C1S

Summary

C1S (complement C1s, HGNC:1247) is a protein-coding gene on chromosome 12p13.31, encoding Complement C1s subcomponent (P09871). 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 serine protease, which is a major constituent of the human complement subcomponent C1. C1s associates with two other complement components C1r and C1q in order to yield the first component of the serum complement system. Defects in this gene are the cause of selective C1s deficiency.

Source: NCBI Gene 716 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complement component C1s deficiency (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 15
• Clinical variants (ClinVar): 711 total — 29 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 32
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001734

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1247
Approved symbol	C1S
Name	complement C1s
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000182326
Ensembl biotype	protein_coding
OMIM	120580
Entrez	716

Gene structure

Transcript identifiers

Ensembl transcripts: 47 — 32 protein_coding, 12 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000328916, ENST00000360817, ENST00000402681, ENST00000403949, ENST00000406697, ENST00000413211, ENST00000423384, ENST00000443875, ENST00000461983, ENST00000463798, ENST00000470326, ENST00000473545, ENST00000488701, ENST00000489541, ENST00000495053, ENST00000495061, ENST00000497061, ENST00000541647, ENST00000542978, ENST00000543187, ENST00000698563, ENST00000698564, ENST00000698565, ENST00000857911, ENST00000857912, ENST00000857913, ENST00000857914, ENST00000857915, ENST00000857916, ENST00000857917, ENST00000857918, ENST00000857919, ENST00000857920, ENST00000857921, ENST00000857922, ENST00000857923, ENST00000857924, ENST00000857925, ENST00000956013, ENST00000956014, ENST00000956015, ENST00000956016, ENST00000956017, ENST00000956018, ENST00000956019, ENST00000956020, ENST00000956021

RefSeq mRNA: 3 — MANE Select: NM_001734 NM_001346850, NM_001734, NM_201442

CCDS: CCDS31735, CCDS86271

Canonical transcript exons

ENST00000360817 — 12 exons

Exon	Start	End
ENSE00001322783	7065817	7065970
ENSE00001491289	7069855	7071032
ENSE00001560603	7066518	7066633
ENSE00001609294	7062475	7062682
ENSE00003469135	7067039	7067117
ENSE00003529430	7061839	7061917
ENSE00003561230	7064267	7064392
ENSE00003624197	7068456	7068530
ENSE00003636973	7065100	7065299
ENSE00003645151	7067643	7067771
ENSE00003662525	7062890	7063067
ENSE00003842214	7060718	7060877

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.1915 / max 1986.5997, expressed in 1125 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
123875	42.3079	1109
123876	4.3766	696
123882	0.6449	277
123885	0.5378	211
123881	0.4159	188
123880	0.2960	147
123883	0.2222	107
123884	0.1973	95
123877	0.1098	10
123886	0.0436	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pericardium	UBERON:0002407	99.80	gold quality
right lobe of liver	UBERON:0001114	99.78	gold quality
parietal pleura	UBERON:0002400	99.77	gold quality
right ovary	UBERON:0002118	99.73	gold quality
gall bladder	UBERON:0002110	99.72	gold quality
left ovary	UBERON:0002119	99.69	gold quality
mucosa of stomach	UBERON:0001199	99.67	gold quality
pleura	UBERON:0000977	99.65	gold quality
tibial nerve	UBERON:0001323	99.60	gold quality
left uterine tube	UBERON:0001303	99.59	gold quality
liver	UBERON:0002107	99.59	gold quality
synovial joint	UBERON:0002217	99.58	gold quality
endocervix	UBERON:0000458	99.55	gold quality
right coronary artery	UBERON:0001625	99.55	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.53	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.52	gold quality
peritoneum	UBERON:0002358	99.51	gold quality
omental fat pad	UBERON:0010414	99.51	gold quality
lower esophagus	UBERON:0013473	99.51	gold quality
germinal epithelium of ovary	UBERON:0001304	99.50	gold quality
visceral pleura	UBERON:0002401	99.49	gold quality
calcaneal tendon	UBERON:0003701	99.49	gold quality
urethra	UBERON:0000057	99.47	gold quality
body of uterus	UBERON:0009853	99.47	gold quality
coronary artery	UBERON:0001621	99.45	gold quality
left coronary artery	UBERON:0001626	99.45	gold quality
descending thoracic aorta	UBERON:0002345	99.45	gold quality
subcutaneous adipose tissue	UBERON:0002190	99.44	gold quality
adipose tissue of abdominal region	UBERON:0007808	99.44	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.40	gold quality

Single-cell (SCXA)

Detected in 32 experiment(s), a significant marker in 28.

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	3825.70
E-MTAB-6678	yes	2519.05
E-MTAB-8322	yes	2450.06
E-HCAD-11	yes	1900.20
E-HCAD-15	yes	1843.56
E-CURD-88	yes	1783.53
E-MTAB-8410	yes	1756.06
E-CURD-46	yes	1671.92
E-MTAB-8530	yes	1618.55
E-MTAB-8142	yes	1561.22
E-GEOD-134144	yes	1525.00
E-MTAB-6701	yes	1479.40
E-HCAD-1	yes	1321.50
E-GEOD-135922	yes	1311.32
E-MTAB-10885	yes	1300.81

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

36 targeting C1S, 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-493-5P	99.96	72.47	2382
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-3681-5P	99.82	66.88	387
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-6849-5P	99.64	66.00	352
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-501-5P	98.77	68.88	1328
HSA-MIR-583	98.71	67.44	1791

Literature-anchored findings (GeneRIF, showing 19)

