C4BPA

Summary

C4BPA (complement component 4 binding protein alpha, HGNC:1325) is a protein-coding gene on chromosome 1q32.2, encoding C4b-binding protein alpha chain (P04003). Controls the classical pathway of complement activation.

This gene encodes a member of a superfamily of proteins composed predominantly of tandemly arrayed short consensus repeats of approximately 60 amino acids. Along with a single, unique beta-chain, seven identical alpha-chains encoded by this gene assemble into the predominant isoform of C4b-binding protein, a multimeric protein that controls activation of the complement cascade through the classical pathway. The genes encoding both alpha and beta chains are located adjacent to each other on human chromosome 1 in the regulator of complement activation gene cluster. Two pseudogenes of this gene are also found in the cluster.

Source: NCBI Gene 722 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 104 total
• MANE Select transcript: NM_000715

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1325
Approved symbol	C4BPA
Name	complement component 4 binding protein alpha
Location	1q32.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000123838
Ensembl biotype	protein_coding
OMIM	120830
Entrez	722

Gene structure

Transcript identifiers

Ensembl transcripts: 53 — 52 protein_coding, 1 nonsense_mediated_decay

ENST00000367070, ENST00000421786, ENST00000424088, ENST00000902659, ENST00000902660, ENST00000902661, ENST00000902662, ENST00000902663, ENST00000902664, ENST00000902665, ENST00000902666, ENST00000902667, ENST00000902668, ENST00000902669, ENST00000902670, ENST00000902671, ENST00000902672, ENST00000902673, ENST00000902674, ENST00000902675, ENST00000902676, ENST00000902677, ENST00000902678, ENST00000902679, ENST00000902680, ENST00000902681, ENST00000902682, ENST00000902683, ENST00000902684, ENST00000902685, ENST00000902686, ENST00000902687, ENST00000902688, ENST00000902689, ENST00000902690, ENST00000902691, ENST00000902692, ENST00000902693, ENST00000902694, ENST00000902695, ENST00000902696, ENST00000902697, ENST00000902698, ENST00000902699, ENST00000902700, ENST00000902701, ENST00000902702, ENST00000902703, ENST00000902704, ENST00000902705, ENST00000902706, ENST00000902707, ENST00000963640

RefSeq mRNA: 1 — MANE Select: NM_000715 NM_000715

CCDS: CCDS1477

Canonical transcript exons

ENST00000367070 — 12 exons

Exon	Start	End
ENSE00000842600	207123922	207124007
ENSE00000842601	207124175	207124366
ENSE00000842604	207134404	207134592
ENSE00000925448	207115416	207115515
ENSE00000925451	207126713	207126895
ENSE00000925452	207131546	207131740
ENSE00000925454	207141106	207141276
ENSE00001168114	207104233	207104430
ENSE00001906660	207144544	207144972
ENSE00002233291	207113001	207113167
ENSE00002279742	207114100	207114285
ENSE00002391805	207143818	207143993

