C1RL

Summary

C1RL (complement C1r subcomponent like, HGNC:21265) is a protein-coding gene on chromosome 12p13.31, encoding Complement C1r subcomponent-like protein (Q9NZP8). Mediates the proteolytic cleavage of HP/haptoglobin in the endoplasmic reticulum.

Predicted to enable serine-type endopeptidase activity. Predicted to be involved in zymogen activation. Located in extracellular exosome.

Source: NCBI Gene 51279 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 93 total
• MANE Select transcript: NM_016546

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21265
Approved symbol	C1RL
Name	complement C1r subcomponent like
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	C1r-LP, C1RL1
Ensembl gene	ENSG00000139178
Ensembl biotype	protein_coding
OMIM	608974
Entrez	51279

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 9 protein_coding, 2 non_stop_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000266542, ENST00000504702, ENST00000534950, ENST00000534969, ENST00000537833, ENST00000539803, ENST00000539927, ENST00000543933, ENST00000543941, ENST00000544702, ENST00000545280, ENST00000545337, ENST00000872919, ENST00000872920, ENST00000872921

RefSeq mRNA: 4 — MANE Select: NM_016546 NM_001297640, NM_001297642, NM_001297643, NM_016546

CCDS: CCDS73431, CCDS76517, CCDS8573

Canonical transcript exons

ENST00000266542 — 6 exons

Exon	Start	End
ENSE00000936876	7108251	7108479
ENSE00001146126	7094554	7097163
ENSE00002267479	7109110	7109214
ENSE00003487635	7101898	7102087
ENSE00003574652	7099686	7099760
ENSE00003678979	7099901	7100026

Expression profiles

Bgee: expression breadth ubiquitous, 137 present calls, max score 98.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.0983 / max 297.8084, expressed in 1620 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129252	18.2669	1612
129251	1.7235	748
129250	0.1080	40

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.19	gold quality
liver	UBERON:0002107	98.16	gold quality
mucosa of stomach	UBERON:0001199	98.10	gold quality
left adrenal gland	UBERON:0001234	97.61	gold quality
left adrenal gland cortex	UBERON:0035825	97.60	gold quality
right adrenal gland	UBERON:0001233	97.44	gold quality
right adrenal gland cortex	UBERON:0035827	96.98	gold quality
right ovary	UBERON:0002118	96.95	gold quality
left ovary	UBERON:0002119	96.62	gold quality
ovary	UBERON:0000992	96.41	gold quality
adrenal gland	UBERON:0002369	96.33	gold quality
tibial nerve	UBERON:0001323	96.31	gold quality
left uterine tube	UBERON:0001303	96.23	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.80	gold quality
lower esophagus	UBERON:0013473	95.77	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.71	gold quality
body of pancreas	UBERON:0001150	95.63	gold quality
right coronary artery	UBERON:0001625	95.33	gold quality
subcutaneous adipose tissue	UBERON:0002190	95.31	gold quality
calcaneal tendon	UBERON:0003701	95.26	gold quality
endocervix	UBERON:0000458	95.14	gold quality
blood	UBERON:0000178	95.05	gold quality
mammary gland	UBERON:0001911	94.98	gold quality
thoracic mammary gland	UBERON:0005200	94.98	gold quality
adipose tissue	UBERON:0001013	94.82	gold quality
gall bladder	UBERON:0002110	94.64	gold quality
descending thoracic aorta	UBERON:0002345	94.61	gold quality
left coronary artery	UBERON:0001626	94.55	gold quality
thoracic aorta	UBERON:0001515	94.53	gold quality
ascending aorta	UBERON:0001496	94.50	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	17.79

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

82 targeting C1RL, 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-5011-5P	100.00	83.46	5820
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826

Literature-anchored findings (GeneRIF, showing 3)