• Interaction with the prime side residues at the cleavage point in C1s enhances the affinity of the enzyme for complement 2 and complement 4 substrates; these prime subsite residues mediate positive cooperativity in the cleavage of the substrate. (PMID:14674770)
• full specificity of the enzyme using a randomized phage display library (PMID:16169853)
• There are splice variants of C1s mRNA transcripts in normal human cells (PMID:18062908)
• Detailed mapping of post-translational modifications and insights into the C1r/C1s binding sites. (PMID:20008834)
• These results provide further structural insights into the architecture of the C1 complex, and the interactions between C1r and C1s. (PMID:20592021)
• Four positively charged amino acids on the serine protease domain appear to form a catalytic exosite that is required for efficient cleavage of C4 in the classical pathway of complement. (PMID:22855709)
• A molecular switch governs the interaction between the human complement protease C1s and its substrate, complement C4. (PMID:23592783)
• 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)
• Data indicate that complement C1s mRNA level was low in ICR-derived glomerulonephritis (ICGN) mice liver as compared with age-matched ICR mice. (PMID:23989031)
• TNT003, an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinins. (PMID:24695853)
• 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)
• 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)
• Two Different Missense C1S Mutations, Associated to Periodontal Ehlers-Danlos Syndrome, Lead to Identical Molecular Outcomes. (PMID:31921203)
• The Impact of Complement Genes on the Risk of Late-Onset Alzheimer’s Disease. (PMID:33804666)
• C1q binding to surface-bound IgG is stabilized by C1r2s2 proteases. (PMID:34155115)
• Degradation of collagen I by activated C1s in periodontal Ehlers-Danlos Syndrome. (PMID:36960056)
• A homozygous loss-of-function C1S mutation is associated with Kikuchi-Fujimoto disease. (PMID:37209807)
• Cytoprotective effects of C1s enzyme in macrophages in atherosclerosis mediated through the LRP5 and Wnt/beta-catenin pathway. (PMID:38218080)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	c1s.2	ENSDARG00000102094
mus_musculus	C1s1	ENSMUSG00000038521
mus_musculus	C1s2	ENSMUSG00000079343
rattus_norvegicus	C1s	ENSRNOG00000011971

Paralogs (16): F7 (ENSG00000057593), F11 (ENSG00000088926), F9 (ENSG00000101981), HGFAC (ENSG00000109758), F10 (ENSG00000126218), KLK10 (ENSG00000129451), F12 (ENSG00000131187), C1RL (ENSG00000139178), C1R (ENSG00000159403), KLKB1 (ENSG00000164344), PRSS55 (ENSG00000184647), CFD (ENSG00000197766), CFI (ENSG00000205403), PRSS51 (ENSG00000253649), HP (ENSG00000257017), HPR (ENSG00000261701)

Protein

Protein identifiers

Complement C1s subcomponent — P09871 (reviewed: P09871)

Alternative names: C1 esterase, Complement component 1 subcomponent s

All UniProt accessions (7): P09871, B5MCV4, C9IZP8, C9JY52, F5H7T4, F8WCZ6, H0Y5D1

UniProt curated annotations — full annotation on UniProt →

Function. 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. C1S is activated following association of the C1 complex with immunoglobulins (IgG or IgM) complexed with antigens to form antigen-antibody complexes on the surface of pathogens. C1S is cleaved and activated by C1R to generate C1s subcomponent heavy and light chains. C1s subcomponent light chain then cleaves and activates C2 and C4, the next components of the classical complement pathway. Serine protease component of the complement C1 complex, which catalyzes cleavage and activation of C2 and C4, the next components of the classical complement pathway. Also able to cleave C1 inhibitor (SERPING1) in vitro; additional evidence is however required to confirm this result in vivo. Also cleaves IGFBP5 and thereby inhibits the trophic effects of IGF1.

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.

Subcellular location. Secreted. Cell surface.

Post-translational modifications. Cleaved and activated by C1R to generate Complement C1s subcomponent heavy and light chains. The iron and 2-oxoglutarate dependent 3-hydroxylation of aspartate and asparagine is (R) stereospecific within EGF domains.

Disease relevance. Complement component C1s deficiency (C1SD) [MIM:613783] A rare defect resulting in C1 deficiency and impaired activation of the complement classical pathway. C1 deficiency generally leads to severe immune complex disease with features of systemic lupus erythematosus and glomerulonephritis. The disease is caused by variants affecting the gene represented in this entry. Ehlers-Danlos syndrome, periodontal type, 2 (EDSPD2) [MIM:617174] A form of Ehlers-Danlos syndrome, a connective tissue disorder characterized by hyperextensible skin, atrophic cutaneous scars due to tissue fragility and joint hyperlaxity. EDSPD2 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. EDSPD2 transmission pattern is consistent with autosomal dominant inheritance. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Cleaved and activated by C1R. Immunoglobulin-binding promotes autoactivation of C1R, which results in the cleavage of the Arg-Ile bond in the catalytic domain. Inhibited by C1 inhibitor (SERPING1).

Similarity. Belongs to the peptidase S1 family.

RefSeq proteins (3): NP_001333779, NP_001725, NP_958850 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000436	Sushi_SCR_CCP_dom	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 3.4.21.42 — complement subcomponent C1s (BRENDA: 7 organisms, 142 substrates, 74 inhibitors, 31 Km, 67 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
2-AMINOBENZOYL-GLQRALEI-LYS(DINITROPHENOL)-NH2	0.012–0.0138	3
COMPLEMENT COMPONENT C4	0.0001–0.0066	3
Z-AGLQR-7-AMIDO-4-METHYLCOUMARIN	0.0654–0.245	3
Z-LGR-7-AMIDO-4-METHYLCOUMARIN	0.0762–0.212	3
COMPLEMENT COMPONENT C2	0.0052–0.0061	2
ACETYL-L-TYR ETHYL ESTER	19	1
C1-INHIBITOR P4-P1 FRAGMENT	0.3408	1
C1-INHIBITOR P4-P4’ FRAGMENT	0.0077	1
COMPLEMENT COMPONENT C2 P4-P1 FRAGMENT	0.1369	1
COMPLEMENT COMPONENT C2 P4-P4’ FRAGMENT	0.0274	1
COMPLEMENT COMPONENT C4 P4-P1 FRAGMENT	0.3581	1
COMPLEMENT COMPONENT C4 P4-P4’ FRAGMENT	0.0136	1
N-BENZOYL-PHE-VAL-ARG P-NITROANILIDE	0.36	1
N-BENZYLOXYCARBONYL-GLY-ARG THIOBENZYL ESTER	0.069	1
N-BENZYLOXYCARBONYL-LYS P-NITROPHENYL ESTER	0.8	1

UniProt features (131 total): strand 53, binding site 14, disulfide bond 13, helix 11, turn 8, mutagenesis site 7, domain 6, sequence variant 5, chain 3, active site 3, sequence conflict 3, glycosylation site 2, signal peptide 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
1NZI	X-RAY DIFFRACTION	1.5
1ELV	X-RAY DIFFRACTION	1.7
8TYP	X-RAY DIFFRACTION	1.8
4LOS	X-RAY DIFFRACTION	2
4LOR	X-RAY DIFFRACTION	2.5
5UBM	X-RAY DIFFRACTION	2.5
8GMN	X-RAY DIFFRACTION	2.6
9X1H	ELECTRON MICROSCOPY	2.6
4J1Y	X-RAY DIFFRACTION	2.66
4LOT	X-RAY DIFFRACTION	2.92
4LMF	X-RAY DIFFRACTION	2.92
8W18	X-RAY DIFFRACTION	3.94
6F1C	X-RAY DIFFRACTION	4.2
6F1H	X-RAY DIFFRACTION	4.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P09871-F1	88.02	0.67

