C1R

Summary

C1R (complement C1r, HGNC:1246) is a protein-coding gene on chromosome 12p13.31, encoding Complement C1r subcomponent (P00736). Serine protease component of the complement C1 complex, a multiprotein complex that initiates the classical pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system.

This gene encodes a member of the peptidase S1 protein family. The encoded protein is a proteolytic subunit in the complement system C1 complex. The complement system acts as a mediator in the innate immune response by ultimately triggering phagocytosis, inflammation, and rupturing the bacterial cell wall. Mutations in this gene are associated with Ehlers-Danlos Syndrome.

Source: NCBI Gene 715 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Ehlers-Danlos syndrome, periodontal type 1 (Definitive, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 158 total — 15 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 40
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001733

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1246
Approved symbol	C1R
Name	complement C1r
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000159403
Ensembl biotype	protein_coding
OMIM	613785
Entrez	715

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 17 protein_coding, 5 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000535233, ENST00000536053, ENST00000536092, ENST00000538050, ENST00000540242, ENST00000540394, ENST00000540610, ENST00000541042, ENST00000543362, ENST00000543835, ENST00000543851, ENST00000545466, ENST00000602298, ENST00000647956, ENST00000648162, ENST00000649804, ENST00000903848, ENST00000903849, ENST00000903850, ENST00000903851, ENST00000903852, ENST00000943404, ENST00000943405, ENST00000943406

RefSeq mRNA: 2 — MANE Select: NM_001733 NM_001354346, NM_001733

CCDS: CCDS81658, CCDS86272

Canonical transcript exons

ENST00000647956 — 11 exons

Exon	Start	End
ENSE00001045385	7088839	7088986
ENSE00001045391	7089293	7089489
ENSE00003475200	7089587	7089733
ENSE00003561893	7082032	7082106
ENSE00003594706	7090056	7090248
ENSE00003721155	7086379	7086457
ENSE00003726987	7091452	7091680
ENSE00003749515	7085861	7086016
ENSE00003755281	7088610	7088731
ENSE00003833667	7092387	7092445
ENSE00003836639	7080219	7081301

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 111.9007 / max 5450.1351, expressed in 1366 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129244	91.1533	1215
129245	7.3695	861
129246	5.6778	1006
129247	1.7952	696
129248	1.6584	690
129239	1.3639	443
129243	1.3395	215
129240	0.4567	233
129238	0.3289	166
206561	0.1950	94

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.79	gold quality
liver	UBERON:0002107	99.74	gold quality
right ovary	UBERON:0002118	99.66	gold quality
gall bladder	UBERON:0002110	99.65	gold quality
right coronary artery	UBERON:0001625	99.64	gold quality
mucosa of stomach	UBERON:0001199	99.63	gold quality
left ovary	UBERON:0002119	99.61	gold quality
left uterine tube	UBERON:0001303	99.58	gold quality
ovary	UBERON:0000992	99.55	gold quality
left coronary artery	UBERON:0001626	99.54	gold quality
urinary bladder	UBERON:0001255	99.50	gold quality
endocervix	UBERON:0000458	99.49	gold quality
omental fat pad	UBERON:0010414	99.47	gold quality
descending thoracic aorta	UBERON:0002345	99.46	gold quality
myometrium	UBERON:0001296	99.44	gold quality
tibial nerve	UBERON:0001323	99.44	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.44	gold quality
adipose tissue	UBERON:0001013	99.42	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.39	gold quality
subcutaneous adipose tissue	UBERON:0002190	99.38	gold quality
lower esophagus	UBERON:0013473	99.38	gold quality
body of uterus	UBERON:0009853	99.37	gold quality
thoracic aorta	UBERON:0001515	99.36	gold quality
ascending aorta	UBERON:0001496	99.35	gold quality
right atrium auricular region	UBERON:0006631	99.34	gold quality
ectocervix	UBERON:0012249	99.32	gold quality
thoracic mammary gland	UBERON:0005200	99.30	gold quality
right lobe of thyroid gland	UBERON:0001119	99.23	gold quality
popliteal artery	UBERON:0002250	99.23	gold quality
tibial artery	UBERON:0007610	99.23	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	1110.34
E-MTAB-6678	yes	1084.69
E-MTAB-10662	yes	983.22
E-MTAB-9543	yes	23.99
E-GEOD-81547	yes	10.43
E-CURD-126	no	2220.04
E-ENAD-17	no	854.42
E-GEOD-124858	no	73.13
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF, IRF1

miRNA regulators (miRDB)

27 targeting C1R, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-12130	99.75	65.47	452
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-549A-3P	99.54	68.17	825
HSA-MIR-12117	99.50	67.57	868
HSA-MIR-8054	99.48	70.81	2084
HSA-MIR-140-5P	99.44	67.20	792
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-4460	99.37	68.52	615
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-3940-5P	99.14	65.26	493
HSA-MIR-4507	99.14	65.27	515
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-520G-3P	98.91	67.38	1914
HSA-MIR-520H	98.91	67.38	1914
HSA-MIR-4711-5P	98.89	68.00	965
HSA-MIR-6074	98.89	69.64	2187
HSA-MIR-518C-5P	98.53	69.20	1640
HSA-MIR-5186	94.63	66.76	627

Literature-anchored findings (GeneRIF, showing 23)

