loss	1.0000	5
5:177404916	acceptor_gain	1.0000
5:177405322	donor_loss	1.0000
5:177405434–177405435	acceptor_loss	1.0000	5
5:177405441	acceptor_gain	1.0000
5:177405447	acceptor_gain	1.0000
5:177405450	acceptor_gain	1.0000
5:177409044–177409045	donor_loss	1.0000	3

AlphaMissense

950 missense substitutions predicted likely pathogenic (of 3,972 scored), across 224 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
M546	9	0.781	0.896
D461	8	0.975	0.991
D562	8	0.957	0.983
D557	8	0.939	0.968
S585	8	0.921	0.992
H412	8	0.913	0.968
C548	7	0.975	0.991
C266	7	0.973	0.987
C413	7	0.973	0.984
C559	7	0.973	0.989
C590	7	0.972	0.990
C397	7	0.968	0.984
W505	7	0.965	0.996
C532	7	0.958	0.986
C290	7	0.957	0.979
F453	7	0.956	0.990
C209	7	0.955	0.978
C47	7	0.949	0.974
C277	7	0.947	0.977
C238	7	0.946	0.972

HPA cancer prognostics

RNA cancer specificity: Cancer enriched (Liver Hepatocellular Carcinoma)

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	favorable	8.62e-05
Liver Hepatocellular Carcinoma (validation)	favorable	0.000155

Disease associations

OMIM: gene MIM:610619 | disease phenotypes: MIM:234000, MIM:610618, MIM:106100

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
hereditary angioedema type 3	Definitive	Autosomal dominant	5
congenital factor XII deficiency	Strong	Autosomal recessive	2

ClinGen Gene-Disease Validity

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

2 validity classifications:

Disease	Classification	Inheritance
congenital factor XII deficiency	Definitive	AR
hereditary angioedema type 3	Definitive	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (5 panels, 5 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

5 panels:

Panel	Rating
Bleeding and platelet disorders	green
COVID-19 research	green
Inherited bleeding disorders	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green
Vascular skin disorders	green

Mondo (7): congenital factor XII deficiency (MONDO:0009315), hereditary angioedema type 3 (MONDO:0012526), hereditary angioedema (MONDO:0019623), hypertensive disorder (MONDO:0005044), urticaria (MONDO:0005492), angioedema (MONDO:0010481), hyperbilirubinemia (MONDO:0024288)

Orphanet (3): F12-related hereditary angioedema with normal C1Inh (Orphanet:100054), Congenital factor XII deficiency (Orphanet:330), Hereditary angioedema (Orphanet:91378)

HPO phenotypes

19 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000282	Facial edema
HP:0001026	Penetrating foot ulcers
HP:0001892	Abnormal bleeding
HP:0001907	Thromboembolism
HP:0001977	Abnormal thrombosis
HP:0002013	Vomiting
HP:0002574	Episodic abdominal pain
HP:0003645	Prolonged partial thromboplastin time
HP:0004841	Reduced factor XII activity
HP:0005225	Intestinal edema
HP:0005542	Prolonged whole-blood clotting time
HP:0007985	Retinal arteriolar occlusion
HP:0011855	Pharyngeal edema
HP:0012271	Episodic upper airway obstruction
HP:0012636	Retinal venous occlusion
HP:0100665	Angioedema
HP:0200067	Recurrent spontaneous abortion

GWAS associations

24 associations:

Study	Trait	p-value
GCST006018_9	Activated partial thromboplastin time	0.000000e+00
GCST001574_7	Activated partial thromboplastin time	6e-88
GCST001853_5	Circulating vasoactive peptide levels	1e-67
GCST012020_253	Serum metabolite levels	2e-45
GCST012021_78	Serum metabolite levels	2e-45
GCST012020_254	Serum metabolite levels	5e-35
GCST012021_79	Serum metabolite levels	5e-35
GCST000631_1	Activated partial thromboplastin time	2e-30
GCST001853_4	Circulating vasoactive peptide levels	6e-24
GCST012020_252	Serum metabolite levels	2e-22
GCST012021_77	Serum metabolite levels	2e-22
GCST004038_3	Circulating chromogranin peptide levels	2e-19
GCST000649_23	Chronic kidney disease	1e-14
GCST001639_21	Metabolite levels	3e-14
GCST007638_40	Glycine levels	7e-14
GCST003793_2	L-arginine levels	1e-12
GCST001432_1	Nephrolithiasis	9e-12
GCST001391_3	Metabolite levels	9e-11
GCST005962_7	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1e-8
GCST005956_31	Waist-to-hip ratio adjusted for BMI	1e-7
GCST008309_14	Cardiac troponin-I levels	2e-7
GCST011541_5	Tinnitus	2e-7
GCST005957_15	Waist-to-hip ratio adjusted for BMI (age <50)	3e-7
GCST001065_1	Platelet function and related traits	1e-6

EFO canonical traits (from GWAS)

10 canonical traits:

EFO ID	Trait name
EFO:0004725	metabolite measurement
EFO:0004723	coronary artery calcification
EFO:0005196	vasoactive peptide measurement
EFO:0006524	L-arginine measurement
EFO:0007909	CHGA cleavage product measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009767	glycine measurement
EFO:0010071	cardiac troponin I measurement

MeSH disease descriptors

7 disease descriptors:

Descriptor	Name	Tree numbers
D000799	Angioedema	C14.907.079; C17.800.862.945.066; C20.543.480.904.066
D054179	Angioedemas, Hereditary	C14.907.079.500; C16.320.798.500.500; C17.800.862.945.066.500; C20.543.480.904.066.500; C20.673.795.500.500
D005175	Factor XII Deficiency	C15.378.100.100.330; C15.378.100.141.330; C15.378.463.330; C16.320.099.330
D056828	Hereditary Angioedema Type III	C14.907.079.500.500; C17.800.862.945.066.500.500; C20.543.480.904.066.500.500
D006932	Hyperbilirubinemia	C23.550.429
D006973	Hypertension	C14.907.489
D014581	Urticaria	C17.800.862.945; C20.543.480.904

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2821 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the F12 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
BISMUTH SUBGALLATE	Small molecule	4
HUMAN C1-ESTERASE INHIBITOR	Protein	4