Antibody-complex structures (SAbDab): 1 — 9X1H

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): 475 (charge relay system); 529 (charge relay system); 632 (charge relay system); 437–438 (cleavage; by c1r)

Ligand- & substrate-binding residues (14): 60; 68; 113; 131; 132; 134; 149; 150; 153; 226; 236; 275 …

Post-translational modifications (1): 149

Disulfide bonds (13): 65–83, 135–147, 143–156, 158–171, 175–202, 234–251, 294–341, 321–354, 359–403, 386–421, 425–549, 595–618, 628–659

Glycosylation sites (2): 174, 406

Mutagenesis-validated functional residues (7):

Position	Phenotype
35	does not affect association with the c1q subcomplex.
60	slightly decreased association with the c1q subcomplex.
63	does not affect association with the c1q subcomplex.
67	does not affect association with the c1q subcomplex.
113	slightly decreased association with the c1q subcomplex.
226	does not affect association with the c1q subcomplex.
275	does not affect association with the c1q subcomplex.

Function

Pathways and Gene Ontology

Reactome pathways

8 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
R-HSA-9920588	Dengue virus activates/modulates innate and adaptive immune responses
R-HSA-166658	Complement cascade
R-HSA-166786	Creation of C4 and C2 activators
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 391 (showing top): MODULE_172, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, TSUNODA_CISPLATIN_RESISTANCE_UP, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_CREATION_OF_C4_AND_C2_ACTIVATORS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOCC_CELL_SURFACE, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GAUSSMANN_MLL_AF4_FUSION_TARGETS_E_UP, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, CEBPB_01, GOBP_B_CELL_MEDIATED_IMMUNITY, CAIRO_HEPATOBLASTOMA_CLASSES_DN, PICCALUGA_ANGIOIMMUNOBLASTIC_LYMPHOMA_UP

GO Biological Process (5): proteolysis (GO:0006508), complement activation, classical pathway (GO:0006958), innate immune response (GO:0045087), immune system process (GO:0002376), complement activation (GO:0006956)

GO Molecular Function (8): serine-type endopeptidase activity (GO:0004252), calcium ion binding (GO:0005509), identical protein binding (GO:0042802), protein binding (GO:0005515), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (6): extracellular region (GO:0005576), complement component C1 complex (GO:0005602), obsolete extracellular space (GO:0005615), cell surface (GO:0009986), blood microparticle (GO:0072562), symbiont cell surface (GO:0106139)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Complement cascade	2
Creation of C4 and C2 activators	1
Dengue Virus-Host Interactions	1
Innate Immune System	1
Initial triggering of complement	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein metabolic process	1
humoral immune response mediated by circulating immunoglobulin	1
complement activation	1
immune response	1
defense response to symbiont	1
biological_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
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
cation binding	1
complement component C1q complex	1
extracellular protein-containing complex	1
extracellular region	1
other organism part	1

Protein interactions and networks

STRING

2246 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C1S	SERPING1	P05155	999
C1S	C1R	P00736	986
C1S	C1QC	P02747	920
C1S	C4A	P01028	915
C1S	C4A	P01028	903
C1S	C1QB	P02746	880
C1S	NDUFAF3	Q9BU61	880
C1S	C1QA	P02745	845
C1S	MBL2	P11226	823
C1S	PTX3	P26022	807
C1S	KLK4	Q9Y5K2	795
C1S	C3	P01024	791
C1S	COLEC11	Q9BWP8	754
C1S	BMP1	P13497	753
C1S	CFP	P27918	747

IntAct

41 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
C1S	SERPING1	psi-mi:“MI:0194”(cleavage reaction)	0.720
C1S	SERPING1	psi-mi:“MI:0915”(physical association)	0.720
SERPING1	C1S	psi-mi:“MI:0407”(direct interaction)	0.720
C1S	SERPING1	psi-mi:“MI:0570”(protein cleavage)	0.720
C1S	CCDC6	psi-mi:“MI:0915”(physical association)	0.670
C1S	C1S	psi-mi:“MI:0407”(direct interaction)	0.620
C1S	CREB3	psi-mi:“MI:0915”(physical association)	0.560
C1S	REEP4	psi-mi:“MI:0915”(physical association)	0.560
	C1S	psi-mi:“MI:0194”(cleavage reaction)	0.440
C1S	C2	psi-mi:“MI:0570”(protein cleavage)	0.440
	C1S	psi-mi:“MI:0407”(direct interaction)	0.440
C1S	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
BMP1	C1R	psi-mi:“MI:0915”(physical association)	0.400
TLL1	C1R	psi-mi:“MI:0915”(physical association)	0.400
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350
IFNG	MMP3	psi-mi:“MI:0914”(association)	0.350
SULF2	IGKV2-29	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350

BioGRID (17): C1R (Affinity Capture-MS), CCDC6 (Affinity Capture-MS), PPP4R1 (Affinity Capture-MS), C1S (Two-hybrid), C1S (Co-purification), C1R (Reconstituted Complex), C1S (Proximity Label-MS), C1S (Affinity Capture-Western), C1S (Affinity Capture-Western), C1R (Affinity Capture-Western), C1R (Affinity Capture-MS), CCDC6 (Affinity Capture-MS), PPP4R1 (Affinity Capture-MS), C1S (Two-hybrid), HK1 (Co-fractionation)

ESM2 similar proteins: A2RT60, A4IHA1, A6YFB5, A9JRB3, B3LVG7, B3P3J9, B4G316, B4HEM8, B4JTT7, B4K835, B4LY58, B4N937, B4PST0, B4QZU6, B5G6G5, D3ZA76, D3ZKF5, E1BJW1, F1N152, G4V4G1, O42422, O88947, P09759, P09871, P15156, P25155, P54759, P54764, P81428, P82807, P83105, P83110, P83370, Q03137, Q07496, Q0VCX1, Q15375, Q297U2, Q58L94, Q69DK8