• The catalytic properties of C1r, the protease that mediates activation of the C1 complex of complement, are mediated by its C-terminal region, comprising two complement control protein (CCP) modules followed by a serine protease (SP) domain (PMID:11445589)
• These findings show no evidence for association between C1r codon 135 polymorphism and Alzheimer’s Disease in our population. (PMID:12499050)
• Six common and rare alleles, C1R*1, C1R*2, C1R*5, C1R*8, C1R*9, and C1R*13, were characterized by five mutations at amino acid positions 114, 135, 146, 167 and 244, in exons 4, 5 and 7 where the (PMID:12914573)
• The activated CCP1-CCP2-SP fragment makes up a dimer in a head-to-tail fashion similarly to the previously characterized zymogen. (PMID:17996945)
• Detailed mapping of C1q post-translational modifications and insights into the C1r/C1s binding sites. (PMID:20008834)
• Using a recombinant CUB2-CCP1 domain pair and the individual CCP1 module, we showed that binding of Ca(2+) induces the folding of the CUB2 domain and stabilizes its structure. (PMID:20178990)
• These results provide further structural insights into the architecture of the C1 complex, and the interactions between C1r and C1s. (PMID:20592021)
• The modular C1r protein is the first protease activated in the classical complement pathway, a key component of innate immunity. (PMID:20796027)
• a structural rearrangement as a switch between functional states of human C1r (PMID:20970424)
• C1r specificity is well suited to its cleavage targets and that efficient cleavage of C1s is achieved through both active site and exosite contributions. (PMID:23589288)
• Analysis of its interaction properties by surface plasmon resonance shows that rC1q retains the ability of serum C1q to associate with the C1s-C1r-C1r-C1s tetramer, to recognize physiological C1q ligands such as IgG and pentraxin 3 (PMID:23650384)
• C1q exists as the C1 complex (C1qC1r2C1s2), and C1q binding to ligands activates the C1r/C1s proteases. Incubation of nucleoli with C1 caused degradation of the nucleolar proteins nucleolin and nucleophosmin 1. T (PMID:26231209)
• We confirmed increased levels of C1R and VTN in sera from patients with Joint hypermobility syndrome by western blot analyses (PMID:26709396)
• Periodontal Ehlers-Danlos Syndrome in at least the great majority of cases results from specific classes of heterozygous mutations in C1R and C1S. (PMID:27745832)
• The serine protease domains of C1r and C1s are at the periphery of the C1r2s2 tetramer both when alone or within the nonactivated C1 complex. The C1 complex adopts a conformation incompatible with intramolecular activation of C1. Instead, intermolecular proteolytic activation between neighboring C1 complexes bound to a complement-activating surface occurs. Many structurally unrelated molecular patterns can activate C1. (PMID:28104818)
• We identified a novel, homozygous, loss-of-function mutation (p.Pro445Leufs*11) in the C1R gene. Using the Sanger method of DNA sequencing in 14 family members, we confirmed the presence of the mutation in 4 patients with early-onset systemic lupus erythematosus and in an asymptomatic 9-year-old girl. Complement levels were low in sera from patients with truncated C1r protein. (PMID:28544690)
• periodontal Ehlers-Danlos syndrome caused by missense mutations in C1R is consistently associated with a leukoencephalopathy (PMID:30535813)
• C1R Mutations Trigger Constitutive Complement 1 Activation in Periodontal Ehlers-Danlos Syndrome. (PMID:31749804)
• C1q binding to surface-bound IgG is stabilized by C1r2s2 proteases. (PMID:34155115)
• C1r Upregulates Production of Matrix Metalloproteinase-13 and Promotes Invasion of Cutaneous Squamous Cell Carcinoma. (PMID:34756877)
• A familial case of periodontal Ehlers-Danlos syndrome lacking skin extensibility and joint hypermobility with a missense mutation in C1R. (PMID:35365885)
• C1R, CCL2, and TNFRSF1A Genes in Coronavirus Disease-COVID-19 Pathway Serve as Novel Molecular Biomarkers of GBM Prognosis and Immune Infiltration. (PMID:35726234)
• Tandem Mass Tag-Labeled Quantitative Proteome Analyses Identify C1R and A2M as Novel Serum Biomarkers in Pregnant Women with Obstructive Sleep Apnea. (PMID:38407963)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	C1ra	ENSMUSG00000055172
mus_musculus	C1rb	ENSMUSG00000098470
rattus_norvegicus	C1r	ENSRNOG00000011796
drosophila_melanogaster	CG31266	FBGN0051266
drosophila_melanogaster	CG31267	FBGN0051267

Paralogs (16): F7 (ENSG00000057593), F11 (ENSG00000088926), F9 (ENSG00000101981), HGFAC (ENSG00000109758), F10 (ENSG00000126218), KLK10 (ENSG00000129451), F12 (ENSG00000131187), C1RL (ENSG00000139178), KLKB1 (ENSG00000164344), C1S (ENSG00000182326), PRSS55 (ENSG00000184647), CFD (ENSG00000197766), CFI (ENSG00000205403), PRSS51 (ENSG00000253649), HP (ENSG00000257017), HPR (ENSG00000261701)

Protein

Protein identifiers

Complement C1r subcomponent — P00736 (reviewed: P00736)

Alternative names: Complement component 1 subcomponent r

All UniProt accessions (10): A0A3B3ISR2, A0A3B3ITU4, B4DPQ0, F5GWL0, F5H1N6, F5H1V0, F5H2D0, F5H3A3, F5H3N3, F5H6Y3

UniProt curated annotations — full annotation on UniProt →

Function. Serine protease component of the complement C1 complex, a multiprotein complex that initiates the classical pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system. C1R catalyzes the first enzymatic step in the classical complement pathway: it is activated by the C1Q subcomplex of the C1 complex, which associates with IgG or IgM immunoglobulins complexed with antigens to form antigen-antibody complexes on the surface of pathogens. Immunoglobulin-binding promotes the autocatalytic cleavage and activation of C1R. Activated C1R then cleaves and activates C1S, the second protease of the classical complement pathway. It is unclear if C1R activates C1S within single, strained C1 complexes or between neighboring C1 complexes on surfaces.

Subunit / interactions. Core component of the complement C1 complex, a calcium-dependent complex composed of 1 molecule of the C1Q subcomplex, 2 molecules of C1R and 2 molecules of C1S. The C1Q subcomplex is composed 18 subunits: 3 chains of C1QA, C1QB, and C1QC trimerize to form 6 collagen-like triple helices connected to six globular ligand-recognition modules. Within the C1 complex, C1R is a dimer of identical chains, each of which is activated by cleavage into two chains, heavy and light, connected by disulfide bonds.

Subcellular location. Secreted. Cell surface.

Post-translational modifications. Cleaved and activated by autocatalytic processing to generate Complement C1r subcomponent heavy and light chains that are connected by disulfide bonds. The iron and 2-oxoglutarate dependent 3-hydroxylation of aspartate and asparagine is (R) stereospecific within EGF domains.