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 99.17.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 7.4103 / max 2838.7844, expressed in 69 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8207	2.5247	45
8209	2.0039	28
8208	1.0947	19
8205	0.9015	28
8206	0.5910	19
8211	0.0952	10
8203	0.0815	13
8204	0.0586	12
8202	0.0332	5
8212	0.0260	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.17	gold quality
liver	UBERON:0002107	98.69	gold quality
lower lobe of lung	UBERON:0008949	97.62	gold quality
adult organism	UBERON:0007023	93.05	gold quality
visceral pleura	UBERON:0002401	89.58	gold quality
lung	UBERON:0002048	89.05	gold quality
upper lobe of lung	UBERON:0008948	88.84	gold quality
upper lobe of left lung	UBERON:0008952	88.20	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.26	gold quality
germinal epithelium of ovary	UBERON:0001304	80.38	gold quality
right lung	UBERON:0002167	80.16	gold quality
body of pancreas	UBERON:0001150	74.29	gold quality
epithelial cell of pancreas	CL:0000083	74.18	silver quality
islet of Langerhans	UBERON:0000006	73.74	gold quality
sperm	CL:0000019	72.97	gold quality
pancreas	UBERON:0001264	72.91	gold quality
endometrium	UBERON:0001295	71.84	gold quality
male germ cell	CL:0000015	71.14	gold quality
bronchial epithelial cell	CL:0002328	70.89	gold quality
palpebral conjunctiva	UBERON:0001812	69.86	gold quality
epithelium of bronchus	UBERON:0002031	69.74	gold quality
pleura	UBERON:0000977	69.67	gold quality
gall bladder	UBERON:0002110	69.17	gold quality
bronchus	UBERON:0002185	69.10	gold quality
vermiform appendix	UBERON:0001154	67.41	gold quality
pancreatic ductal cell	CL:0002079	66.94	silver quality
blood	UBERON:0000178	66.20	gold quality
epithelium of mammary gland	UBERON:0003244	65.87	silver quality
caecum	UBERON:0001153	65.22	gold quality
mammary duct	UBERON:0001765	64.40	silver quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	82.69
E-MTAB-10287	yes	33.64
E-GEOD-130148	yes	21.84
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXJ2, HNF1A, SSRP1

miRNA regulators (miRDB)

17 targeting C4BPA, 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-548P	99.98	72.25	3784
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-2113	99.58	71.22	1521
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-1272	99.34	68.79	878
HSA-MIR-4777-5P	99.33	67.53	1148
HSA-MIR-3145-3P	98.85	69.07	2031
HSA-MIR-382-3P	98.83	67.10	1074
HSA-MIR-4742-3P	98.73	69.82	1803
HSA-MIR-1248	98.47	67.54	1314
HSA-MIR-6847-5P	97.93	66.74	1808
HSA-MIR-6890-3P	97.50	65.71	997
HSA-MIR-219B-3P	97.31	66.96	672

Literature-anchored findings (GeneRIF, showing 40)