Diamond homologs: A0A126GUP6, A0A182C2Z2, A0A1S4H5M5, A8JUP7, B5U2W0, B7YZU2, F5HKX0, O15393, O35453, O60235, O60259, O97366, P00774, P03951, P03952, P05049, P05981, P08419, P09871, P10323, P13582, P14272, P21902, P23578, P25155, P26262, P28175, P29293, P31394, P33587, P35035, P35036, P35037, P35039, P35041, P35045, P35046, P35047, P40313, P48038

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
C1S	“form complex”	“Complement C1 complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	29
Likely pathogenic	8
Uncertain significance	385
Likely benign	218
Benign	23

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1210007	NM_001734.5(C1S):c.1537G>T (p.Gly513Ter)	Pathogenic
1363920	NM_001734.5(C1S):c.1714C>T (p.Arg572Ter)	Pathogenic
1384223	NM_001734.5(C1S):c.1441_1442del (p.Arg481fs)	Pathogenic
17067	NM_001734.5(C1S):c.1132_1135del (p.Phe378fs)	Pathogenic
1938833	NM_001734.5(C1S):c.532dup (p.Asp178fs)	Pathogenic
1966220	NM_001734.5(C1S):c.804_805dup (p.Asp269fs)	Pathogenic
2008415	NM_001734.5(C1S):c.1350del (p.Trp451fs)	Pathogenic
2015221	NM_001734.5(C1S):c.689C>G (p.Ser230Ter)	Pathogenic
2048853	NM_001734.5(C1S):c.1096G>T (p.Glu366Ter)	Pathogenic
2080661	NM_001734.5(C1S):c.1399G>T (p.Glu467Ter)	Pathogenic
2131837	NM_001734.5(C1S):c.309C>A (p.Tyr103Ter)	Pathogenic
2137294	NM_001734.5(C1S):c.1567C>T (p.Arg523Ter)	Pathogenic
267348	NM_001734.5(C1S):c.945_947del (p.Asp315_Val316delinsGlu)	Pathogenic
267349	NM_001734.5(C1S):c.880T>C (p.Cys294Arg)	Pathogenic
2696183	NM_001734.5(C1S):c.241_242dup (p.Leu82fs)	Pathogenic
2698081	NM_001734.5(C1S):c.741del (p.Phe247fs)	Pathogenic
2699997	NM_001734.5(C1S):c.1595del (p.Leu532fs)	Pathogenic
2787167	NM_001734.5(C1S):c.842del (p.Lys281fs)	Pathogenic
2819067	NM_001734.5(C1S):c.80del (p.Asn27fs)	Pathogenic
2838992	NM_001734.5(C1S):c.952C>T (p.Gln318Ter)	Pathogenic
2857893	NM_001734.5(C1S):c.1029_1038del (p.Asn344fs)	Pathogenic
2863263	NM_001734.5(C1S):c.211_212del (p.Gln71fs)	Pathogenic
3336211	NM_001734.5(C1S):c.343del (p.Ser115fs)	Pathogenic
3639509	NM_001734.5(C1S):c.1786A>T (p.Lys596Ter)	Pathogenic
4716786	NM_001734.5(C1S):c.698del (p.Asn233fs)	Pathogenic
4716805	NM_001734.5(C1S):c.750C>A (p.Tyr250Ter)	Pathogenic
4730295	NM_001734.5(C1S):c.1353_1354insAAGTGAGGAGCCCCTCTGCCCGGCCAGCCGCCCCGCCCAGGAGGGAGGTGGGGGGGTCAGCCCCCCGCCTGGCCNNNNNNNNNNAAAAAAAAAAAAAAAAAAAATAAAAACTTCCCCTGG (p.Gln452delinsLysTer)	Pathogenic
4773897	NM_001734.5(C1S):c.1737del (p.Val580fs)	Pathogenic
4849179	NC_000012.11:g.(7168182_7169142)(7178337?)del	Pathogenic
1705563	NM_001734.5(C1S):c.1729_1730del (p.Asp577fs)	Likely pathogenic

SpliceAI

2682 predictions. Top by Δscore:

Variant	Effect	Δscore
12:6988370:GTGA:G	donor_loss	1.0000
12:6988371:T:G	donor_loss	1.0000
12:7018268:CCTTA:C	donor_loss	1.0000
12:7018269:CTTAC:C	donor_loss	1.0000
12:7018270:TTACC:T	donor_loss	1.0000
12:7018271:TACCC:T	donor_loss	1.0000
12:7018272:A:AC	donor_gain	1.0000
12:7018272:A:AT	donor_loss	1.0000
12:7018272:AC:A	donor_gain	1.0000
12:7018272:ACC:A	donor_gain	1.0000
12:7018273:C:CC	donor_gain	1.0000
12:7018273:CC:C	donor_gain	1.0000
12:7018273:CCC:C	donor_gain	1.0000
12:7018273:CCCA:C	donor_gain	1.0000
12:7064265:A:AG	acceptor_gain	1.0000
12:7064266:G:GG	acceptor_gain	1.0000
12:7065258:G:GT	donor_gain	1.0000
12:7065278:A:T	donor_gain	1.0000
12:7065293:T:G	donor_gain	1.0000
12:7065297:GTT:G	donor_gain	1.0000
12:7066506:T:TA	acceptor_gain	1.0000
12:7066516:A:G	acceptor_gain	1.0000
12:7067637:T:TA	acceptor_gain	1.0000
12:7067766:G:GT	donor_gain	1.0000
12:7068455:GGGGA:G	acceptor_gain	1.0000
12:7069850:CCTA:C	acceptor_loss	1.0000
12:7069851:CTAGT:C	acceptor_loss	1.0000
12:7069852:TAG:T	acceptor_loss	1.0000
12:7069853:A:AG	acceptor_gain	1.0000
12:7069853:AGTCT:A	acceptor_gain	1.0000