Disease relevance. Ehlers-Danlos syndrome, periodontal type, 1 (EDSPD1) [MIM:130080] A form of Ehlers-Danlos syndrome, a connective tissue disorder characterized by hyperextensible skin, atrophic cutaneous scars due to tissue fragility and joint hyperlaxity. EDSPD1 is characterized by the association of typical features of Ehlers-Danlos syndrome with gingival recession and severe early-onset periodontal disease, leading to premature loss of permanent teeth. EDSPD1 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by the C1Q subcomplex of the C1 complex following C1Q binding to immunoglobulins (IgG or IgM) complexed with antigens to form antigen-antibody complexes on the surface of pathogens. Immunoglobulin-binding promotes autoactivation of C1R, which results in the cleavage of the Arg-Ile bond in the catalytic domain.

Domain organisation. The CUB domain 2 shows a compact folded structure in the presence of Ca(2+), whereas it has a flexible, disordered conformation in the absence of Ca(2+). Ca(2+) could provide a switch between the folded and disordered forms; low Ca(2+) could provide flexibility to promote autoprocessing and activation of CIR.

Polymorphism. Complement component C1r deficiency [MIM:216950] leads to the failure of the classical complement system activation pathway (C1 deficiency). Individuals with C1 deficiency are highly susceptible to infections by microorganisms and have greater risk in developing autoimmune diseases such as systemic lupus erythematosus (SLE).

Similarity. Belongs to the peptidase S1 family.

RefSeq proteins (2): NP_001341275, NP_001724* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000436	Sushi_SCR_CCP_dom	Domain
IPR000742	EGF	Domain
IPR000859	CUB_dom	Domain
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR024175	Pept_S1A_C1r/C1S/mannan-bd	Family
IPR033116	TRYPSIN_SER	Active_site
IPR035914	Sperma_CUB_dom_sf	Homologous_superfamily
IPR035976	Sushi/SCR/CCP_sf	Homologous_superfamily
IPR043504

Pfam: PF00084, PF00089, PF00431, PF14670

Enzyme classification (BRENDA):

• EC 3.4.21.41 — complement subcomponent C1r (BRENDA: 5 organisms, 33 substrates, 23 inhibitors, 7 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ACETYL-GLY-LYS METHYL ESTER	20	1
MASP-3 K448Q ZYMOGEN	0.0001	1
ZYMOGEN C1S	—	1
N-ACETYL-ARG METHYL ESTER	—	0
N-ACETYL-GLY-LYS METHYL ESTER	—	0

UniProt features (137 total): strand 45, sequence variant 20, binding site 13, disulfide bond 13, mutagenesis site 10, turn 8, helix 8, domain 6, glycosylation site 4, chain 3, active site 3, modified residue 2, signal peptide 1, site 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
6F1D	X-RAY DIFFRACTION	1.95
2QY0	X-RAY DIFFRACTION	2.6
1MD8	X-RAY DIFFRACTION	2.8
1GPZ	X-RAY DIFFRACTION	2.9
9EKE	X-RAY DIFFRACTION	3.1
1MD7	X-RAY DIFFRACTION	3.2
9EKD	X-RAY DIFFRACTION	3.28
7MZT	X-RAY DIFFRACTION	4.07
6F1C	X-RAY DIFFRACTION	4.2
6F1H	X-RAY DIFFRACTION	4.5
6F39	X-RAY DIFFRACTION	5.8
1APQ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P00736-F1	87.33	0.65

Functional residue map

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

Catalytic / active sites (4): 502 (charge relay system); 557 (charge relay system); 654 (charge relay system); 463–464 (cleavage; by autolysis)

Ligand- & substrate-binding residues (13): 66; 74; 119; 142; 143; 145; 167; 168; 171; 243; 253; 290 …

Post-translational modifications (2): 167, 206

Disulfide bonds (13): 71–89, 146–165, 161–174, 176–189, 193–220, 250–268, 309–358, 338–371, 376–429, 406–447, 451–577, 620–639, 650–680

Glycosylation sites (4): 125, 221, 514, 581

Mutagenesis-validated functional residues (10):

Position	Phenotype
66	abolished association with the c1q subcomplex.
73	abolished association with the c1q subcomplex.
81	does not affect association with the c1q subcomplex.
144	does not affect association with the c1q subcomplex.
154	does not affect association with the c1q subcomplex.
155	does not affect association with the c1q subcomplex.
156	does not affect association with the c1q subcomplex.
290	decreased association with the c1q subcomplex.
463	abolished autoprocessing, but promotes extrinsic cleavage by thermolysin.
654	abolished protease activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-166663	Initial triggering of complement
R-HSA-173623	Classical antibody-mediated complement activation
R-HSA-977606	Regulation of Complement cascade

MSigDB gene sets: 354 (showing top): MODULE_172, JI_RESPONSE_TO_FSH_UP, REACTOME_INNATE_IMMUNE_SYSTEM, PAL_PRMT5_TARGETS_UP, REACTOME_CREATION_OF_C4_AND_C2_ACTIVATORS, ENK_UV_RESPONSE_KERATINOCYTE_UP, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOCC_CELL_SURFACE, IIZUKA_LIVER_CANCER_PROGRESSION_L1_G1_UP, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_B_CELL_MEDIATED_IMMUNITY, CAIRO_HEPATOBLASTOMA_CLASSES_DN, PICCALUGA_ANGIOIMMUNOBLASTIC_LYMPHOMA_UP, GOBP_REGULATION_OF_IMMUNE_RESPONSE, LIU_VAV3_PROSTATE_CARCINOGENESIS_DN

GO Biological Process (7): immune response (GO:0006955), complement activation, classical pathway (GO:0006958), zymogen activation (GO:0031638), innate immune response (GO:0045087), immune system process (GO:0002376), proteolysis (GO:0006508), complement activation (GO:0006956)

GO Molecular Function (8): serine-type endopeptidase activity (GO:0004252), calcium ion binding (GO:0005509), serine-type peptidase activity (GO:0008236), identical protein binding (GO:0042802), molecular sequestering activity (GO:0140313), peptidase activity (GO:0008233), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (7): extracellular region (GO:0005576), complement component C1 complex (GO:0005602), obsolete extracellular space (GO:0005615), cell surface (GO:0009986), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), symbiont cell surface (GO:0106139)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Complement cascade	2
Creation of C4 and C2 activators	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
immune system process	1
response to stimulus	1
humoral immune response mediated by circulating immunoglobulin	1
complement activation	1
protein processing	1
immune response	1
defense response to symbiont	1
biological_process	1
protein metabolic process	1
immune effector process	1
activation of immune response	1
humoral immune response	1
protein activation cascade	1
endopeptidase activity	1
serine-type peptidase activity	1
metal ion binding	1
peptidase activity	1
serine hydrolase activity	1
protein binding	1
molecular_function	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cation binding	1
complement component C1q complex	1
extracellular protein-containing complex	1
extracellular vesicle	1
extracellular region	1
other organism part	1