• CLSPa itself possesses little protease activity, but it plays an inhibitory role in other active protease catalytic processes (PMID:15358180)
• coexpression of the proform of Hp (proHp) and C1r-LP effected cleavage of proHp in the endoplasmic reticulum (PMID:15385675)
• Immunological and clinicopathological characteristics of C1RL in 2120 glioma patients. (PMID:32993564)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	f9a	ENSDARG00000010097
danio_rerio	habp2	ENSDARG00000057498
mus_musculus	C1rl	ENSMUSG00000038527
rattus_norvegicus	C1rl	ENSRNOG00000011718
drosophila_melanogaster	CG31266	FBGN0051266
drosophila_melanogaster	CG31267	FBGN0051267

Paralogs (16): F7 (ENSG00000057593), F11 (ENSG00000088926), F9 (ENSG00000101981), HGFAC (ENSG00000109758), F10 (ENSG00000126218), KLK10 (ENSG00000129451), F12 (ENSG00000131187), C1R (ENSG00000159403), KLKB1 (ENSG00000164344), C1S (ENSG00000182326), PRSS55 (ENSG00000184647), CFD (ENSG00000197766), CFI (ENSG00000205403), PRSS51 (ENSG00000253649), HP (ENSG00000257017), HPR (ENSG00000261701)

Protein

Protein identifiers

Complement C1r subcomponent-like protein — Q9NZP8 (reviewed: Q9NZP8)

Alternative names: C1r-like serine protease analog protein

All UniProt accessions (9): Q9NZP8, F5GWF3, F5H2Z5, F5H6S5, F5H7C8, H0YF87, H0YFJ9, H0YFL7, H0YGP8

UniProt curated annotations — full annotation on UniProt →

Function. Mediates the proteolytic cleavage of HP/haptoglobin in the endoplasmic reticulum.

Subcellular location. Secreted.

Tissue specificity. Highly expressed in placenta, liver, kidney, pancreas, moderately in lung, spleen, prostate, ovary, colon, and PBL, and weakly in heart, skeletal muscle, thymus, testis, and small intestine. Expressed in PC-3 (prostate adenocarcinoma) and SK-OV-3 (ovary adenocarcinoma) cells, but not in LoVo and HT-29 (colon adenocarcinoma), SMMC7721 (hepatocellular carcinoma), CaoV-3 (ovary adenocarcinoma), HeLa (cervix epithelioid carcinoma), MCF-7 (breast adenocarcinoma), U-251MG (glioma) or A-549 (lung carcinoma) cells. Widely expressed in myeloid leukemia cell lines, including K-562 (chronic myelogenous leukemia), THP-1 (myelomonocytic leukemia), HL-60 and NB4 (promyelocytic leukemia), and KG-1 (acute myelogenous leukemia) cells. Expressed mainly in the liver and in serum (at protein level).

Induction. Up-regulated in monocytes and dendritic cells (DC) undergoing maturation or activation.

Similarity. Belongs to the peptidase S1 family.

RefSeq proteins (4): NP_001284569, NP_001284571, NP_001284572, NP_057630* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000859	CUB_dom	Domain
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR033116	TRYPSIN_SER	Active_site
IPR035914	Sperma_CUB_dom_sf	Homologous_superfamily
IPR035976	Sushi/SCR/CCP_sf	Homologous_superfamily
IPR043504

Pfam: PF00089, PF00431

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 (22 total): glycosylation site 5, disulfide bond 4, sequence conflict 3, domain 3, active site 3, signal peptide 1, chain 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZP8-F1	77.42	0.48

Functional residue map

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

Catalytic / active sites (3): 283 (charge relay system); 339 (charge relay system); 436 (charge relay system)

Disulfide bonds (4): 94–112, 195–228, 402–421, 432–462

Glycosylation sites (5): 242, 296, 363, 147, 166

Mutagenesis-validated functional residues (1):