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 9,350 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

3 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL87563	GABEXATE	3	2,044
CHEMBL273264	NAFAMOSTAT	3	7,150
CHEMBL114586	SEPIMOSTAT	2	156

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

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

Variant	Association	Level	Drugs	Phenotypes
rs1801020	Efficacy	3	Enzymes	Stroke

PharmGKB variants

1 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1801020	F12, SLC34A1	3	3.50	1	Enzymes

PharmGKB variant annotations

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

2 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs1801020	Enzymes	Toxicity	Genotype GG is associated with increased risk of Death when treated with Enzymes in people with Stroke as compared to genotypes AA + AG.	PMID:23280790
rs1801020		Metabolism/PK	Allele G is associated with increased enzyme activity of F12 as compared to allele A.	PMID:23280790

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — S1: Chymotrypsin

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
garadacimab	Binding	9.82	pKd
anti-FXII nanobody N4-38	Binding	8.51	pKd
methyl 5-[(4-tert-butylbenzoyl)amino]-2H-1,2,4-triazole-3-carboxylate	Inhibition	8.0	pIC50

Binding affinities (BindingDB)

1164 measured of 2146 human assays (2167 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-chloro-3,4-dimethylphenyl (3S)-4- (N2-cyclohexyl-N2,N6,N6-trimethyl-D- lysyl)-3-[(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	0.1 nM	US-10875851: Factor XIIa inhibitors
(R)-5-guanidino-N-(2-((S)-5-guanidino-1-oxo-1-(thiazol-2-yl)pentan-2-ylamino)-2-oxoethyl)-2-(phenylmethylsulfonamido)pentanamide	IC50	0.13 nM
2-chloro-3,4-dimethylphenyl (3S)-4- [N-(2-benzyl-2-azaspiro[4.5]dec-8- yl)-6-piperidin-1-yl-D-norleucyl]-3- [(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	0.2 nM	US-10875851: Factor XIIa inhibitors
2-chloro-3,4-dimethylphenyl (3S)-4- [N2-(2-benzyl-2-azaspiro[4.5]dec-8- yl)-N6,N6-dimethyl-D-lysyl]-3- [(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	0.3 nM	US-10875851: Factor XIIa inhibitors
2-chloro-3,4-dimethylphenyl (3S)-4- [N-(2-benzyl-2-azaspiro[4.5]dec-8- yl)-6-(2-methylpyrrolidin-1-yl)-D- norleucyl]-3-[(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	0.3 nM	US-10875851: Factor XIIa inhibitors
(2S)-1-[N2-(2-benzyl-2- azaspiro[4.5]dec-8-yl)-N6,N6- dimethyl-D-lysyl]-4-[(4S,5S)-4- methyl-5-phenyl-4,5-dihydro-1,3- oxazol-2-yl]-N-(thiophen-2- ylmethyl)piperazine-2-carboxamide	IC50	0.4 nM	US-10875851: Factor XIIa inhibitors
2-chloro-3,4-dimethylphenyl (3S)-4- [N2-(2-benzyl-2-azaspiro[4.5]dec-8- yl)-N2,N6,N6-trimethyl-D-lysyl]-3- [(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	0.5 nM	US-10875851: Factor XIIa inhibitors
2-chloro-3,4-dimethylphenyl (3S)-4- [N2-(2-benzyl-2-azaspiro[4.5]dec-8- yl)-N6-(1-methylethyl)-D-lysyl]-3- [(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	0.5 nM	US-10875851: Factor XIIa inhibitors
(2S)-N-[(3-chloro-1H-indol-5- yl)methyl]-1-[N-(1-methylethyl)-6- piperidin-1-yl-D-norleucyl]-4- [(4S,5S)-4-methyl-5-phenyl-4,5- dihydro-1,3-oxazol-2-yl]piperazine-2- carboxamide	IC50	0.5 nM	US-10875851: Factor XIIa inhibitors
(2S)-1-{N-[4- (aminomethyl)cyclohexyl]-6- piperidin-1-yl-D-norleucyl}-N-[(3- chloro-1H-indol-5-yl)methyl]-4- [(4S,5S)-4-methyl-5-phenyl-4,5- dihydro-1,3-oxazol-2-yl]piperazine-2- carboxamide	IC50	0.6 nM	US-10875851: Factor XIIa inhibitors
2-chlorophenyl (3S)-4-[N2-(2-benzyl- 2-azaspiro[4.5]dec-8-yl)-N6,N6- dimethyl-D-lysyl]-3-[(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	0.7 nM	US-10875851: Factor XIIa inhibitors
2-chlorophenyl (3S)-4-(N-cyclohexyl- 6-piperidin-1-yl-D-norleucyl)-3- [(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	0.7 nM	US-10875851: Factor XIIa inhibitors
2-chloro-3,4-dimethylphenyl (3S)-4- [N2-cyclohexyl-N6-(1-methylethyl)-D- lysyl]-3-[(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	0.7 nM	US-10875851: Factor XIIa inhibitors
(2S)-1-[N2-(2-benzyl-2- azaspiro[4.5]dec-8-yl)-N6,N6- dimethyl-D-lysyl]-4-[(4S,5S)-4- methyl-5-phenyl-4,5-dihydro-1,3- oxazol-2-yl]-N-(thiophen-2- ylmethyl)piperazine-2-carboxamide	IC50	0.8 nM	US-10875851: Factor XIIa inhibitors
CHEMBL4088217	KI	0.84 nM
CHEMBL4098389	KI	0.89 nM
2-chlorophenyl (3S)-4-[N2-(2-benzyl- 2-azaspiro[4.5]dec-8-yl)-N6,N6- dimethyl-D-lysyl]-3-[(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	0.9 nM	US-10875851: Factor XIIa inhibitors
2-chlorophenyl (3S)-4-[N-(2-benzyl- 2-azaspiro[4.5]dec-8-yl)-6-piperidin- 1-yl-D-norleucyl]-3-[(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	0.9 nM	US-10875851: Factor XIIa inhibitors
1-chloronaphthalen-2-yl (3S)-3-{[4- (aminomethyl)-3- methoxybenzyl]carbamoyl}-4-[N2-(2- benzyl-2-azaspiro[4.5]dec-8-yl)- N2,N6,N6-trimethyl-D- lysyl]piperazine-1-carboxylate	IC50	1 nM	US-10875851: Factor XIIa inhibitors
2-chloro-3,4-dimethylphenyl (3S)-4- [N-(2-benzyl-2-azaspiro[4.5]dec-8- yl)-6-pyrrolidin-1-yl-D-norleucyl]-3- [(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	1 nM	US-10875851: Factor XIIa inhibitors