Protein interactions and networks

STRING

2106 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C1R	SERPING1	P05155	999
C1R	C1S	P09871	986
C1R	C1QC	P02747	933
C1R	C1QB	P02746	879
C1R	C4A	P01028	876
C1R	C4A	P01028	868
C1R	BMP1	P13497	865
C1R	C3	P01024	840
C1R	MBL2	P11226	824
C1R	C1QA	P02745	820
C1R	CRP	P02741	772
C1R	COLEC11	Q9BWP8	753
C1R	CFP	P27918	740
C1R	CFH	P08603	732
C1R	FCN2	Q15485	724

IntAct

26 interactions, top by confidence:

A	B	Type	Score
C1S	C1R	psi-mi:“MI:0914”(association)	0.900
C1R	C1S	psi-mi:“MI:0407”(direct interaction)	0.900
C1S	C1R	psi-mi:“MI:0407”(direct interaction)	0.900
C1R	C1S	psi-mi:“MI:0915”(physical association)	0.900
C1R	C1S	psi-mi:“MI:0570”(protein cleavage)	0.900
C1R	C1R	psi-mi:“MI:0407”(direct interaction)	0.620
C1R	SERPING1	psi-mi:“MI:0915”(physical association)	0.540
SERPING1	C1R	psi-mi:“MI:0407”(direct interaction)	0.540
C1R	BIRC2	psi-mi:“MI:0914”(association)	0.530
BMP1	C1R	psi-mi:“MI:0915”(physical association)	0.400
TLL1	C1R	psi-mi:“MI:0915”(physical association)	0.400
	LECT2	psi-mi:“MI:0915”(physical association)	0.400
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
	C1R	psi-mi:“MI:0915”(physical association)	0.400
EP300	C1R	psi-mi:“MI:0915”(physical association)	0.370
PCK1	C1R	psi-mi:“MI:0915”(physical association)	0.370
SULF2	IGKV2-29	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
DISC1	C1R	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (21): C1R (Affinity Capture-MS), C1RL (Affinity Capture-MS), BIRC2 (Affinity Capture-MS), LRRC15 (Affinity Capture-MS), C1R (Affinity Capture-MS), C1R (Reconstituted Complex), C1R (Affinity Capture-Western), C1S (Affinity Capture-Western), C1R (Affinity Capture-Western), C1R (Co-crystal Structure), C1R (Affinity Capture-MS), DSG4 (Affinity Capture-MS), C1RL (Affinity Capture-MS), BIRC2 (Affinity Capture-MS), SERPING1 (Co-fractionation)

ESM2 similar proteins: A1KZ92, A2ARA8, A2VCU8, A6QR11, O00187, P00736, P09871, P15156, P32004, P48740, P53708, P57110, P59384, P59511, P85171, P97857, P98064, Q0PMG2, Q0VCX1, Q15113, Q2VWQ2, Q4R577, Q4VC17, Q5R1W3, Q5R3Z7, Q5R544, Q61220, Q62918, Q62919, Q69DK8, Q69Z28, Q6P6T1, Q7ZXL5, Q8CFG8, Q8CFG9, Q8CG14, Q8CG16, Q8CHN8, Q8TE57, Q8TE58

Diamond homologs: A0A1D5NSM8, A2AVA0, B6D985, B6E141, O35086, P00736, P00738, P00739, P00743, P06866, P09871, P15156, P19006, P19007, P43430, P50417, P57727, P70375, P80010, Q0VCX1, Q28801, Q2TBU0, Q3UZ09, Q4R577, Q5R1W3, Q5R544, Q5R5F6, Q5VAN1, Q60574, Q61646, Q62558, Q69DK8, Q6IE14, Q6IE64, Q6P6T1, Q7SZE1, Q8CFG8, Q8CFG9, Q8CG14, Q8CG16

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CSNK2A1	“down-regulates activity”	C1R	phosphorylation
C1R	“form complex”	“Complement C1 complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	5
Uncertain significance	42
Likely benign	48
Benign	27

Top pathogenic / likely-pathogenic (20)

Variant ID	HGVS	Classification
1527672	GRCh37/hg19 12p13.33-q11(chr12:173786-37869301)	Pathogenic
267351	NM_001733.7(C1R):c.1073G>T (p.Cys358Phe)	Pathogenic
267352	NM_001733.7(C1R):c.902G>C (p.Arg301Pro)	Pathogenic
267353	NM_001733.7(C1R):c.927C>G (p.Cys309Trp)	Pathogenic
267354	NM_001733.7(C1R):c.899T>C (p.Leu300Pro)	Pathogenic
267355	NM_001733.7(C1R):c.917_927delinsGGACA (p.Ile306_Cys309delinsArgThr)	Pathogenic
267356	NM_001733.7(C1R):c.869A>G (p.Asp290Gly)	Pathogenic
372130	NM_001733.7(C1R):c.149_150delinsAT (p.Val50Asp)	Pathogenic
375577	NM_001733.7(C1R):c.905A>G (p.Tyr302Cys)	Pathogenic
375578	NM_001733.7(C1R):c.1012T>C (p.Cys338Arg)	Pathogenic
375579	NM_001733.7(C1R):c.1092G>C (p.Trp364Cys)	Pathogenic
375580	NM_001733.7(C1R):c.1113C>G (p.Cys371Trp)	Pathogenic
375581	NM_001733.7(C1R):c.1200_1215delinsTCATGTAATA (p.Arg401_Tyr405delinsHisValIle)	Pathogenic
375582	NM_001733.7(C1R):c.1303T>C (p.Trp435Arg)	Pathogenic
973553	NM_001733.7(C1R):c.1427_1428dup (p.Trp477fs)	Pathogenic
2444516	NM_001733.7(C1R):c.1073G>A (p.Cys358Tyr)	Likely pathogenic
3898059	NM_001733.7(C1R):c.925T>C (p.Cys309Arg)	Likely pathogenic
4531436	NM_001733.7(C1R):c.1111T>C (p.Cys371Arg)	Likely pathogenic
546697	NM_001733.7(C1R):c.926G>A (p.Cys309Tyr)	Likely pathogenic
972707	NM_001733.7(C1R):c.265T>C (p.Cys89Arg)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