Position	Phenotype
436	unable to cleave hp.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 132 (showing top): GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_B_CELL_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_COMPLEMENT_ACTIVATION, GOBP_PROTEIN_MATURATION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, ODONNELL_TARGETS_OF_MYC_AND_TFRC_UP, CAIRO_HEPATOBLASTOMA_DN, GOBP_HUMORAL_IMMUNE_RESPONSE, GOBP_ADAPTIVE_IMMUNE_RESPONSE, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_DN, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_UP, GOBP_HUMORAL_IMMUNE_RESPONSE_MEDIATED_BY_CIRCULATING_IMMUNOGLOBULIN

GO Biological Process (5): complement activation, classical pathway (GO:0006958), zymogen activation (GO:0031638), innate immune response (GO:0045087), immune system process (GO:0002376), proteolysis (GO:0006508)

GO Molecular Function (4): serine-type endopeptidase activity (GO:0004252), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
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
endopeptidase activity	1
serine-type peptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
serine hydrolase activity	1
catalytic activity	1
extracellular vesicle	1
extracellular region	1

Protein interactions and networks

STRING

996 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C1RL	CD163	Q86VB7	755
C1RL	LCAT	P04180	591
C1RL	HPX	P02790	565
C1RL	APRT	P07741	546
C1RL	C1S	P09871	544
C1RL	C8A	P07357	514
C1RL	WWOX	Q9NZC7	474
C1RL	C8B	P07358	367
C1RL	CLSTN3	Q9BQT9	367
C1RL	CMA1	P23946	356
C1RL	C8G	P07360	356
C1RL	C1QC	P02747	337
C1RL	ITIH4	Q14624	333
C1RL	C1QL3	Q5VWW1	327
C1RL	C4A	P01028	326
C1RL	SFTPD	P35247	326

IntAct

9 interactions, top by confidence:

A	B	Type	Score
C1R	BIRC2	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
C1RL	PTBP3	psi-mi:“MI:0914”(association)	0.350
LY86	TMEM131L	psi-mi:“MI:0914”(association)	0.350
CLGN	TMEM131L	psi-mi:“MI:0914”(association)	0.350

BioGRID (10): C1RL (Affinity Capture-MS), C1RL (Affinity Capture-RNA), GUCA1B (Affinity Capture-MS), C1RL (Affinity Capture-MS), PTBP3 (Affinity Capture-MS), C1RL (Affinity Capture-MS), C1RL (Affinity Capture-MS), C1RL (Proximity Label-MS), C1RL (Two-hybrid), C1RL (Affinity Capture-MS)

ESM2 similar proteins: D3ZTE0, O35453, O97507, P00743, P00745, P00748, P00750, P04070, P05981, P08709, P11214, P22457, P22891, P26927, P26928, P31394, P33587, P59509, P70375, P98139, P98140, Q04756, Q04962, Q05511, Q0IIH7, Q24K22, Q28198, Q28278, Q28661, Q2F9P2, Q2F9P4, Q2TV78, Q3UZ09, Q5R5E8, Q5R8J0, Q6IE64, Q6QNF4, Q769J6, Q7M761, Q7RTY7

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

1 interactions.

A	Effect	B	Mechanism
C1RL	“up-regulates activity”	HP	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	66
Likely benign	12
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1045 predictions. Top by Δscore:

Variant	Effect	Δscore
12:7108249:A:AC	donor_gain	1.0000
12:7108250:C:CC	donor_gain	1.0000
12:7108273:T:TA	donor_gain	1.0000
12:7109108:A:AC	donor_gain	1.0000
12:7109109:C:CC	donor_gain	1.0000
12:7097164:C:CC	acceptor_gain	0.9900
12:7099896:CTCA:C	donor_loss	0.9900
12:7099897:TCACC:T	donor_loss	0.9900
12:7099898:CA:C	donor_loss	0.9900
12:7099899:A:C	donor_loss	0.9900
12:7099900:C:G	donor_loss	0.9900
12:7101896:A:AC	donor_gain	0.9900
12:7101896:AC:A	donor_gain	0.9900
12:7101897:C:CC	donor_gain	0.9900
12:7101897:CC:C	donor_gain	0.9900
12:7101897:CCCA:C	donor_gain	0.9900
12:7108259:AGTCC:A	donor_gain	0.9900
12:7108263:C:A	donor_gain	0.9900
12:7108271:AGT:A	donor_gain	0.9900
12:7109104:ACTC:A	donor_loss	0.9900
12:7109105:CTCA:C	donor_loss	0.9900
12:7109106:T:TA	donor_loss	0.9900
12:7109107:CAC:C	donor_loss	0.9900
12:7109108:A:AG	donor_loss	0.9900
12:7109109:CA:C	donor_gain	0.9900
12:7109109:CATTG:C	donor_gain	0.9900
12:7099894:GACTC:G	donor_loss	0.9800
12:7099895:ACTC:A	donor_loss	0.9800
12:7099900:CCTG:C	donor_gain	0.9800
12:7100022:CACAG:C	acceptor_gain	0.9800

AlphaMissense

3203 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:7097081:C:A	W258C	0.989
12:7097081:C:G	W258C	0.989
12:7097083:A:G	W258R	0.989
12:7097083:A:T	W258R	0.989
12:7096727:A:C	S376R	0.988
12:7096727:A:T	S376R	0.988
12:7096729:T:G	S376R	0.988
12:7096834:C:G	A341P	0.986
12:7096421:C:A	W478C	0.982
12:7096421:C:G	W478C	0.982
12:7096721:A:C	F378L	0.982
12:7096721:A:T	F378L	0.982
12:7096723:A:G	F378L	0.982
12:7096830:A:G	L342P	0.981
12:7096833:G:T	A341D	0.980
12:7096782:A:T	V358D	0.978
12:7096830:A:T	L342H	0.977
12:7101920:G:C	F156L	0.974
12:7101920:G:T	F156L	0.974
12:7101922:A:G	F156L	0.974
12:7097026:A:G	W277R	0.973
12:7097026:A:T	W277R	0.973
12:7096593:C:G	C421S	0.969
12:7096594:A:T	C421S	0.969
12:7097010:G:T	A282D	0.967
12:7096423:A:G	W478R	0.962
12:7096423:A:T	W478R	0.962
12:7097019:A:G	L279P	0.961
12:7097019:A:T	L279H	0.961
12:7097022:A:G	I278T	0.961

dbSNP variants (sampled 300 via entrez): RS1000037896 (12:7096700 T>A,C), RS1000093468 (12:7102958 C>A), RS1000884969 (12:7107338 T>C), RS1000975041 (12:7100267 T>C), RS1001290109 (12:7094852 T>G), RS1001313103 (12:7103308 A>G), RS1001441360 (12:7097253 G>C), RS1001654536 (12:7107417 G>A), RS1001660998 (12:7103543 G>A,T), RS1001749742 (12:7109723 C>T), RS1002029498 (12:7108608 A>T), RS1002080495 (12:7108344 C>A,T), RS1002162879 (12:7101459 G>A), RS1002892477 (12:7104413 A>G), RS1002954427 (12:7097514 C>G)

Disease associations

OMIM: gene MIM:608974 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003542_196	Night sleep phenotypes	5.000000e-06
GCST006585_563	Blood protein levels	6.000000e-24

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, increases expression, affects expression, decreases expression	5
Cyclosporine	decreases expression, increases methylation	3
sodium arsenite	increases abundance, decreases expression, affects cotreatment	2
(+)-JQ1 compound	decreases expression	2
Air Pollutants	increases abundance, decreases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	decreases expression	2
Aflatoxin B1	decreases expression	2
GSK-J4	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	increases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
1-nitropyrene	decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, increases expression	1
Decitabine	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	decreases expression, increases abundance, affects cotreatment	1
Carbamazepine	affects expression	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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