• The primary binding site on C4bp is located on the alpha-chain complement control protein 4 (CCP4) domain which, unlike C4bp alpha-chain amino-terminal CCP1 and CCP2, is not involved in complement regulatory activity. (PMID:11441101)
• structural requirements for the intracellular subunit polymerization (PMID:12135356)
• C4b and C3b do not undergo the same conformational changes upon binding to the C4BP mutants as during the interaction with the wild type C4BP, which then results in an observed loss of the cofactor activity (PMID:12893820)
• Localization of binding sites for a number of C4BP ligands in relation to well-established and novel functions of C4BP. Review (PMID:15179322)
• To determine the regions of C4b contributing to C4BP binding, the binding of the C4c and C4dg subfragments of C4b to C4BP was examined. (PMID:16819837)
• Data show that C4BP does not bind CD40, but it forms stable high molecular weight complexes with soluble CD40 ligand (sCD154). (PMID:17225862)
• Non-small cell lung cancer (NSCLC) cells produce soluble complement inhibitors factor I (FI) and C4b-binding protein (C4BP). (PMID:17548110)
• The binding sites to Neisseria gonorrhoeae Por1A protein have been mapped within complement control protein domain 1 of C4BP. (PMID:17579075)
• various conformational isoforms (native, amyloid fibrils, and beta-oligomers) of recombinant human PrP (90-231 and 121-231) bind C1q and activate complement. (PMID:18406463)
• A novel non-synonymous polymorphism (p.Arg240His) in C4b-binding protein is associated with atypical hemolytic uremic syndrome and leads to impaired alternative pathway cofactor activity. (PMID:18424762)
• C4BP binds to dead brain cells and Abeta peptide in vitro, is present in CSF and possibly protects against excessive complement activation in AD brains. (PMID:18556068)
• These results reinforce the case for the occupation of some of the seven arms of C4BP in a multivalent interaction with DNA or surface bound glycosaminoglycans while other arms engage C4b or C3b. (PMID:18715646)
• Mainly the central core of C4BP mediates binding to small leucine-rich repeat proteins (SLRPs). Binding of SLRPs to C4BP does not not affect its ability to inhibit complement. (PMID:19155499)
• isoforms of a group B streptococcus-secreted component named Fib displayed differential binding capacities for fibronectin, fibrinogen, and C4BP (PMID:19417080)
• C4BP binding varies between strains but is dependent on the expression of pneumococcal surface protein C, PspC of group 4 (PMID:19494311)
• Binding of the classical pathway inhibitor, C4b-binding protein (C4bp), to three genospecies of B. burgdorferi sensu lato, is demonstrated. (PMID:20022381)
• C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S-independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies. (PMID:20212171)
• Show that B. recurrentis spirochetes express another potential outer membrane lipoprotein, termed CihC, and acquire C4b-binding protein (C4bp) and human C1 esterase inhibitor (C1-Inh). (PMID:20532227)
• Serum C4BP level in 89 patients showed a strong association with the clinical staging of non small cell lung carcinoma. (PMID:21262398)
• NC4 Domain of cartilage-specific collagen IX inhibits complement directly due to attenuation of membrane attack formation and indirectly through binding and enhancing activity of complement inhibitors C4B-binding protein and factor H. (PMID:21659506)
• Human pentraxin 3 binds to the complement regulator c4b-binding protein. (PMID:21915248)
• C4BP is recruited to the S. aureus surface where it functions to inhibit C4 complement effectors, suggesting a previously undescribed immune evasion strategy for this pathogen. (PMID:22333221)
• The Lsa30 (LIC110870) is a novel adhesin that binds plasminogen and the complement regulator C4bp. (PMID:22732096)
• Human pneumococcal glycolytic enzyme enolase, a nonclassical cell surface and plasminogen-binding protein, is a pneumococcal C4BP-binding protein. (PMID:22925928)
• The heptameric core structure is stabilized by intermolecular disulfide bonds. (PMID:23274142)
• C4BP alpha7beta0 isoform complement control protein-6 domain of C4BP alpha-chain is necessary for tolerogenic activity of the acute-phase C4BPbeta chain. (PMID:23390292)
• mutations in women experiencing recurrent miscarriages (PMID:23508668)
• these data suggest that when C4BP is bound to Ail, fI can cleave and inactivate C4b that has bound covalently to bacterial surface structures as well as C4b bound noncovalently to Ail. (PMID:24760758)
• In patients treated with tacrolimus and mycophenolate mophetil as a maintenance immunosuppression, the lower C4d urinary excretion in early post-transplant period seems to be a low significance prognostic marker of a better long-term kidney outcome. (PMID:24779215)
• C4BPB/C4BPA may not confer susceptibility to schizophrenia among Han Chinese (PMID:25660618)
• whereas the presence of plasminogen did not affect the factor I cofactor activity of C4BP, the activation of plasminogen by urokinase-type plasminogen activator to active plasmin was significantly augmented in the presence of C4BP. (PMID:26067271)
• genetic polymorphism is associated with spontaneous abortion; review (PMID:26658464)
• C4BP is deposited in the diseased aortic valve, coincident with C3d expression. (PMID:26897815)
• Proteomics study showed a strong association of FN1, A2M, C4BPA and CFB in molecular subtypes of breast cancer, in which, C4BPA and A2M demonstrated a potent signature in blood plasma and tissue samples of Luminal-B (LB) and Triple-negative (TN)subtypes in BC patients, respectively. (PMID:27498393)
• INDEED also identified some candidates previously reported to be relevant to HCC, such as intercellular adhesion molecule 2 (ICAM2) and c4b-binding protein alpha chain (C4BPA), which were missed by both Differential expression and differential network analyses (PMID:27592383)
• Exposure to arterial blood pressure leads to a transient presence of C4bp in the saphenous vein wall. (PMID:28163174)
• The rs73079108 polymorphism in the 5’ upstream region of C4BPA was associated with EH, and rs73079108A may be an independent predictor. (PMID:28627632)
• Observation of Complement Protein Gene Expression Before and After Surgery in Opioid-Consuming and Opioid-Naive Patients. (PMID:30169415)
• The authors conclude that Streptococcus pneumoniae PspA and PspC help the pneumococcus to evade complement attack by binding C4BP and so inactivating C4b. (PMID:30323030)
• Fetal lung C4BPA induces p100 processing in human placenta. (PMID:30940885)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	C4bp	ENSMUSG00000026405
rattus_norvegicus	C4bpa	ENSRNOG00000004062