4687 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:7081221:A:G	W477R	0.999
12:7081221:A:T	W477R	0.999
12:7080562:C:A	W696C	0.998
12:7080562:C:G	W696C	0.998
12:7080622:C:A	W676C	0.998
12:7080622:C:G	W676C	0.998
12:7081219:C:A	W477C	0.998
12:7081219:C:G	W477C	0.998
12:7088863:A:G	W298R	0.998
12:7088863:A:T	W298R	0.998
12:7080701:C:G	C650S	0.997
12:7080701:C:T	C650Y	0.997
12:7080702:A:T	C650S	0.997
12:7080862:G:C	F596L	0.997
12:7080862:G:T	F596L	0.997
12:7080864:A:G	F596L	0.997
12:7080868:A:C	S594R	0.997
12:7080868:A:T	S594R	0.997
12:7080870:T:G	S594R	0.997
12:7080971:A:G	L560P	0.997
12:7080974:G:T	A559D	0.997
12:7080975:C:G	A559P	0.997
12:7080980:T:A	D557V	0.997
12:7082040:C:G	C447S	0.997
12:7082041:A:T	C447S	0.997
12:7082075:C:A	W435C	0.997
12:7082075:C:G	W435C	0.997
12:7086404:C:A	W364C	0.997
12:7086404:C:G	W364C	0.997
12:7086423:C:G	C358S	0.997

dbSNP variants (sampled 300 via entrez): RS1000247449 (12:7089582 C>G), RS1000580057 (12:7088474 T>C), RS1000833400 (12:7090896 T>A), RS1000884094 (12:7090741 G>A), RS1001015882 (12:7085180 G>A), RS1001468085 (12:7084990 G>A,C,T), RS1001742891 (12:7091284 C>T), RS1002183308 (12:7085656 G>A,T), RS1002234211 (12:7085335 T>C), RS1002291763 (12:7091708 G>A), RS1002467363 (12:7079948 C>G), RS1003027376 (12:7081097 T>A,G), RS1003181612 (12:7087140 G>A,T), RS1003234005 (12:7086883 A>C), RS1003673331 (12:7092848 G>C)

Disease associations

OMIM: gene MIM:613785 | disease phenotypes: MIM:130080, MIM:617174, MIM:130000

GenCC curated gene-disease

Disease	Classification	Inheritance
Ehlers-Danlos syndrome, periodontal type 1	Definitive	Autosomal dominant
autosomal systemic lupus erythematosus type 16	Supportive	Autosomal dominant
Ehlers-Danlos syndrome, periodontitis type	Supportive	Autosomal dominant

Mondo (6): Ehlers-Danlos syndrome, periodontal type 1 (MONDO:0020684), vascular dementia (MONDO:0004648), Ehlers-Danlos syndrome, periodontal type 2 (MONDO:0014954), Ehlers-Danlos syndrome (MONDO:0020066), autosomal systemic lupus erythematosus type 16 (MONDO:0013743), Ehlers-Danlos syndrome, periodontitis type (MONDO:0007527)

Orphanet (2): Periodontal Ehlers-Danlos syndrome (Orphanet:75392), Ehlers-Danlos syndrome (Orphanet:98249)

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000098	Tall stature
HP:0000212	Gingival overgrowth
HP:0000225	Gingival bleeding
HP:0000347	Micrognathia
HP:0000592	Blue sclerae
HP:0000691	Microdontia
HP:0000704	Periodontitis
HP:0000963	Thin skin
HP:0000974	Hyperextensible skin
HP:0000977	Soft skin
HP:0000978	Bruising susceptibility
HP:0001015	Prominent superficial veins
HP:0001030	Fragile skin
HP:0001034	Hypermelanotic macule
HP:0001058	Poor wound healing
HP:0001075	Atrophic scars
HP:0001166	Arachnodactyly
HP:0001373	Joint dislocation
HP:0001382	Joint hypermobility
HP:0001537	Umbilical hernia
HP:0001609	Hoarse voice
HP:0002036	Hiatus hernia
HP:0002650	Scoliosis
HP:0002719	Recurrent infections
HP:0002761	Generalized joint hypermobility
HP:0002829	Arthralgia
HP:0002960	Autoimmunity
HP:0004322	Short stature

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D015140	Dementia, Vascular	C10.228.140.300.400; C10.228.140.300.510.800.500; C10.228.140.380.230; C10.228.140.695.500; C14.907.137.126.372.500; C14.907.253.560.350.500; F03.615.400.350
D004535	Ehlers-Danlos Syndrome	C14.907.454.240; C15.378.463.515.240; C16.131.831.428; C16.320.850.260; C17.300.200.310; C17.800.804.428; C17.800.827.260
C562626	Ehlers-Danlos Syndrome, Type VIII (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4611 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 7,063 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL273264	NAFAMOSTAT	3	7,063

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — S1: Chymotrypsin

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

Ligand	Action	Affinity	Parameter
nafamostat	Inhibition	4.92	pIC50

Binding affinities (BindingDB)