AlphaMissense

4534 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:7065147:A:C	S189R	0.997
12:7065149:T:A	S189R	0.997
12:7065149:T:G	S189R	0.997
12:7067092:G:C	W347C	0.997
12:7067092:G:T	W347C	0.997
12:7063040:G:T	G122W	0.996
12:7063043:T:C	F123L	0.996
12:7063044:T:C	F123S	0.996
12:7063045:T:A	F123L	0.996
12:7063045:T:G	F123L	0.996
12:7064278:T:A	C135S	0.996
12:7064279:G:C	C135S	0.996
12:7064314:T:A	C147S	0.994
12:7064315:G:C	C147S	0.994
12:7062923:T:A	C83S	0.993
12:7062924:G:C	C83S	0.993
12:7063041:G:A	G122E	0.993
12:7063044:T:G	F123C	0.993
12:7063049:G:C	A125P	0.993
12:7063050:C:A	A125E	0.993
12:7064315:G:A	C147Y	0.993
12:7065946:T:A	W283R	0.993
12:7065946:T:C	W283R	0.993
12:7062630:T:C	F54S	0.992
12:7064278:T:C	C135R	0.992
12:7064386:T:A	C171S	0.992
12:7064387:G:C	C171S	0.992
12:7069935:T:A	W451R	0.992
12:7069935:T:C	W451R	0.992
12:7069937:G:C	W451C	0.992

dbSNP variants (sampled 300 via entrez): RS1000056659 (12:7066458 A>G), RS1000233865 (12:7059968 C>A,G,T), RS1000755446 (12:7071303 A>G,T), RS1001336351 (12:7060477 C>T), RS1001390135 (12:7060727 A>G), RS1002251749 (12:7064949 G>A,C), RS1003225190 (12:7068105 A>G), RS1006193641 (12:7063686 G>A), RS1006227155 (12:7070111 T>G), RS1006256422 (12:7064187 A>T), RS1006720599 (12:7070964 A>G), RS1006774458 (12:7070735 A>C,G), RS1007806533 (12:7064560 T>C), RS1008205247 (12:7061195 A>C), RS1008761970 (12:7065520 T>C)

Disease associations

OMIM: gene MIM:120580 | disease phenotypes: MIM:617174, MIM:613783, MIM:130080

GenCC curated gene-disease

Disease	Classification	Inheritance
complement component C1s deficiency	Strong	Autosomal recessive
Ehlers-Danlos syndrome, periodontal type 2	Strong	Autosomal dominant
Ehlers-Danlos syndrome, periodontitis type	Supportive	Autosomal dominant

Mondo (5): Ehlers-Danlos syndrome, periodontal type 2 (MONDO:0014954), complement component C1s deficiency (MONDO:0013419), Ehlers-Danlos syndrome, periodontal type 1 (MONDO:0020684), hereditary angioedema with normal C1Inh (MONDO:0100567), Ehlers-Danlos syndrome, periodontitis type (MONDO:0007527)

Orphanet (2): Periodontal Ehlers-Danlos syndrome (Orphanet:75392), Hereditary angioedema with normal C1Inh (Orphanet:528647)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000212	Gingival overgrowth
HP:0000225	Gingival bleeding
HP:0000347	Micrognathia
HP:0000691	Microdontia
HP:0000704	Periodontitis
HP:0000872	Hashimoto thyroiditis
HP:0000974	Hyperextensible skin
HP:0000978	Bruising susceptibility
HP:0000987	Atypical scarring of skin
HP:0001015	Prominent superficial veins
HP:0001030	Fragile skin
HP:0001034	Hypermelanotic macule
HP:0001075	Atrophic scars
HP:0001373	Joint dislocation
HP:0001382	Joint hypermobility
HP:0001537	Umbilical hernia
HP:0002650	Scoliosis
HP:0002667	Nephroblastoma
HP:0002725	Systemic lupus erythematosus
HP:0002829	Arthralgia
HP:0003003	Colon cancer
HP:0004322	Short stature
HP:0005339	Abnormality of complement system
HP:0006308	Atrophy of alveolar ridges
HP:0006323	Premature loss of primary teeth
HP:0006349	Agenesis of permanent teeth
HP:0012115	Hepatitis
HP:0030816	Gingival recession

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST002712_10	Red blood cell fatty acid levels	3.000000e-30
GCST002712_13	Red blood cell fatty acid levels	3.000000e-49
GCST004621_29	Red cell distribution width	2.000000e-17
GCST004747_3	Lung cancer in never smokers	9.000000e-06
GCST005194_151	Coronary artery disease	1.000000e-09
GCST005195_82	Coronary artery disease	6.000000e-10
GCST006018_3	Activated partial thromboplastin time	1.000000e-09
GCST010002_206	Refractive error	3.000000e-62
GCST010866_90	Coronary artery disease	9.000000e-09
GCST012214_7	Alzheimer’s disease	3.000000e-06
GCST90002381_536	Eosinophil count	9.000000e-10
GCST90002382_305	Eosinophil percentage of white cells	2.000000e-09
GCST90002396_516	Mean reticulocyte volume	3.000000e-16
GCST90002397_415	Mean spheric corpuscular volume	4.000000e-15
GCST90002404_132	Red cell distribution width	7.000000e-36

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0006807	linoleic acid measurement
EFO:0006810	oleic acid measurement
EFO:0009188	Red cell distribution width
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C565170	Complement Component C1s Deficiency (supp.)
C562626	Ehlers-Danlos Syndrome, Type VIII (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3913 (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 (2 total), top 2:

Ligand	Action	Affinity	Parameter
sutimlimab	Binding	9.59	pKd
compound 28 [PMID: 16460935]	Inhibition	8.0	pKi

Binding affinities (BindingDB)