5-N-[[4-methyl-6-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-3-pyridinyl]methyl]isoquinoline-1,5-diamine	IC50	1 nM	US-20240059691: ENZYME INHIBITORS
3-(aminomethyl)-2-chlorophenyl (3S)- 4-(N,3-dicyclohexyl-D-alanyl)-3- [(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	1.1 nM	US-10875851: Factor XIIa inhibitors
2-chlorophenyl (3S)-4-(N2- cyclohexyl-N6,N6-dimethyl-D-lysyl)- 3-[(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	1.1 nM	US-10875851: Factor XIIa inhibitors
2-chlorophenyl (3S)-4-[N2-(2-benzyl- 2-azaspiro[4.5]dec-8-yl)-N2,N6,N6- trimethyl-D-lysyl]-3-[(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	1.1 nM	US-10875851: Factor XIIa inhibitors
(2S)-1-[N2-(2-benzyl-2- azaspiro[4.5]dec-8-yl)-N6,N6- dimethyl-D-lysyl]-4-[(4S,5S)-4- methyl-5-phenyl-4,5-dihydro-1,3- oxazol-2-yl]-N-(thiophen-2- ylmethyl)piperazine-2-carboxamide	IC50	1.2 nM	US-10875851: Factor XIIa inhibitors
2-chloro-3,4-dimethylphenyl (3S)-4- [N2,N6-bis(1-methylethyl)-D-lysyl]-3- [(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	1.4 nM	US-10875851: Factor XIIa inhibitors
(2S)-4[(4S,5S)-5-(3-cyanophenyl)-4- methyl-4,5-dihydro-1,3-oxazol-2-yl]- 1-(N2-cyclohexyl-N6,N6-dimethyl-D- lysyl)-N-(thiophen-2- ylmethyl)piperazine-2-carboxamide	IC50	1.4 nM	US-10875851: Factor XIIa inhibitors
(2S)-1-[(2R)-2-[(4- carbamoylcyclohexyl)amino]-2-(trans- 4-piperidin-1-ylcyclohexyl)acetyl]-4- [(4S,5S)-4-methyl-5-phenyl-4,5- dihydro-1,3-oxazol-2-yl]-N-(thiophen- 2-ylmethyl)piperazine-2-carboxamide	IC50	1.5 nM	US-10875851: Factor XIIa inhibitors
N-{(3S,4R)-1-[N2- (2-benzyl-2- azaspiro[4.5]dec-8-yl)- N6,N6-dimethyl- D-lysyl]-3-[(thiophen-2- ylmethyl)carbamoyl]pi- peridin-4-yl}-6- azaspiro[2.5]octane-6- carboxamide	IC50	1.5 nM	US-11014920: Factor XIIa inhibitors
naphthalen-1-yl (3S)-3-[[4-(aminomethyl)-3-methoxyphenyl]methylcarbamoyl]-4-[(2R)-3-cyclohexyl-2-(cyclohexylamino)propanoyl]piperazine-1-carboxylate	IC50	1.6 nM	US-10875851: Factor XIIa inhibitors
CHEMBL4087027	KI	1.6 nM
CHEMBL4059973	KI	1.6 nM
2-chlorophenyl (3S)-4-{(2R)-2- (cyclohexylamino)-2-[1- (cyclopropylsulfonyl)piperidin-4- yl]acetyl}-3-[(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	1.7 nM	US-10875851: Factor XIIa inhibitors
1-chloronaphthalen-2-yl (3S)-3-{[4- (aminomethyl)-3- methoxybenzyl]carbamoyl}-4-(N6,N6- dimethyl-D-lysyl)piperazine-1- carboxylate	IC50	1.7 nM	US-10875851: Factor XIIa inhibitors
(2S)-N-[4-(aminomethyl)-3- chlorobenzyl]-1-[N-(1-methylethyl)-6- piperidin-1-yl-D-norleucyl]-4- [(4S,5S)-4-methyl-5-phenyl-4,5- dihydro-1,3-oxazol-2-yl]piperazine-2- carboxamide	IC50	1.7 nM	US-10875851: Factor XIIa inhibitors
2-chlorophenyl (3S)-4-[N-(2-benzyl- 2-azaspiro[4.5]dec-8-yl)-6-morpholin- 4-yl-D-norleucyl]-3-[(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	1.8 nM	US-10875851: Factor XIIa inhibitors
N-[[6-[(1-methylpiperidin-4-yl)methoxy]-3-pyridinyl]methyl]isoquinolin-6-amine	IC50	2 nM	US-20240059691: ENZYME INHIBITORS
N-[[4-[(1-methylpiperidin-4-yl)oxymethyl]phenyl]methyl]isoquinolin-6-amine	IC50	2 nM	US-20240059691: ENZYME INHIBITORS
5-N-[[2-fluoro-4-[(1-methylpiperidin-4-yl)oxymethyl]phenyl]methyl]isoquinoline-1,5-diamine	IC50	2 nM	US-20240059691: ENZYME INHIBITORS
5-N-[[4-[(1-ethylpiperidin-4-yl)oxymethyl]-2-fluorophenyl]methyl]isoquinoline-1,5-diamine	IC50	2 nM	US-20240059691: ENZYME INHIBITORS
5-N-[[2-[(1-methylpiperidin-4-yl)methoxy]-4-pyridinyl]methyl]isoquinoline-1,5-diamine	IC50	2 nM	US-20240059691: ENZYME INHIBITORS
3-(aminomethyl)-2-chlorophenyl (3S)- 4-[N2-(2-benzyl-2-azaspiro[4.5]dec-8- yl)-N6-(methylsulfonyl)-D-lysyl]-3- [(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	2.1 nM	US-10875851: Factor XIIa inhibitors
(2S)-[N-cyclohexyl-3-(1- cyclohexylpiperidin-4-yl)-D-alanyl]-4- [(4S,5S)-4-methyl-5-phenyl-4,5- dihydro-1,3-oxazol-2-yl]-N-(thiophen- 2-ylmethyl)piperazine-2-carboxamide	IC50	2.4 nM	US-10875851: Factor XIIa inhibitors
(2S)-N-(3-chlorobenzyl)-4-[(4S,5S)-4- methyl-5-phenyl-4,5-dihydro-1,3- oxazol-2-yl]-1-{N-[(1R)-1- methylpropyl]-6-piperidin-1-yl-D- norleucyl}piperazine-2-carboxamide	IC50	2.5 nM	US-10875851: Factor XIIa inhibitors
2-chlorophenyl (3S)-4-[(2R)-2- (cyclohexylamino)-2-{1-[(1- methylethyl)sulfonyl]piperidin-4- yl}acetyl]-3-[(thiophen-2- ylmethyl)carbamoyl]piperazine-1- carboxylate	IC50	2.6 nM	US-10875851: Factor XIIa inhibitors
1-chloronaphthalen-2-yl (3S)-3-{[4- (aminomethyl)-3- methoxybenzyl]carbamoyl}-4-(N,3- dicyclohexyl-D-alanyl)piperazine-1- carboxylate	IC50	2.7 nM	US-10875851: Factor XIIa inhibitors
1-chloronaphthalen-2-yl (3S)-4-{N2- [4-(aminomethyl)cyclohexyl]-N6,N6- dimethyl-D-lysyl}-3-{[4- (aminomethyl)-3- methoxybenzyl]carbamoyl}piperazine- 1-carboxylate	IC50	2.9 nM	US-10875851: Factor XIIa inhibitors
(2S)-1-{N-[4- (aminomethyl)cyclohexyl]-6- piperidin-1-yl-D-norleucyl}-4- [(4S,5S)-4-methyl-5-phenyl-4,5- dihydro-1,3-oxazol-2-yl]-N- (thieno[3,2-c]pyridin-2- ylmethyl)piperazine-2-carboxamide	IC50	3 nM	US-10875851: Factor XIIa inhibitors
CHEMBL4102962	KI	3 nM
5-N-[[6-[(1-methylpiperidin-4-yl)methoxy]-3-pyridinyl]methyl]isoquinoline-1,5-diamine	IC50	3 nM	US-20240059691: ENZYME INHIBITORS