19 measured of 19 human assays (19 total across all organisms); most potent 19 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-pyridin-4-ylbutanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	20 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-piperidin-4-ylbutanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	90 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-(1-oxidopyridin-1-ium-4-yl)butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	120 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2R)-2-(benzylsulfonylamino)-N-[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]-5-piperidin-4-ylpentanamide	KI	300 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2R)-2-(benzylsulfonylamino)-N-[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]-5-(1-oxidopyridin-1-ium-4-yl)pentanamide	KI	400 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
methyl 4-[(4R)-4-(benzylsulfonylamino)-5-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-5-oxopentyl]piperidine-1-carboxylate	KI	400 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
BDBM108100	KI	750 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2R)-2-(benzylsulfonylamino)-N-[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]-5-pyridin-4-ylpentanamide	KI	850 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-[1-(2-methoxyacetyl)piperidin-4-yl]butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	1600 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
4-[(3R)-3-(benzylsulfonylamino)-4-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-4-oxobutyl]-N-methylpiperidine-1-carboxamide	KI	1700 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-4-(1-acetylpiperidin-4-yl)-2-(benzylsulfonylamino)butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	1900 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
methyl 4-[(3R)-3-(benzylsulfonylamino)-4-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-4-oxobutyl]piperidine-1-carboxylate	KI	2000 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-(1-butanoylpiperidin-4-yl)butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	2200 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-[1-(cyclopropanecarbonyl)piperidin-4-yl]butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	2300 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-(1-propanoylpiperidin-4-yl)butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	2300 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
3-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-1-oxo-5-phenylpentan-2-yl]sulfamoylmethyl]benzoic acid	KI	2400 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
4-[(3R)-3-(benzylsulfonylamino)-4-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-4-oxobutyl]-N,N-dimethylpiperidine-1-carboxamide	KI	2500 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
(2S)-2-[[(2R)-2-(benzylsulfonylamino)-4-[1-(2-methylpropanoyl)piperidin-4-yl]butanoyl]amino]-N-[(4-carbamimidoylphenyl)methyl]-4-piperidin-4-ylbutanamide	KI	3200 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
methyl 3-[[(2R)-1-[[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]amino]-1-oxo-5-phenylpentan-2-yl]sulfamoylmethyl]benzoate	KI	5900 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use

ChEMBL bioactivities

68 potent at pChembl≥5 of 113 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.70	IC50	200	nM	CHEMBL10770
6.40	IC50	400	nM	CHEMBL10312
6.40	IC50	400	nM	CHEMBL10610
6.30	IC50	500	nM	CHEMBL10569
6.22	IC50	600	nM	CHEMBL4247936
6.16	IC50	700	nM	CHEMBL158926
6.16	IC50	700	nM	CHEMBL166801
6.16	IC50	700	nM	CHEMBL10432
6.10	IC50	800	nM	NAFAMOSTAT
6.10	IC50	800	nM	CHEMBL10065
6.10	IC50	800	nM	CHEMBL274319
6.10	IC50	800	nM	CHEMBL10248
6.05	IC50	900	nM	CHEMBL10132
6.05	IC50	900	nM	CHEMBL10610
6.05	IC50	900	nM	CHEMBL10432
6.05	IC50	900	nM	CHEMBL10252
6.00	IC50	1000	nM	NAFAMOSTAT
5.98	IC50	1040	nM	NAFAMOSTAT
5.86	IC50	1370	nM	CHEMBL10378
5.85	IC50	1400	nM	CHEMBL10378
5.85	IC50	1400	nM	CHEMBL10132
5.85	IC50	1400	nM	CHEMBL10554
5.85	IC50	1400	nM	CHEMBL10768
5.82	IC50	1500	nM	CHEMBL167523
5.82	IC50	1500	nM	CHEMBL10527
5.82	IC50	1500	nM	CHEMBL10248
5.77	IC50	1700	nM	CHEMBL157862
5.77	IC50	1700	nM	CHEMBL10435
5.70	IC50	2000	nM	CHEMBL274816
5.70	IC50	2000	nM	CHEMBL274137
5.55	IC50	2800	nM	CHEMBL169044
5.55	IC50	2800	nM	CHEMBL10435
5.52	IC50	3000	nM	CHEMBL158577
5.52	IC50	3000	nM	CHEMBL161460
5.52	IC50	3000	nM	CHEMBL167523
5.50	IC50	3200	nM	CHEMBL168038
5.46	IC50	3500	nM	CHEMBL276438
5.40	IC50	4000	nM	CHEMBL10312
5.40	IC50	4000	nM	CHEMBL10254
5.40	IC50	4000	nM	CHEMBL10246
5.40	IC50	4000	nM	CHEMBL166632
5.38	IC50	4200	nM	CHEMBL352443
5.38	IC50	4200	nM	CHEMBL10527
5.30	IC50	5000	nM	CHEMBL157987
5.29	IC50	5100	nM	CHEMBL274211
5.22	IC50	6000	nM	CHEMBL159104
5.22	IC50	6000	nM	CHEMBL166801
5.22	IC50	6000	nM	CHEMBL166632
5.22	IC50	6000	nM	CHEMBL167163
5.19	IC50	6500	nM	CHEMBL10050