62 measured of 635 human assays (638 total across all organisms); most potent 50 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
(S)-N-((R)-1-(4-(1H- imidazol-4-yl)thiophen- 2-yl)ethyl)-7-((9,9- difluoro-9H-fluorene-3- carbonyl)glycyl)-1,4- dioxa-7- azaspiro[4.4]nonane-8- carboxamide	IC50	550 nM	US-20250346585: PHARMACEUTICAL COMPOUNDS FOR THE TREATMENT OF COMPLEMENT MEDIATED DISORDERS
(S)-N-((R)-1-(4-(4H- 1,2,4-triazol-3- yl)thiophen-2-yl)ethyl)- 7-((9,9-difluoro-9H- fluorene-3- carbonyl)glycyl)-1,4- dioxa-7- azaspiro[4.4]nonane-8- carboxamide	IC50	550 nM	US-20250346585: PHARMACEUTICAL COMPOUNDS FOR THE TREATMENT OF COMPLEMENT MEDIATED DISORDERS
(S)-7-((4-(4- fluorophenoxy)benzoyl) glycyl)-N-((4-(pyrrolidin- 1-yl)thiophen-2- yl)methyl)-1,4-dioxa-7- azaspiro[4.4]nonane-8- carboxamide	IC50	550 nM	US-20250346585: PHARMACEUTICAL COMPOUNDS FOR THE TREATMENT OF COMPLEMENT MEDIATED DISORDERS
(1S,3S,5S)-N-((7- amino-4,5- dihydrothieno[2,3- c]pyridin-2-yl)methyl)-5- methyl-2-((4- phenoxybenzoyl)glycyl)- 2- azabicyclo[3.1.0]hexane- 3-carboxamide	IC50	550 nM	US-20250346585: PHARMACEUTICAL COMPOUNDS FOR THE TREATMENT OF COMPLEMENT MEDIATED DISORDERS
(S)-N-((4-(2- aminoacetamido) thiophen-2-yl) methyl)-7-((4- (4- fluorophenoxy)benzoyl) glycyl)-1,4-dioxa-7- azaspiro[4.4]nonane-8- carboxamide	IC50	550 nM	US-20250346585: PHARMACEUTICAL COMPOUNDS FOR THE TREATMENT OF COMPLEMENT MEDIATED DISORDERS
BDBM108100	KI	750 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
2-Furan-2-yl-benzo[d][1,3]oxazin-4-one	IC50	793 nM
(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
MLS000097371	IC50	923 nM
2-furancarboxylic acid [5-amino-1-(4-methoxyphenyl)sulfonyl-3-pyrazolyl] ester	IC50	924 nM
1,3-benzodioxol-5-yl(1-benzotriazolyl)methanone	IC50	957 nM
MLS000115326	IC50	1020 nM
(2R)-2-(benzylsulfonylamino)-N-[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]-5-phenylpentanamide	KI	1100 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
3-(2-furyl)-5-(methylthio)-1-(2-thienylcarbonyl)-1H-1,2,4-triazole	IC50	1780 nM
(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
2-thiophenecarboxylic acid [5-amino-1-(4-methylphenyl)sulfonyl-3-pyrazolyl] ester	IC50	1990 nM
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
MLS000081703	IC50	2260 nM
(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
(2R)-2-(benzylsulfonylamino)-N-[(2S)-1-[(4-carbamimidoylphenyl)methylamino]-1-oxo-4-piperidin-4-ylbutan-2-yl]-5-(tetrazol-1-yl)pentanamide	KI	2400 nM	US-8598206: Trypsin-like serine protease inhibitors, and their preparation and use
MLS000087424	IC50	2480 nM
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
MLS000116425	IC50	2520 nM
(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
MLS000090237	IC50	3430 nM
1-(4,5,6,7-tetrahydro-1-benzothien-3-ylcarbonyl)-1H-pyrazole	IC50	3610 nM
2-(benzotriazole-1-carbonyl)benzoic acid propargyl ester	IC50	3970 nM
1-(1-benzothien-3-ylcarbonyl)-1H-pyrazole	IC50	4330 nM
(5-azanyl-3-morpholin-4-ylcarbonyl-1,2,4-triazol-1-yl)-(4-chlorophenyl)methanone	IC50	4510 nM
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
1-[2-(ethylthio)benzoyl]-1H-1,2,3-benzotriazole	IC50	7110 nM
1-benzoyl-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one	IC50	10800 nM
MLS000027597	IC50	11000 nM
2-furanyl-[3-(2-furanyl)-5-(methylthio)-1,2,4-triazol-1-yl]methanone	IC50	11700 nM
1,3-Bis-(furan-2-carbonyl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid ethyl ester	IC50	12000 nM
(4-ethyl-7-methyl-2-oxidanylidene-chromen-5-yl) furan-2-carboxylate	IC50	12900 nM
1-(2-furoyl)-3-(4-methoxyphenyl)-5-(methylthio)-1H-1,2,4-triazole	IC50	15600 nM
(4-methoxycarbonylphenyl) furan-2-carboxylate	IC50	17100 nM
(3,4-dimethoxyphenyl)-[3-(2-furanyl)-5-(methylthio)-1,2,4-triazol-1-yl]methanone	IC50	22000 nM

ChEMBL bioactivities

125 potent at pChembl≥5 of 139 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.80	IC50	1.6	nM	CHEMBL2220483
8.80	IC50	1.6	nM	CHEMBL5723340
8.22	Ki	6	nM	CHEMBL4244141
8.15	IC50	7	nM	CHEMBL5435382
8.00	Ki	10	nM	CHEMBL205904
7.96	Ki	11	nM	CHEMBL4242095
7.85	Ki	14	nM	CHEMBL399284
7.70	Ki	20	nM	CHEMBL377090
7.70	Ki	20	nM	CHEMBL401398
7.66	Ki	22	nM	CHEMBL403782
7.54	IC50	29	nM	NAFAMOSTAT
7.52	Ki	30	nM	CHEMBL377281
7.52	Ki	30	nM	CHEMBL438807
7.52	Ki	30	nM	CHEMBL4239924
7.52	Ki	30	nM	CHEMBL413993
7.44	IC50	36	nM	CHEMBL5417464
7.40	Ki	40	nM	CHEMBL382350
7.40	Ki	40	nM	CHEMBL252004
7.40	Ki	40	nM	CHEMBL252998
7.38	Ki	42	nM	CHEMBL252203
7.34	IC50	46	nM	CHEMBL2220483
7.30	Ki	50	nM	CHEMBL206020
7.30	Ki	50	nM	CHEMBL253646
7.22	Ki	60	nM	CHEMBL319394
7.19	Ki	64	nM	CHEMBL254283
7.16	Ki	70	nM	CHEMBL381771
7.16	Ki	70	nM	CHEMBL3901198
7.16	Ki	70	nM	CHEMBL317917
7.05	Ki	90	nM	CHEMBL321341
7.00	Ki	100	nM	CHEMBL382443
7.00	Ki	100	nM	CHEMBL205385
6.92	Ki	120	nM	CHEMBL252619
6.92	Ki	120	nM	CHEMBL252794
6.85	Ki	140	nM	CHEMBL253430
6.85	IC50	140	nM	NAFAMOSTAT
6.82	Ki	150	nM	CHEMBL400375
6.82	Ki	150	nM	CHEMBL252793
6.82	Ki	150	nM	CHEMBL322834
6.80	Ki	160	nM	CHEMBL426490
6.77	Ki	170	nM	CHEMBL381097
6.77	Ki	170	nM	CHEMBL205804
6.77	IC50	170	nM	CHEMBL5418327
6.75	Ki	180	nM	CHEMBL205342
6.72	Ki	190	nM	CHEMBL400497
6.72	Ki	190	nM	CHEMBL106388
6.70	Ki	200	nM	CHEMBL380315
6.68	Ki	210	nM	CHEMBL377934
6.62	Ki	240	nM	CHEMBL438267
6.60	Ki	250	nM	CHEMBL252591
6.58	Ki	260	nM	CHEMBL252393