ChEMBL bioactivities

612 potent at pChembl≥5 of 729 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	IC50	0.1	nM	CHEMBL5758818
9.70	IC50	0.2	nM	CHEMBL6054063
9.52	IC50	0.3	nM	CHEMBL6043307
9.52	IC50	0.3	nM	CHEMBL5805584
9.40	IC50	0.4	nM	CHEMBL5923412
9.30	IC50	0.5	nM	CHEMBL5777358
9.30	IC50	0.5	nM	CHEMBL6046462
9.30	IC50	0.5	nM	CHEMBL5864799
9.22	IC50	0.6	nM	CHEMBL5895805
9.15	IC50	0.7	nM	CHEMBL5857165
9.15	IC50	0.7	nM	CHEMBL5868011
9.15	IC50	0.7	nM	CHEMBL5850559
9.10	IC50	0.8	nM	CHEMBL5923412
9.08	Ki	0.84	nM	CHEMBL4088217
9.05	Ki	0.89	nM	CHEMBL4098389
9.05	IC50	0.9	nM	CHEMBL5857165
9.05	IC50	0.9	nM	CHEMBL5959689
9.00	IC50	1	nM	CHEMBL5903837
9.00	IC50	1	nM	CHEMBL6042515
8.96	IC50	1.1	nM	CHEMBL5856084
8.96	IC50	1.1	nM	CHEMBL5878932
8.96	IC50	1.1	nM	CHEMBL5740724
8.92	IC50	1.2	nM	CHEMBL5865847
8.85	IC50	1.4	nM	CHEMBL5980829
8.85	IC50	1.4	nM	CHEMBL5957724
8.82	IC50	1.5	nM	CHEMBL5772996
8.82	IC50	1.5	nM	CHEMBL6014897
8.80	IC50	1.6	nM	CHEMBL5994109
8.79	Ki	1.64	nM	CHEMBL4059973
8.79	Ki	1.63	nM	CHEMBL4087027
8.77	IC50	1.7	nM	CHEMBL5874485
8.77	IC50	1.7	nM	CHEMBL5890124
8.77	IC50	1.7	nM	CHEMBL6053959
8.74	IC50	1.8	nM	CHEMBL6032652
8.74	IC50	1.8	nM	CHEMBL5865847
8.68	IC50	2.1	nM	CHEMBL5969008
8.62	IC50	2.4	nM	CHEMBL5782144
8.60	IC50	2.5	nM	CHEMBL6044778
8.59	IC50	2.6	nM	CHEMBL5799619
8.57	IC50	2.7	nM	CHEMBL5961528
8.54	IC50	2.9	nM	CHEMBL6057827
8.52	Ki	3	nM	CHEMBL4102962
8.52	IC50	3	nM	CHEMBL6015163
8.48	IC50	3.3	nM	CHEMBL5954361
8.47	IC50	3.4	nM	CHEMBL5871675
8.43	Ki	3.7	nM	CHEMBL4065450
8.43	IC50	3.7	nM	CHEMBL5874818
8.42	IC50	3.8	nM	CHEMBL5787807
8.41	IC50	3.9	nM	CHEMBL6006497
8.41	IC50	3.9	nM	CHEMBL5825188