PubChem BioAssay actives

53 with measured affinity, of 134 total; 34 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
2-(2-iodoanilino)benzo[g][3,1]benzoxazin-4-one	43030: Inhibition of 50% of human C1r Serine Protease by initially using Cbz-Gly-Arg-S-Bzl as substrate	ic50	0.2000	uM
2-(2-iodoanilino)-7-(trifluoromethyl)-3,1-benzoxazin-4-one	43030: Inhibition of 50% of human C1r Serine Protease by initially using Cbz-Gly-Arg-S-Bzl as substrate	ic50	0.4000	uM
7-chloro-2-(2,6-dichloroanilino)-3,1-benzoxazin-4-one	43030: Inhibition of 50% of human C1r Serine Protease by initially using Cbz-Gly-Arg-S-Bzl as substrate	ic50	0.4000	uM
6,7-dichloro-2-(2-iodoanilino)-3,1-benzoxazin-4-one	43030: Inhibition of 50% of human C1r Serine Protease by initially using Cbz-Gly-Arg-S-Bzl as substrate	ic50	0.5000	uM
N-[(5-carbamimidoylthiophen-2-yl)methyl]-1-[(2R)-2-[[2-(2,6-dichlorophenyl)acetyl]amino]-3-methylbutanoyl]-2,5-dihydropyrrole-2-carboxamide	1393219: Inhibition of human plasma C1r using Cbz-Gly-Arg-S-Bzl as substrate preincubated for 10 mins followed by substrate addition and measured after 30 mins by DTNB reagent-based two-beam microtiter plate photometer	ic50	0.6000	uM
4-methoxy-N-methyl-N-(4-oxo-3,1-benzoxazin-2-yl)benzenesulfonamide	50879: In vitro inhibition of purified human C1r protease.	ic50	0.7000	uM
7-chloro-2-(2-iodoanilino)-3,1-benzoxazin-4-one	43030: Inhibition of 50% of human C1r Serine Protease by initially using Cbz-Gly-Arg-S-Bzl as substrate	ic50	0.7000	uM
7-chloro-2-(2-chloroanilino)-3,1-benzoxazin-4-one	43029: 50% inhibition of human C1r serine protease after 60 mins using Cbz-Gly-Arg-S-Bzl as substrate	ic50	0.8000	uM
2-(2-iodoanilino)-7-methyl-3,1-benzoxazin-4-one	43030: Inhibition of 50% of human C1r Serine Protease by initially using Cbz-Gly-Arg-S-Bzl as substrate	ic50	0.8000	uM
2-(2-iodoanilino)-7-nitro-3,1-benzoxazin-4-one	43030: Inhibition of 50% of human C1r Serine Protease by initially using Cbz-Gly-Arg-S-Bzl as substrate	ic50	0.8000	uM
(6-carbamimidoylnaphthalen-2-yl) 4-(diaminomethylideneamino)benzoate	1393211: Inhibition of human serum C1r using AAME as substrate after 30 mins	ic50	0.8000	uM
2-(2,6-dichloroanilino)-3,1-benzoxazin-4-one	43029: 50% inhibition of human C1r serine protease after 60 mins using Cbz-Gly-Arg-S-Bzl as substrate	ic50	0.9000	uM
2-(2-chloroanilino)-7-methyl-3,1-benzoxazin-4-one	43029: 50% inhibition of human C1r serine protease after 60 mins using Cbz-Gly-Arg-S-Bzl as substrate	ic50	0.9000	uM
2-(2-chloroanilino)-7-nitro-3,1-benzoxazin-4-one	43030: Inhibition of 50% of human C1r Serine Protease by initially using Cbz-Gly-Arg-S-Bzl as substrate	ic50	1.4000	uM
2-(2-iodo-N-methylanilino)-3,1-benzoxazin-4-one	43030: Inhibition of 50% of human C1r Serine Protease by initially using Cbz-Gly-Arg-S-Bzl as substrate	ic50	1.4000	uM
2-(2,6-dichloroanilino)-7-(trifluoromethyl)-3,1-benzoxazin-4-one	43030: Inhibition of 50% of human C1r Serine Protease by initially using Cbz-Gly-Arg-S-Bzl as substrate	ic50	1.5000	uM
2-[4-[methyl-(4-oxo-3,1-benzoxazin-2-yl)sulfamoyl]phenyl]guanidine	50879: In vitro inhibition of purified human C1r protease.	ic50	1.5000	uM
7-fluoro-2-(2-iodoanilino)-3,1-benzoxazin-4-one	43030: Inhibition of 50% of human C1r Serine Protease by initially using Cbz-Gly-Arg-S-Bzl as substrate	ic50	1.7000	uM
6,7-dichloro-2-(2-chloroanilino)-3,1-benzoxazin-4-one	43030: Inhibition of 50% of human C1r Serine Protease by initially using Cbz-Gly-Arg-S-Bzl as substrate	ic50	2.0000	uM
2-(2,5-dichloroanilino)-3,1-benzoxazin-4-one	43029: 50% inhibition of human C1r serine protease after 60 mins using Cbz-Gly-Arg-S-Bzl as substrate	ic50	2.0000	uM
2-bromo-N-methyl-N-(4-oxo-3,1-benzoxazin-2-yl)benzenesulfonamide	50879: In vitro inhibition of purified human C1r protease.	ic50	2.8000	uM
N-ethyl-N-(4-oxo-3,1-benzoxazin-2-yl)benzenesulfonamide	50879: In vitro inhibition of purified human C1r protease.	ic50	3.2000	uM
2-(2-iodoanilino)-3,1-benzoxazin-4-one	43030: Inhibition of 50% of human C1r Serine Protease by initially using Cbz-Gly-Arg-S-Bzl as substrate	ic50	3.5000	uM
6-chloro-2-(2-iodoanilino)-3,1-benzoxazin-4-one	43030: Inhibition of 50% of human C1r Serine Protease by initially using Cbz-Gly-Arg-S-Bzl as substrate	ic50	4.0000	uM
2-[2-(trifluoromethoxy)anilino]-3,1-benzoxazin-4-one	43030: Inhibition of 50% of human C1r Serine Protease by initially using Cbz-Gly-Arg-S-Bzl as substrate	ic50	4.0000	uM
N-methyl-N-(4-oxo-3,1-benzoxazin-2-yl)benzenesulfonamide	50879: In vitro inhibition of purified human C1r protease.	ic50	4.0000	uM
2-(2-bromoanilino)-3,1-benzoxazin-4-one	43030: Inhibition of 50% of human C1r Serine Protease by initially using Cbz-Gly-Arg-S-Bzl as substrate	ic50	5.1000	uM
N-methyl-N-(4-oxo-3,1-benzoxazin-2-yl)naphthalene-1-sulfonamide	50879: In vitro inhibition of purified human C1r protease.	ic50	6.0000	uM
(6-carbamimidoylnaphthalen-2-yl) 4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoate;methanesulfonic acid	72361: Binding affinity against factor C1r.	ki	6.4000	uM
2-(2-chloroanilino)-3,1-benzoxazin-4-one	43030: Inhibition of 50% of human C1r Serine Protease by initially using Cbz-Gly-Arg-S-Bzl as substrate	ic50	6.5000	uM
6,7-difluoro-2-(2-iodoanilino)-3,1-benzoxazin-4-one	43030: Inhibition of 50% of human C1r Serine Protease by initially using Cbz-Gly-Arg-S-Bzl as substrate	ic50	7.0000	uM
4-amino-N-methyl-N-(4-oxo-3,1-benzoxazin-2-yl)benzenesulfonamide	50879: In vitro inhibition of purified human C1r protease.	ic50	7.0000	uM
2,6-dichloro-N-methyl-N-(4-oxo-3,1-benzoxazin-2-yl)benzenesulfonamide	50879: In vitro inhibition of purified human C1r protease.	ic50	7.5000	uM
N,4-dimethyl-N-(4-oxo-3,1-benzoxazin-2-yl)benzenesulfonamide	50879: In vitro inhibition of purified human C1r protease.	ic50	7.8000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects cotreatment, decreases expression, increases abundance, affects expression, increases expression	4
Tobacco Smoke Pollution	affects expression, decreases expression	4
bisphenol A	decreases methylation, increases expression, affects cotreatment	3
Estradiol	affects cotreatment, increases expression, decreases expression	3
Ozone	affects cotreatment, decreases expression, increases abundance, affects expression, increases reaction	3
Valproic Acid	affects expression, decreases expression, increases expression, increases methylation	3
Cadmium	affects binding, increases abundance, increases expression	2
Nickel	affects binding, increases expression	2
Tetrachlorodibenzodioxin	increases expression, affects cotreatment, decreases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
afuresertib	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
sotorasib	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
propionaldehyde	decreases expression	1
beta-lapachone	increases expression	1
sulforaphane	decreases expression	1
sodium arsenite	decreases expression	1
cupric chloride	decreases expression	1
nickel sulfate	increases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
perfluorooctane sulfonic acid	decreases expression	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
abrine	decreases expression	1
MRK 003	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
3’,4’-dimethoxy-alpha-naphthoflavone	increases expression, decreases reaction	1
trametinib	increases expression, affects cotreatment	1