Paralogs (39): CFH (ENSG00000000971), SELE (ENSG00000007908), C8B (ENSG00000021852), C6 (ENSG00000039537), SEZ6 (ENSG00000063015), CFHR2 (ENSG00000080910), APOH (ENSG00000091583), SEZ6L (ENSG00000100095), SUSD6 (ENSG00000100647), SRPX (ENSG00000101955), SRPX2 (ENSG00000102359), C7 (ENSG00000112936), C9 (ENSG00000113600), PAPPA2 (ENSG00000116183), CFHR3 (ENSG00000116785), CR2 (ENSG00000117322), CD46 (ENSG00000117335), CSMD2 (ENSG00000121904), C4BPB (ENSG00000123843), CFHR4 (ENSG00000134365), CFHR5 (ENSG00000134389), F13B (ENSG00000143278), SUSD4 (ENSG00000143502), C8A (ENSG00000157131), SUSD3 (ENSG00000157303), CSMD3 (ENSG00000164796), SVEP1 (ENSG00000165124), C2 (ENSG00000166278), SELP (ENSG00000174175), SEZ6L2 (ENSG00000174938), PRF1 (ENSG00000180644), PAPPA (ENSG00000182752), CSMD1 (ENSG00000183117), SELL (ENSG00000188404), CD55 (ENSG00000196352), CR1L (ENSG00000197721), CR1 (ENSG00000203710), CFB (ENSG00000243649), CFHR1 (ENSG00000244414)

Protein

Protein identifiers

C4b-binding protein alpha chain — P04003 (reviewed: P04003)

Alternative names: Proline-rich protein

All UniProt accessions (3): A6PVY5, P04003, F2Z2V7

UniProt curated annotations — full annotation on UniProt →

Function. Controls the classical pathway of complement activation. It binds as a cofactor to C3b/C4b inactivator (C3bINA), which then hydrolyzes the complement fragment C4b. It also accelerates the degradation of the C4bC2a complex (C3 convertase) by dissociating the complement fragment C2a. Alpha chain binds C4b. It also interacts with anticoagulant protein S and with serum amyloid P component.

Subunit / interactions. Disulfide-linked complex of alpha and beta chains of 3 possible sorts: a 570 kDa complex of 7 alpha chains and 1 beta chain, a 530 kDa homoheptamer of alpha chains or a 500 kDa complex of 6 alpha chains and 1 beta chain. The central body of the alpha chain homomer supports tentacles, each with the binding site for C4b at the end. (Microbial infection) Interacts with Staphylococcus aureus protein SdrE; this interaction inhibits complement-mediated bacterial opsonization.

Subcellular location. Secreted.

Tissue specificity. Chylomicrons in the plasma.

RefSeq proteins (1): NP_000706* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000436	Sushi_SCR_CCP_dom	Domain
IPR035976	Sushi/SCR/CCP_sf	Homologous_superfamily
IPR040514	C4bp_oligo	Domain
IPR050350	Compl-Cell_Adhes-Reg	Family

Pfam: PF00084, PF18453

UniProt features (55 total): disulfide bond 18, strand 15, domain 8, sequence variant 6, glycosylation site 3, helix 3, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
5I0Q	X-RAY DIFFRACTION	2.29
8TGT	X-RAY DIFFRACTION	2.5
5HYT	X-RAY DIFFRACTION	2.54
5HYU	X-RAY DIFFRACTION	2.56
8TCB	X-RAY DIFFRACTION	2.69
5HZP	X-RAY DIFFRACTION	2.74
4B0F	X-RAY DIFFRACTION	2.8
5HYP	X-RAY DIFFRACTION	3.02
2A55	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04003-F1	81.62	0.43