PubChem BioAssay actives

347 with measured affinity, of 885 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
(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-33-(3-amino-3-oxopropyl)-15,30,39-tris(3-carbamimidamidopropyl)-12-[(4-fluorophenyl)methyl]-18,36-bis(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0008	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-33-(3-amino-3-oxopropyl)-15,30,39-tris(3-carbamimidamidopropyl)-12-[(4-fluorophenyl)methyl]-18,36-bis(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0009	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-33-(3-amino-3-oxopropyl)-15,30,39-tris(3-carbamimidamidopropyl)-18,36-bis(2-methylpropyl)-12-[(4-nitrophenyl)methyl]-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0016	uM
(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-4-carbamimidamidobutanoyl]amino]-33-(3-amino-3-oxopropyl)-15,30,39-tris(3-carbamimidamidopropyl)-12-[(4-fluorophenyl)methyl]-18,36-bis(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0016	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-33-(3-amino-3-oxopropyl)-15,30,39-tris(3-carbamimidamidopropyl)-18,36-bis(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-12-(pyridin-3-ylmethyl)-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0030	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-33-(3-amino-3-oxopropyl)-15,30,39-tris(3-carbamimidamidopropyl)-12-[(3-methylphenyl)methyl]-18,36-bis(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0037	uM
1-(3,4-dimethylphenyl)-2-phenylethane-1,2-dione	1798224: Enzyme Inhibition Assay from Article 10.1021/jm049011j: “Identification and characterization of novel benzil (diphenylethane-1,2-dione) analogues as inhibitors of mammalian carboxylesterases.”	ki	0.0041	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-33-(3-amino-3-oxopropyl)-15,30,39-tris(3-carbamimidamidopropyl)-12-[(3-fluorophenyl)methyl]-18,36-bis(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0045	uM
1,2-dicyclohexylethane-1,2-dione	1798260: Enzyme Inhibition Assay from Article 10.1021/jm0706867: “Planarity and constraint of the carbonyl groups in 1,2-diones are determinants for selective inhibition of human carboxylesterase 1.”	ki	0.0050	uM
1-[4-(2-oxo-2-phenylacetyl)phenyl]-2-phenylethane-1,2-dione	1798224: Enzyme Inhibition Assay from Article 10.1021/jm049011j: “Identification and characterization of novel benzil (diphenylethane-1,2-dione) analogues as inhibitors of mammalian carboxylesterases.”	ki	0.0056	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-33-(3-amino-3-oxopropyl)-15,30,39-tris(3-carbamimidamidopropyl)-18,36-bis(2-methylpropyl)-12-(naphthalen-2-ylmethyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0060	uM
(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-33-(3-amino-3-oxopropyl)-12-benzyl-15,30,39-tris(3-carbamimidamidopropyl)-9-[[(2R)-2,7-diaminoheptanoyl]amino]-18,36-bis(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0065	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-33-(3-amino-3-oxopropyl)-12-(1-benzothiophen-3-ylmethyl)-15,30,39-tris(3-carbamimidamidopropyl)-18,36-bis(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0068	uM
aceanthrylene-1,2-dione	1798260: Enzyme Inhibition Assay from Article 10.1021/jm0706867: “Planarity and constraint of the carbonyl groups in 1,2-diones are determinants for selective inhibition of human carboxylesterase 1.”	ki	0.0077	uM
1-(4-methyl-3-nitrophenyl)-2-phenylethane-1,2-dione	1798224: Enzyme Inhibition Assay from Article 10.1021/jm049011j: “Identification and characterization of novel benzil (diphenylethane-1,2-dione) analogues as inhibitors of mammalian carboxylesterases.”	ki	0.0079	uM
1-dodecylindole-2,3-dione	1798240: Enzyme Inhibition Assay from Article 10.1021/jm061471k: “Selective inhibition of carboxylesterases by isatins, indole-2,3-diones.”	ki	0.0080	uM
(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2R)-2-amino-6-carbamimidamidohexanoyl]amino]-33-(3-amino-3-oxopropyl)-12-benzyl-15,30,39-tris(3-carbamimidamidopropyl)-18,36-bis(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0088	uM
1-(2-chlorophenyl)-2-(3,4-dimethoxyphenyl)ethane-1,2-dione	1798224: Enzyme Inhibition Assay from Article 10.1021/jm049011j: “Identification and characterization of novel benzil (diphenylethane-1,2-dione) analogues as inhibitors of mammalian carboxylesterases.”	ki	0.0089	uM
(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-33-(3-amino-3-oxopropyl)-12-benzyl-15,30,39-tris(3-carbamimidamidopropyl)-9-[[(2S)-2,6-diaminohexanoyl]amino]-18,36-bis(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0090	uM
(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-33-(3-amino-3-oxopropyl)-12-benzyl-15,30,39-tris[3-(diaminomethylideneamino)propyl]-18,36-bis(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carboxylic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0093	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-33-(3-amino-3-oxopropyl)-15,30,39-tris(3-carbamimidamidopropyl)-18,36-bis(2-methylpropyl)-12-(naphthalen-1-ylmethyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0100	uM
5-N-[[4-methyl-6-[(8S)-8-methyl-3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-3-pyridinyl]methyl]isoquinoline-1,5-diamine	2066075: Inhibition of human FXIIa (unknown origin)	ic50	0.0100	uM
1-[[4-[[4-[(2,3-dioxoindol-1-yl)methyl]phenyl]methyl]phenyl]methyl]indole-2,3-dione	1798240: Enzyme Inhibition Assay from Article 10.1021/jm061471k: “Selective inhibition of carboxylesterases by isatins, indole-2,3-diones.”	ki	0.0100	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-33-(3-amino-3-oxopropyl)-12-benzyl-15,30,39-tris(3-carbamimidamidopropyl)-18,36-bis(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0102	uM
1-(4-methoxyphenyl)-2-phenylethane-1,2-dione	1798224: Enzyme Inhibition Assay from Article 10.1021/jm049011j: “Identification and characterization of novel benzil (diphenylethane-1,2-dione) analogues as inhibitors of mammalian carboxylesterases.”	ki	0.0103	uM
1-hexadecylindole-2,3-dione	1798240: Enzyme Inhibition Assay from Article 10.1021/jm061471k: “Selective inhibition of carboxylesterases by isatins, indole-2,3-diones.”	ki	0.0110	uM
(5-amino-3-pyridin-2-yl-1,2,4-triazol-1-yl)-[4-(4-propan-2-yl-1,4-diazepan-1-yl)naphthalen-1-yl]methanone	2066015: Binding affinity to FXIIa (unknown origin) assessed as inhibition constant using H-D-Pro-Phe-Arg-pNA.2HCl as substrate by spectrophotometric analysis	ki	0.0114	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-33-(3-amino-3-oxopropyl)-15,30,39-tris(3-carbamimidamidopropyl)-12-(1H-indol-3-ylmethyl)-18,36-bis(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0120	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,21S,24R,27S,30S,33S,36S,39R)-39-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-18-(3-amino-3-oxopropyl)-36-benzyl-12,21,33-tris(3-carbamimidamidopropyl)-15,27,30-tris(2-methylpropyl)-4,11,14,17,20,23,26,29,32,35,38,44,47-tridecaoxo-7,41,50-trithia-1,3,10,13,16,19,22,25,28,31,34,37,45-tridecazatricyclo[22.22.5.13,45]dopentacontane-9-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0130	uM