PubChem BioAssay actives

113 with measured affinity, of 174 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
(2-carbamimidoyl-1-benzothiophen-6-yl) thiophene-2-carboxylate	1393213: Inhibition of human C1s esterolytic activity using benzyloxycarbonyl-Lys-thiobenzyl as substrate	ic50	0.0016	uM
4-[3-(3-formylphenyl)phenyl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	1393221: Inhibition of C1s (unknown origin) using Cbz-Gly-Arg-S-Bzl as substrate preincubated with substrate for 15 mins followed by enzyme addition and measured after 5 mins	ki	0.0060	uM
6-[(3R)-4-(3-fluorophenyl)-3-(5-methyl-1,2-oxazol-3-yl)piperazin-1-yl]phthalazin-1-amine;2,2,2-trifluoroacetic acid	2031332: Inhibition of human recombinant N-terminal IgG tagged and C-terminal His tagged C1S (358 to 688 aa residues) expressed in HEK293 cells using Z-Lys-SBzl peptide as substrate pretreated with compound followed by substrate addition incubated for 60 mins	ic50	0.0070	uM
4-[7-bromo-1-[(2,5-difluorophenyl)methyl]benzimidazol-5-yl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	263641: Inhibition of C1S	ki	0.0100	uM
[3-[[[3-[2-amino-4-(diaminomethylideneamino)-6-methylphenyl]phenyl]-(5-carbamimidoyl-2-methylsulfanylthiophen-3-yl)-oxo-lambda6-sulfanylidene]amino]sulfonylphenyl]urea	1393222: Inhibition of human plasma C1s using Cbz-Gly-Arg-S-Bzl as substrate preincubated with substrate for 15 mins followed by enzyme addition and measured after 5 mins	ki	0.0110	uM
N-[2-[3-(5-carbamimidoyl-2-methylsulfanylthiophen-3-yl)sulfonylphenyl]-3-methylphenyl]-4-methylsulfonylbutanamide	314381: Inhibition of Complement C1s subcomponent	ki	0.0140	uM
4-[7-bromo-1-[(2,6-dichlorophenyl)methyl]benzimidazol-5-yl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	263641: Inhibition of C1S	ki	0.0200	uM
4-[3-(2-amino-6-methylphenyl)phenyl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	314381: Inhibition of Complement C1s subcomponent	ki	0.0200	uM
6-[[2-[3-(5-carbamimidoyl-2-methylsulfanylthiophen-3-yl)sulfonylphenyl]-3-methylphenyl]carbamoylamino]hexanoic acid	314381: Inhibition of Complement C1s subcomponent	ki	0.0220	uM
(6-carbamimidoylnaphthalen-2-yl) 4-(diaminomethylideneamino)benzoate	1393212: Inhibition of human serum C1s using AGLME as substrate after 30 mins	ic50	0.0290	uM
4-[4-[3-[(2,4-difluorophenyl)sulfonylamino]phenyl]-1,3-thiazol-2-yl]-5-methylsulfanylthiophene-2-carboximidamide	1393221: Inhibition of C1s (unknown origin) using Cbz-Gly-Arg-S-Bzl as substrate preincubated with substrate for 15 mins followed by enzyme addition and measured after 5 mins	ki	0.0300	uM
4-(1-benzyl-7-bromobenzimidazol-5-yl)sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	263641: Inhibition of C1S	ki	0.0300	uM
4-[7-bromo-1-[(2-fluoro-5-nitrophenyl)methyl]benzimidazol-5-yl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	263641: Inhibition of C1S	ki	0.0300	uM
4-[3-(2-methylphenyl)phenyl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	314381: Inhibition of Complement C1s subcomponent	ki	0.0300	uM
8-fluoro-6-[(3R)-4-(3-fluorophenyl)-3-(5-methyl-1,2-oxazol-3-yl)piperazin-1-yl]phthalazin-1-amine	2031332: Inhibition of human recombinant N-terminal IgG tagged and C-terminal His tagged C1S (358 to 688 aa residues) expressed in HEK293 cells using Z-Lys-SBzl peptide as substrate pretreated with compound followed by substrate addition incubated for 60 mins	ic50	0.0360	uM
4-[7-bromo-1-[(2,6-difluorophenyl)methyl]benzimidazol-5-yl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	263641: Inhibition of C1S	ki	0.0400	uM
4-[3-(2-chlorophenyl)phenyl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	314381: Inhibition of Complement C1s subcomponent	ki	0.0400	uM
4-[3-(6-methyl-2-pyridinyl)phenyl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	314381: Inhibition of Complement C1s subcomponent	ki	0.0400	uM
6-[2-[3-(5-carbamimidoyl-2-methylsulfanylthiophen-3-yl)sulfonylphenyl]-3-methylanilino]-6-oxohexanoic acid	314381: Inhibition of Complement C1s subcomponent	ki	0.0420	uM
4-[7-bromo-1-(3-methylbut-2-enyl)benzimidazol-5-yl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	263641: Inhibition of C1S	ki	0.0500	uM
4-[3-[2-(hydroxymethyl)-6-methylphenyl]phenyl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	314381: Inhibition of Complement C1s subcomponent	ki	0.0500	uM
5-methylsulfanyl-4-[4-(1-phenyl-5-propylpyrazol-4-yl)-1,3-thiazol-2-yl]thiophene-2-carboximidamide	50889: In vitro binding affinity towards human Complement C1s subcomponent	ki	0.0600	uM
1-[2-[3-(5-carbamimidoyl-2-methylsulfanylthiophen-3-yl)sulfonylphenyl]-3-methylphenyl]-3-[2-(2H-tetrazol-5-yl)ethyl]urea	314381: Inhibition of Complement C1s subcomponent	ki	0.0640	uM
5-methylsulfanyl-4-[4-(5-propyl-1-pyridin-2-ylpyrazol-4-yl)-1,3-thiazol-2-yl]thiophene-2-carboximidamide	2031326: Binding affinity to human C1S assessed as inhibition constant	ki	0.0700	uM
4-(7-bromo-1-prop-2-enylbenzimidazol-5-yl)sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	263641: Inhibition of C1S	ki	0.0700	uM
5-methylsulfanyl-4-[4-(5-propoxy-1-pyridin-2-ylpyrazol-4-yl)-1,3-thiazol-2-yl]thiophene-2-carboximidamide	50889: In vitro binding affinity towards human Complement C1s subcomponent	ki	0.0700	uM
4-[4-(5-ethoxy-1-phenylpyrazol-4-yl)-1,3-thiazol-2-yl]-5-methylsulfanylthiophene-2-carboximidamide	50889: In vitro binding affinity towards human Complement C1s subcomponent	ki	0.0900	uM
4-[7-chloro-3-[(2,6-difluorophenyl)methyl]benzimidazol-5-yl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	263641: Inhibition of C1S	ki	0.1000	uM