ChEMBL screening assays

29 unique, capped per target: 29 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2320208	Binding	Inhibition of human C1r	Development of new cyclic plasmin inhibitors with excellent potency and selectivity. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00165763	PHASE4	COMPLETED	Efficacy and Safety of Donepezil Hydrochloride (Aricept) in Vascular Dementia
NCT00847860	PHASE4	COMPLETED	Cilostazol Verse Asprin for Vascular Dementia in Poststroke Patients With White Matter Lesions
NCT00947531	PHASE4	COMPLETED	A Clinical Trial to Evaluate the Safety and Efficacy of 20 ml Cerebrolysin in Patients With Vascular Dementia
NCT00950430	PHASE4	ENROLLING_BY_INVITATION	Imaging of Brain Amyloid Plaques in the Aging Population
NCT04890431	PHASE4	UNKNOWN	Impact of Oxygen Therapy on Fatigue in Patients With Hypermobile-type Ehlers-Danlos Syndrome
NCT05603741	PHASE4	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT00099216	PHASE3	COMPLETED	Efficacy and Safety of Rivastigmine Capsules in Patients With Probable Vascular Dementia
NCT00130338	PHASE3	COMPLETED	Rivastigmine Capsules in Patients With Probable Vascular Dementia
NCT00209456	PHASE3	COMPLETED	Dopamine Transporter Scintigraphy Imaging (DAT-Imaging) in Patients With Lewy Body Dementia
NCT00249158	PHASE3	COMPLETED	A Study of the Effectiveness and Safety of Risperidone in the Treatment of Behavioral Disturbances in Patients With Dementia
NCT00261573	PHASE3	COMPLETED	A Study of the Safety and Effectiveness of Galantamine Versus Placebo in the Treatment of Patients With Vascular Dementia or Mixed Dementia
NCT00621647	PHASE3	COMPLETED	Seroquel- Agitation Associated With Dementia
NCT02453932	PHASE3	COMPLETED	Efficacy and Safety of Tianzhi Granule in Mild to Moderate Vascular Dementia
NCT03682185	PHASE3	COMPLETED	The Healthy Patterns Sleep Study
NCT03789760	PHASE3	COMPLETED	The Clinical Trial of Chinese Herbal Medicine (SaiLuoTong) Capsule
NCT03804229	PHASE3	ACTIVE_NOT_RECRUITING	Efficacy and Safety of Butylphthalide Soft Capsule for the Treatment of Vascular Dementia
NCT03986424	PHASE3	COMPLETED	Local Study of Akatinol Memantine in VaD in Russia
NCT04552041	PHASE3	COMPLETED	Prospekta in the Treatment of Cognitive, Behavioral and Psychiatric Disorders in Patients With Vascular Dementia.
NCT05279937	PHASE3	NOT_YET_RECRUITING	The Ultrasound-Guided Dextrose Prolotherapy in Ehlers-Danlos Syndrome Patients
NCT01466543	PHASE2	UNKNOWN	Effect of Zydena (Udenafil) on Cerebral Blood Flow and Peripheral Blood Viscosity
NCT01475578	PHASE2	COMPLETED	Study of STA-1 Capsule in Patients With Vascular Dementia (Marrow-Sea Deficiency)
NCT01608217	PHASE2	COMPLETED	Delta-THC in Dementia
NCT01761227	PHASE2	COMPLETED	Efficacy and Safety of Fufangdanshen Tablets in Mild to Moderate Vascular Dementia
NCT01953705	PHASE2	UNKNOWN	n-3 PUFA for Vascular Cognitive Aging
NCT01965756	PHASE2	COMPLETED	Effect of Insulin Sensitizer Metformin on AD Biomarkers
NCT01978730	PHASE2	UNKNOWN	The Clinical Trial of Chinese Herbal Medicine SaiLuoTong Capsule
NCT02467413	PHASE2	WITHDRAWN	BAC in Patient With Alzheimer’s Disease or Vascular Dementia
NCT03230071	PHASE2	COMPLETED	Efficacy and Safety of TMBCZG in Mild to Moderate Vascular Dementia
NCT04109963	PHASE2	UNKNOWN	Trial of Remote Ischemic Pre-conditioning in Vascular Cognitive Impairment
NCT05371639	PHASE2	UNKNOWN	Efficacy and Safety of Tian Ma Bian Chun Zhi Gan Tablets in Mild to Moderate Vascular Dementia
NCT00001966	PHASE2	COMPLETED	Mind-Body Therapy for Pain in Ehlers-Danlos Syndrome
NCT00457769	PHASE1	UNKNOWN	Aricept to Improve Functional Tasks in Vascular Dementia
NCT03702543	PHASE1	UNKNOWN	Managing Vascular Dementia Risk Factors With SymTrend
NCT04567745	PHASE1	COMPLETED	Automated Retinal Image Analysis System (EyeQuant) for Computation of Vascular Biomarkers
NCT02098824	PHASE2/PHASE3	UNKNOWN	Symptomatic Treatment of Vascular Cognitive Impairment
NCT04248270	PHASE1/PHASE2	UNKNOWN	A Noval Tau Tracer in Young Onset Dementia
NCT00172900	Not specified	UNKNOWN	MRS and DTI of White Matter in Alzheimer’s Disease
NCT00506818	Not specified	COMPLETED	Cognitive and Emotional Impairment After Stroke
NCT00889603	Not specified	COMPLETED	Non-Interventional Study With Aricept® Evess
NCT01208675	Not specified	COMPLETED	The Swedish BioFINDER Study