(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2R)-2-amino-4-carbamimidamidobutanoyl]amino]-33-(3-amino-3-oxopropyl)-12-benzyl-15,30,39-tris(3-carbamimidamidopropyl)-18,36-bis(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0140	uM
1,2-diphenylethane-1,2-dione	1798224: Enzyme Inhibition Assay from Article 10.1021/jm049011j: “Identification and characterization of novel benzil (diphenylethane-1,2-dione) analogues as inhibitors of mammalian carboxylesterases.”	ki	0.0147	uM
(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2R)-2-amino-3-(4-carbamimidamidophenyl)propanoyl]amino]-33-(3-amino-3-oxopropyl)-12-benzyl-15,30,39-tris(3-carbamimidamidopropyl)-18,36-bis(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0150	uM
(2S)-1-[(2R)-3-cyclohexyl-2-(cyclohexylamino)propanoyl]-4-[(4R,5S)-4-methyl-5-phenyl-4,5-dihydro-1,3-oxazol-2-yl]-N-(thiophen-2-ylmethyl)piperazine-2-carboxamide	2066075: Inhibition of human FXIIa (unknown origin)	ic50	0.0171	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-33-(3-amino-3-oxopropyl)-12-benzyl-15,30,39-tris(3-carbamimidamidopropyl)-36-(2,2-dimethylpropyl)-18-(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0177	uM
1-(4-chlorophenyl)-2-phenylethane-1,2-dione	1798224: Enzyme Inhibition Assay from Article 10.1021/jm049011j: “Identification and characterization of novel benzil (diphenylethane-1,2-dione) analogues as inhibitors of mammalian carboxylesterases.”	ki	0.0182	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,21S,24R,27S,30S,33S,36S,39R)-39-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-18-(3-amino-3-oxopropyl)-36-benzyl-12,21,33-tris(3-carbamimidamidopropyl)-27-methyl-15,30-bis(2-methylpropyl)-4,11,14,17,20,23,26,29,32,35,38,44,47-tridecaoxo-7,41,50-trithia-1,3,10,13,16,19,22,25,28,31,34,37,45-tridecazatricyclo[22.22.5.13,45]dopentacontane-9-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0196	uM
(6-carbamimidoylnaphthalen-2-yl) 4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoate	1705182: Non-competitive inhibition of factor 12a (unknown origin) using BQGR as substrate	ki	0.0210	uM
1-[4-(bromomethyl)phenyl]-2-phenylethane-1,2-dione	1798224: Enzyme Inhibition Assay from Article 10.1021/jm049011j: “Identification and characterization of novel benzil (diphenylethane-1,2-dione) analogues as inhibitors of mammalian carboxylesterases.”	ki	0.0213	uM
1-(4-chlorophenyl)-2-(4-methylphenyl)ethane-1,2-dione	1798224: Enzyme Inhibition Assay from Article 10.1021/jm049011j: “Identification and characterization of novel benzil (diphenylethane-1,2-dione) analogues as inhibitors of mammalian carboxylesterases.”	ki	0.0228	uM
1,2-bis(3,5-difluorophenyl)ethane-1,2-dione	1798224: Enzyme Inhibition Assay from Article 10.1021/jm049011j: “Identification and characterization of novel benzil (diphenylethane-1,2-dione) analogues as inhibitors of mammalian carboxylesterases.”	ki	0.0234	uM
1-[3,5-bis(3-methylsulfanylpropanoyl)-1,3,5-triazinan-1-yl]-3-methylsulfanylpropan-1-one	1802515: Protease Inhibition Assay from Article 10.1002/cbic.201600612: “Polar Hinges as Functionalized Conformational Constraints in (Bi)cyclic Peptides.”	ki	0.0250	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-33-(3-amino-3-oxopropyl)-15,30,39-tris(3-carbamimidamidopropyl)-12-[(2-fluorophenyl)methyl]-18,36-bis(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0268	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-33-(3-amino-3-oxopropyl)-15,30,39-tris(3-carbamimidamidopropyl)-12,18,36-tris(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0280	uM
(5-amino-3-pyridin-2-yl-1,2,4-triazol-1-yl)-naphthalen-1-ylmethanone	1681854: Inhibition of human coagulation factor XIIA using Boc-Gln-Gly-Arg-AMC as fluorogenic substrate measured at 1 min interval for 1 hr by fluorometric assay	ic50	0.0290	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,21S,24R,27S,30S,33S,36S,39R)-39-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-18-(3-amino-3-oxopropyl)-36-benzyl-12,21,33-tris(3-carbamimidamidopropyl)-27-(hydroxymethyl)-15,30-bis(2-methylpropyl)-4,11,14,17,20,23,26,29,32,35,38,44,47-tridecaoxo-7,41,50-trithia-1,3,10,13,16,19,22,25,28,31,34,37,45-tridecazatricyclo[22.22.5.13,45]dopentacontane-9-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0294	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-33-(3-amino-3-oxopropyl)-12-benzyl-15,30,39-tris(3-carbamimidamidopropyl)-36-(3-methylbutyl)-18-(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0294	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-33-(3-amino-3-oxopropyl)-12-benzyl-36-butyl-15,30,39-tris(3-carbamimidamidopropyl)-18-(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0306	uM
1-(4-nitrophenyl)-2-phenylethane-1,2-dione	1798224: Enzyme Inhibition Assay from Article 10.1021/jm049011j: “Identification and characterization of novel benzil (diphenylethane-1,2-dione) analogues as inhibitors of mammalian carboxylesterases.”	ki	0.0306	uM
1-[(4-chlorophenyl)methyl]indole-2,3-dione	1798240: Enzyme Inhibition Assay from Article 10.1021/jm061471k: “Selective inhibition of carboxylesterases by isatins, indole-2,3-diones.”	ki	0.0320	uM
(2S)-2-[[(2S)-2-[[(9R,12S,15S,18S,24S,27R,30S,33S,36S,39S,42R)-9-[[(2S)-2-amino-5-carbamimidamidopentanoyl]amino]-33-(3-amino-3-oxopropyl)-15,30,39-tris(3-carbamimidamidopropyl)-12-[(4-hydroxyphenyl)methyl]-18,36-bis(2-methylpropyl)-4,10,13,16,19,25,28,31,34,37,40,47,50-tridecaoxo-7,44,53-trithia-1,3,11,14,17,20,26,29,32,35,38,41,48-tridecazatetracyclo[25.22.5.13,48.020,24]pentapentacontane-42-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1426468: Inhibition of human beta factor 12a using fluorogenic substrate Boc-Gln-Gly-Arg-AMC preincubated for 10 mins followed by addition of substrate measured every min for 30 mins	ki	0.0322	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, increases methylation	6
sodium arsenite	affects expression, decreases expression	3
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression	3
Cyclosporine	decreases expression	3
(+)-JQ1 compound	decreases expression	2
Acetaminophen	decreases expression	2
Copper	affects binding, decreases expression	2
Nickel	affects binding, increases expression	2
Aflatoxin B1	affects expression, decreases expression	2
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
sulforaphane	decreases expression	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases response to substance, decreases expression	1
jinfukang	increases expression	1
NSC 689534	affects binding, decreases expression	1
Rosiglitazone	decreases expression	1
Decitabine	affects expression	1
Arsenic Trioxide	decreases response to substance	1
Angiotensin-Converting Enzyme Inhibitors	decreases expression	1
Cadmium	affects binding	1
Chondroitin Sulfates	increases activity	1