Functional residue map

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

Disulfide bonds (18): 50–96, 81–108, 113–154, 140–170, 175–217, 203–234, 239–281, 267–294, 299–348, 332–360, 365–409, 399–422, 426–468, 454–480, 484–525, 511–538, 546, 558

Glycosylation sites (3): 221, 506, 528

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
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-168249	Innate Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 174 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY, GNF2_HPN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_VESICLE_MEDIATED_TRANSPORT, LEE_LIVER_CANCER_CIPROFIBRATE_DN, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_B_CELL_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_IMMUNE_RESPONSE, MODULE_75, GOBP_COMPLEMENT_ACTIVATION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM

GO Biological Process (10): T cell mediated immunity (GO:0002456), complement activation, classical pathway (GO:0006958), response to symbiotic bacterium (GO:0009609), innate immune response (GO:0045087), positive regulation of protein catabolic process (GO:0045732), negative regulation of complement activation, classical pathway (GO:0045959), regulation of opsonization (GO:1903027), immune system process (GO:0002376), regulation of immune response (GO:0050776), response to other organism (GO:0051707)

GO Molecular Function (2): RNA binding (GO:0003723), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), blood microparticle (GO:0072562)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Complement cascade	1
Dengue Virus-Host Interactions	1
Innate Immune System	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
immune response	2
cellular anatomical structure	2
lymphocyte mediated immunity	1
adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
humoral immune response mediated by circulating immunoglobulin	1
complement activation	1
response to symbiont	1
response to bacterium	1
defense response to symbiont	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
negative regulation of humoral immune response mediated by circulating immunoglobulin	1
complement activation, classical pathway	1
regulation of complement activation, classical pathway	1
negative regulation of complement activation	1
regulation of immune effector process	1
opsonization	1
regulation of cellular process	1
biological_process	1
regulation of immune system process	1
regulation of response to stimulus	1
response to external biotic stimulus	1
biological process involved in interspecies interaction between organisms	1
nucleic acid binding	1
binding	1
membrane	1
cell periphery	1
extracellular region	1

Protein interactions and networks

STRING

1114 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C4BPA	C4A	P01028	986
C4BPA	C4A	P01028	984
C4BPA	PRB1	P04280	819
C4BPA	C3	P01024	798
C4BPA	PNRC1	Q12796	778
C4BPA	STATH	P02808	774
C4BPA	PRH1	P02810	769
C4BPA	PRB4	P02813	750
C4BPA	PRB3	Q04118	744
C4BPA	PRB2	P02811	729
C4BPA	SPRR3	Q9UBC9	721
C4BPA	LORICRIN	P23490	721
C4BPA	A0A087WZY1	A0A087WZY1	714
C4BPA	SPRR1B	P22528	705
C4BPA	C1S	P09871	681

IntAct

53 interactions, top by confidence:

A	B	Type	Score
C4BPA	arp4	psi-mi:“MI:0407”(direct interaction)	0.620
arp4	C4BPA	psi-mi:“MI:0407”(direct interaction)	0.620
C4BPA	CRP	psi-mi:“MI:0407”(direct interaction)	0.560
CRP	C4BPA	psi-mi:“MI:0407”(direct interaction)	0.560
PTX3	C4BPA	psi-mi:“MI:0407”(direct interaction)	0.440
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
	LECT2	psi-mi:“MI:0915”(physical association)	0.400
C4BPA	GTF2I	psi-mi:“MI:0915”(physical association)	0.370
FXYD6	C4BPA	psi-mi:“MI:0915”(physical association)	0.370
LBP	C4BPA	psi-mi:“MI:0915”(physical association)	0.370
SMARCD1	C4BPA	psi-mi:“MI:0915”(physical association)	0.370
C4BPA	GIT2	psi-mi:“MI:0915”(physical association)	0.370
Tubg1	BDP1	psi-mi:“MI:0914”(association)	0.350
Cenpe	BBX	psi-mi:“MI:0914”(association)	0.350
Rhoa	CLK2	psi-mi:“MI:0914”(association)	0.350
Edc4	C4BPA	psi-mi:“MI:0914”(association)	0.350
Ccdc9	ACIN1	psi-mi:“MI:0914”(association)	0.350
TSNAX		psi-mi:“MI:0914”(association)	0.350
Ccdc12	PLRG1	psi-mi:“MI:0914”(association)	0.350
Sidt2	PRSS1	psi-mi:“MI:0914”(association)	0.350
ARMC6		psi-mi:“MI:0914”(association)	0.350
SEC16A	NCOR2	psi-mi:“MI:0914”(association)	0.350
Mtx1	BDP1	psi-mi:“MI:0914”(association)	0.350
MYH11	TBC1D31	psi-mi:“MI:0914”(association)	0.350