4-[7-chloro-1-[(2,6-difluorophenyl)methyl]benzimidazol-5-yl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	263641: Inhibition of C1S	ki	0.1000	uM
N-[2-[3-(5-carbamimidoyl-2-methylsulfanylthiophen-3-yl)sulfonylphenyl]-3-methylphenyl]-2-methylsulfonylacetamide	314381: Inhibition of Complement C1s subcomponent	ki	0.1200	uM
4-[3-[2-(hydroxymethyl)phenyl]phenyl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	314381: Inhibition of Complement C1s subcomponent	ki	0.1200	uM
4-[3-(2-ethenylphenyl)phenyl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	314381: Inhibition of Complement C1s subcomponent	ki	0.1400	uM
4-[3-(3-hydroxyphenyl)phenyl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	314381: Inhibition of Complement C1s subcomponent	ki	0.1500	uM
2-[3-(5-carbamimidoyl-2-methylsulfanylthiophen-3-yl)sulfonylphenyl]-3-methylbenzoic acid	314381: Inhibition of Complement C1s subcomponent	ki	0.1500	uM
5-methylsulfanyl-4-[4-(1-phenylpyrazol-4-yl)-1,3-thiazol-2-yl]thiophene-2-carboximidamide	50889: In vitro binding affinity towards human Complement C1s subcomponent	ki	0.1500	uM
4-[7-bromo-3-[(2,6-dichlorophenyl)methyl]benzimidazol-5-yl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	263641: Inhibition of C1S	ki	0.1600	uM
6-[(3S)-4-(3-fluorophenyl)-3-methylpiperazin-1-yl]phthalazin-1-amine	2031332: Inhibition of human recombinant N-terminal IgG tagged and C-terminal His tagged C1S (358 to 688 aa residues) expressed in HEK293 cells using Z-Lys-SBzl peptide as substrate pretreated with compound followed by substrate addition incubated for 60 mins	ic50	0.1700	uM
4-[7-bromo-3-[(2,6-difluorophenyl)methyl]benzimidazol-5-yl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	263641: Inhibition of C1S	ki	0.1700	uM
4-[7-bromo-3-[(2-fluoro-5-nitrophenyl)methyl]benzimidazol-5-yl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	263641: Inhibition of C1S	ki	0.1700	uM
4-(7-bromo-3-phenylbenzimidazol-5-yl)sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	263641: Inhibition of C1S	ki	0.1800	uM
4-[3-(4-hydroxyphenyl)phenyl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	314381: Inhibition of Complement C1s subcomponent	ki	0.1900	uM
4-[4-(1-methyl-3-propylpyrazol-4-yl)-1,3-thiazol-2-yl]-5-methylsulfanylthiophene-2-carboximidamide	50889: In vitro binding affinity towards human Complement C1s subcomponent	ki	0.1900	uM
4-[7-bromo-3-(3-methylbut-2-enyl)benzimidazol-5-yl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	263641: Inhibition of C1S	ki	0.2000	uM
4-(7-bromo-3-prop-2-enylbenzimidazol-5-yl)sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	263641: Inhibition of C1S	ki	0.2100	uM
4-[7-bromo-3-[(2,5-difluorophenyl)methyl]benzimidazol-5-yl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	263641: Inhibition of C1S	ki	0.2400	uM
4-[3-(4-methylphenyl)phenyl]sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	314381: Inhibition of Complement C1s subcomponent	ki	0.2500	uM
5-methylsulfanyl-4-(3-phenylphenyl)sulfonylthiophene-2-carboximidamide	314381: Inhibition of Complement C1s subcomponent	ki	0.2600	uM
4-(7-bromo-1-phenylbenzimidazol-5-yl)sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	263641: Inhibition of C1S	ki	0.3100	uM
4-(7-bromo-3-methylbenzimidazol-5-yl)sulfonyl-5-methylsulfanylthiophene-2-carboximidamide	263641: Inhibition of C1S	ki	0.3300	uM
4-[4-(1-methyl-5-propylpyrazol-4-yl)-1,3-thiazol-2-yl]-5-methylsulfanylthiophene-2-carboximidamide	50889: In vitro binding affinity towards human Complement C1s subcomponent	ki	0.3300	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases expression, affects methylation	6
sodium arsenite	affects expression, affects splicing, increases expression	4
Air Pollutants	decreases expression, affects cotreatment, increases abundance, increases oxidation, increases expression	4
Copper	affects binding, increases expression	3
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases expression	3
Tobacco Smoke Pollution	affects expression, decreases methylation	3
Valproic Acid	decreases expression, affects expression	3
Cyclosporine	decreases expression	3
bisphenol A	increases expression, affects cotreatment	2
mercuric bromide	affects cotreatment, increases expression	2
Formaldehyde	increases expression	2
Nickel	affects binding, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Smoke	decreases expression, decreases reaction, increases abundance	2
p-Chloromercuribenzoic Acid	increases expression, affects cotreatment	2
afuresertib	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
sotorasib	affects cotreatment, increases expression	1
methylmercuric chloride	increases expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
2-aminothiophenol	affects binding, decreases reaction	1
propionaldehyde	decreases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1
4-nitroaniline	increases hydrolysis	1
perfluorooctanoic acid	decreases expression	1
cupric chloride	decreases expression	1
nickel sulfate	increases expression	1
cupric oxide	increases expression	1

ChEMBL screening assays

30 unique, capped per target: 28 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1613966	Functional	PUBCHEM_BIOASSAY: Complement C1s ELISA. (Class of assay: confirmatory) [Related pubchem assays: 538, 787 ]	PubChem BioAssay data set
CHEMBL2320209	Binding	Inhibition of human C1s	Development of new cyclic plasmin inhibitors with excellent potency and selectivity. — J Med Chem

Clinical trials (associated diseases)

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