ChEMBL screening assays

128 unique, capped per target: 123 binding, 3 functional, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1005173	Binding	Inhibition of human factor 12a	Novel 3-carboxamide-coumarins as potent and selective FXIIa inhibitors. — *J Med Chem*
CHEMBL1737911	Functional	PUBCHEM_BIOASSAY: Factor XIIa Dose Response Confirmation. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID684]	PubChem BioAssay data set
CHEMBL4774638	ADMET	Inhibition of factor 12a (unknown origin) at IC90 using kallikrein chromogenic substrate preincubated for 1 min followed by chromogenic substrate addition and measured for 2 mins in presence of AT-III	The components and activities analysis of a novel anticoagulant candidate dHG-5. — *Eur J Med Chem*

Clinical trials (associated diseases)

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

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00914966	Phase 4	COMPLETED	A Study to Evaluate the Safety and Effect of Escalating Doses of CINRYZE
NCT01151735	Phase 4	WITHDRAWN	C1-INH Compared to Placebo at the Time of Prodromal Symptoms for Hereditary Angioedema (HAE) Exacerbation
NCT01457430	Phase 4	COMPLETED	Efficacy, Safety and Tolerability of Icatibant for the Treatment of HAE
NCT01679912	Phase 4	COMPLETED	A Call Center During HAE Attacks (SOS HAE)
NCT06690047	Phase 4	COMPLETED	Treatment of Hereditary Angioedema Prodrome with Recombinant C1-esterase Inhibitor (Ruconest)
NCT06806657	Phase 4	COMPLETED	Safety Study in Subjects ≥ 12 Years of Age With Hereditary Angioedema Switching to Garadacimab
NCT07290855	Phase 4	COMPLETED	A Study to Evaluate the Safety and Efficacy of Icatibant in Patients With Bradykinin Induced Angioedema
NCT07654829	Phase 4	RECRUITING	Safety and Effectiveness of Sebetralstat (KVD900) for Short-Term Prophylaxis Before Procedures in People With Hereditary Angioedema (KONTROL)
NCT00000521	Phase 4	COMPLETED	Sodium-Potassium Blood Pressure Trial in Children
NCT00018759	Phase 4	COMPLETED	Treatment Effects on Platelet Calcium in Hypertensive and Depressed Patients
NCT00034840	Phase 4	COMPLETED	Telmisartan vs. Valsartan in Patients With Mild to Moderate Hypertension Following a Missed Dose
NCT00044265	Phase 4	COMPLETED	Treatment of Pediatric Hypertension With Altace Trial
NCT00060918	Phase 4	COMPLETED	Glycemic Control Of Carvedilol Versus Metoprolol In Patients With Type II Diabetes Mellitus And Hypertension
NCT00060931	Phase 4	COMPLETED	Effect Of Carvedilol Versus Metoprolol On Glycemic Control In Patients With Type II Diabetes And Hypertension
NCT00110422	Phase 4	COMPLETED	Irbesartan in the Treatment of Hypertensive Patients With Metabolic Syndrome
NCT00115726	Phase 4	COMPLETED	Trial Assessing the Effect of Preoperative Furosemide on Intraoperative Blood Pressure
NCT00120380	Phase 4	TERMINATED	Combination Therapy of Bosentan and Aerosolized Iloprost in Idiopathic Pulmonary Arterial Hypertension (IPAH)
NCT00122811	Phase 4	UNKNOWN	The Hypertension in the Very Elderly Trial (HYVET)
NCT00123045	Phase 4	COMPLETED	Patient-Physician Partnership to Improve High Blood Pressure Adherence
NCT00123604	Phase 4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00126516	Phase 4	COMPLETED	Angiotensin II Receptor Blockers (ARB) and ACE Inhibitors (ACEI) on Silent Brain Infarction and Cognitive Decline
NCT00127348	Phase 4	COMPLETED	Effect of Continuous Positive Airway Pressure (CPAP) on Hypertension and Cardiovascular Morbidity-Mortality in Patients With Sleep Apnea and no Daytime Sleepiness
NCT00128518	Phase 4	COMPLETED	IDEAL Study: Identification of the Determinants of the Efficacy of Arterial Blood Pressure Lowering Drugs
NCT00129233	Phase 4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00129909	Phase 4	COMPLETED	STITCH (Simplified Therapeutic Intervention To Control Hypertension)
NCT00130156	Phase 4	COMPLETED	Effects of Combination Therapy With Alpha-1 Blocker (Bunazosin or Doxazosin) in the Treatment of Patients With Mild to Moderate Essential Hypertension
NCT00131846	Phase 4	COMPLETED	Diuretics In the Management of Essential Hypertension (DIME) Study
NCT00133068	Phase 4	COMPLETED	Collaboration to Reduce Disparities in Hypertension
NCT00133328	Phase 4	UNKNOWN	A Morbidity-Mortality and Remodeling Study With Valsartan
NCT00133692	Phase 4	COMPLETED	INVEST: INternational VErapamil SR Trandolapril STudy