BioGRID (44): C4BPA (Affinity Capture-MS), C4BPA (Affinity Capture-MS), C4BPA (Affinity Capture-MS), C4BPA (Affinity Capture-MS), C4BPA (Affinity Capture-MS), C4BPA (Affinity Capture-MS), C4BPA (Affinity Capture-MS), C4BPA (Affinity Capture-MS), C4BPA (Affinity Capture-MS), C4BPA (Affinity Capture-MS), C4BPA (Affinity Capture-MS), C4BPA (Affinity Capture-MS), C4BPA (Affinity Capture-MS), C4BPA (Affinity Capture-MS), C4BPA (Affinity Capture-MS)

ESM2 similar proteins: O02839, O08569, O19124, O62685, O62837, O88174, P02749, P04003, P05160, P08607, P14151, P15529, P16109, P17690, P19070, P20023, P26644, P27113, P30836, P42201, P49457, P70105, P79138, P98107, P98109, P98131, Q01102, Q03472, Q07968, Q28065, Q28768, Q2VPA4, Q5R4D0, Q60401, Q60736, Q61475, Q61476, Q63135, Q63514, Q64735

Diamond homologs: A0A1D5NSM8, A2AVA0, D3YXF5, O02839, O19124, O35764, O43405, O62685, O62837, O70340, O76536, O95502, O96530, P00751, P04003, P04186, P06205, P06206, P06207, P06681, P07629, P08174, P08607, P0C6B8, P13944, P14151, P14650, P15529, P17690, P18337, P26022, P32018, P33703, P35419, P42201, P47970, P47971, P47972, P48199, P48759

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	71
Likely benign	7
Benign	21

Top pathogenic / likely-pathogenic (0)

SpliceAI

1865 predictions. Top by Δscore:

Variant	Effect	Δscore
1:207114090:T:TA	acceptor_gain	1.0000
1:207124004:GAAA:G	donor_gain	1.0000
1:207124006:AAG:A	donor_loss	1.0000
1:207124007:AGTA:A	donor_loss	1.0000
1:207124008:G:GG	donor_gain	1.0000
1:207124009:TAA:T	donor_loss	1.0000
1:207124168:A:AG	acceptor_gain	1.0000
1:207124363:GAAA:G	donor_gain	1.0000
1:207124366:AGT:A	donor_loss	1.0000
1:207124367:G:GG	donor_gain	1.0000
1:207124368:TAA:T	donor_loss	1.0000
1:207134589:GACA:G	donor_gain	1.0000
1:207134593:G:GG	donor_gain	1.0000
1:207115414:A:AG	acceptor_gain	0.9900
1:207115415:G:GG	acceptor_gain	0.9900
1:207115511:GAAGG:G	donor_gain	0.9900
1:207115514:GG:G	donor_gain	0.9900
1:207115515:GG:G	donor_gain	0.9900
1:207123554:G:GT	donor_gain	0.9900
1:207123934:T:A	acceptor_gain	0.9900
1:207124003:TGAAA:T	donor_gain	0.9900
1:207124004:GAAAG:G	donor_gain	0.9900
1:207124006:AA:A	donor_gain	0.9900
1:207124010:AAG:A	donor_loss	0.9900
1:207124160:A:AG	acceptor_gain	0.9900
1:207124164:A:AG	acceptor_gain	0.9900
1:207124165:C:G	acceptor_gain	0.9900
1:207124173:A:AG	acceptor_gain	0.9900
1:207124174:G:GG	acceptor_gain	0.9900
1:207124362:TGA:T	donor_gain	0.9900