NCT00134160	Phase 4	COMPLETED	OlmeSartan and Calcium Antagonists Randomized (OSCAR) Study
NCT00136851	Phase 4	COMPLETED	Study Comparing the Efficacy of Amlodipine Besylate/Benazepril Versus Amlodipine in the Treatment of Severe Hypertension
NCT00139386	Phase 4	COMPLETED	Candesartan for Prevention of Cardiovascular Events After Cypher or Taxus Coronary Stenting (4C) Trial
NCT00139555	Phase 4	COMPLETED	Effects of Amlodipine/Benazepril in Reducing Left Ventricular Hypertrophy in Patients With High Risk Hypertension
NCT00139984	Phase 4	COMPLETED	Ambulatory Blood Pressure Monitoring for Antihypertensive Treatment Guidance
NCT00140790	Phase 4	TERMINATED	Valsartan in Cardiovascular Disease With Renal Dysfunction (The V-CARD) Study
NCT00140907	Phase 4	COMPLETED	ALLOGRAFT, A Study to Evaluate the Renal Protective Effects of Losartan (0954-222)(COMPLETED)
NCT00140959	Phase 4	COMPLETED	Losartan and HCTZ and Amlodipine vs Atenolol and Amlodipine (0954A-309)(COMPLETED)
NCT00144144	Phase 4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00144937	Phase 4	UNKNOWN	Multifactorial Intervention on Cardiovascular Risk Factors in Subjects With Peripheral Arterial Disease
NCT00147251	Phase 4	COMPLETED	Stop Atherosclerosis in Native Diabetics Study
NCT00147524	Phase 4	COMPLETED	Non-Comparative Study To Evaluate Changes In FMD After Quinapril Therapy In Hypertensive Women
NCT00147563	Phase 4	COMPLETED	Compare Effectiveness of Eplerenone vs Atenolol in Reversing the Remodelling Resistance Arteries in Subjects With HT
NCT00149227	Phase 4	COMPLETED	Add-on Effects of Valsartan on Morbi- Mortality (KYOTO HEART Study)
NCT00150358	Phase 4	COMPLETED	To Yield Further Information On The Efficacy And Safety Of Viagra Among Subjects With Arterial Hypertension .
NCT00150384	Phase 4	COMPLETED	Clinical Utility of Caduet in Achieving Blood Pressure and Lipid Endpoints in a Specific Patient Population
NCT00153023	Phase 4	COMPLETED	1 Year Trial Telmisartan 80 mg Versus Valsartan 160 mg in Hypertensive Type 2 Diabetic Patients With Overt Nephropathy
NCT00154271	Phase 4	COMPLETED	Effects of Blood Pressure Reduction on High Sensitivity C-Reactive Protein (hsCRP)
NCT00157638	Phase 4	COMPLETED	Integrating Family Medicine and Pharmacy to Advance Primary Care Therapeutics
NCT00159692	Phase 4	COMPLETED	Amlodipine Diabetic Hypertension Efficacy Response Trial
NCT00168779	Phase 4	COMPLETED	Randomized, Double-Blind, Placebo-Controlled, Forced-Titration, Comparing Telmisartan vs Valsartan. Taken Orally for Eight Weeks in Patients With Stage 1 and Stage 2 Hypertension
NCT00168857	Phase 4	COMPLETED	A Prospective, Randomised, Double-blind, Double-dummy, Forced-titration, Multicentre, Parallel Group, One Year Treatment Trial to Compare Telmisartan (MICARDIS) 80 mg Versus Losartan (COZAAR) 100 mg, in Hypertensive Type 2 Diabetic Patients With Overt Nephropathy (AMADEO Study)
NCT00170924	Phase 4	COMPLETED	To Find Out Whether Valsartan With or Without Other Blood Pressure Medications Would Improve the Ability of the Heart to Fill and Empty, and the Ability of the Heart Muscle to Relax Adequately in People With High Blood Pressure.
NCT00170937	Phase 4	COMPLETED	A 16 Week Study to Evaluate the Effect on Insulin Sensitivity of Valsartan (320 mg) and Hydrochlorothiazide (25 mg) Combined and Alone, in Patients With Metabolic Syndrome
NCT00171054	Phase 4	COMPLETED	Efficacy and Safety of Valsartan Versus Amlodipine in Postmenopausal Women With Hypertension
NCT00171119	Phase 4	TERMINATED	A Study in Patients With Diabetes Mellitus Type II of the Effect on Albuminuria of 24 Week Treatment With Valsartan, Benazepril, and Valsartan+Benazepril
NCT00171132	Phase 4	COMPLETED	VALENCE: Valsartan Versus Atenolol on Exercise Capacity in Hypertensive Overweight Postmenopausal Women
NCT00171327	Phase 4	COMPLETED	Efficacy and Safety of Fluvastatin or Valsartan and Their Combination in Dyslipidemic Patients With Hypertension and Endothelial Dysfunction
NCT00171353	Phase 4	COMPLETED	A Study to Describe Vascular and Renal Effects and Safety of Valsartan in Patients With High Blood Pressure
NCT00171444	Phase 4	COMPLETED	Comparison of Two Treatment Strategies in Hypertensive Patients

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for F12 across ~30M SureChEMBL compounds — explore on Sugi Predict.