AlphaMissense

3909 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:207123982:G:C	W163C	0.999
1:207123982:G:T	W163C	0.999
1:207124341:G:C	W227C	0.998
1:207124341:G:T	W227C	0.998
1:207114263:G:C	W102C	0.997
1:207114263:G:T	W102C	0.997
1:207126867:G:C	W287C	0.996
1:207126867:G:T	W287C	0.996
1:207131718:G:C	W354C	0.996
1:207131718:G:T	W354C	0.996
1:207134564:G:C	W415C	0.996
1:207134564:G:T	W415C	0.996
1:207123980:T:A	W163R	0.994
1:207123980:T:C	W163R	0.994
1:207124339:T:A	W227R	0.994
1:207124339:T:C	W227R	0.994
1:207123953:T:A	C154S	0.993
1:207123954:G:C	C154S	0.993
1:207124001:T:A	C170S	0.992
1:207124002:G:C	C170S	0.992
1:207126865:T:A	W287R	0.992
1:207126865:T:C	W287R	0.992
1:207131716:T:A	W354R	0.991
1:207131716:T:C	W354R	0.991
1:207124309:T:A	C217S	0.989
1:207124310:G:C	C217S	0.989
1:207143966:G:C	W531C	0.989
1:207143966:G:T	W531C	0.989
1:207131698:T:A	C348S	0.988
1:207131699:G:C	C348S	0.988

dbSNP variants (sampled 300 via entrez): RS1000055904 (1:207111397 G>A), RS1000073006 (1:207117973 G>A), RS1000126453 (1:207118181 C>A), RS1000188784 (1:207128720 A>C), RS1000298800 (1:207136961 A>G), RS1000343206 (1:207111693 A>C), RS1000408269 (1:207122625 G>A,T), RS1000427323 (1:207132701 G>A), RS1000538847 (1:207115840 C>T), RS1000593768 (1:207125834 C>T), RS1000650724 (1:207136759 G>A), RS1000656962 (1:207131728 C>A,T), RS1000735425 (1:207122272 C>T), RS1000760067 (1:207130984 A>G), RS1000934122 (1:207145207 T>C)

Disease associations

OMIM: gene MIM:120830 | disease phenotypes: MIM:266600, MIM:614699

GenCC curated gene-disease

Mondo (2): inflammatory bowel disease (MONDO:0005265), immunodeficiency, common variable, 7 (MONDO:0013862)

Orphanet (3): Rare inflammatory bowel disease (Orphanet:104012), OBSOLETE: Common variable immunodeficiency (Orphanet:1572), Common variable immunodeficiency phenotype due to CD21 deficiency (Orphanet:696894)

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000621_1	C4b binding protein levels	4.000000e-10
GCST004599_264	Mean platelet volume	4.000000e-12
GCST006291_31	Spherical equivalent or myopia (age of diagnosis)	3.000000e-13
GCST009030_28	Venous thromboembolism	3.000000e-10
GCST009097_12	Venous thromboembolism	4.000000e-09
GCST010002_375	Refractive error	2.000000e-54
GCST011354_9	Bell’s palsy	8.000000e-06
GCST90002395_554	Mean platelet volume	3.000000e-24
GCST90002401_403	Platelet distribution width	2.000000e-28
GCST90002405_97	Reticulocyte count	7.000000e-10
GCST90002406_119	Reticulocyte fraction of red cells	1.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004572	C4BP measurement
EFO:0004847	age at onset
EFO:0007984	platelet component distribution width
EFO:0007986	reticulocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D015212	Inflammatory Bowel Diseases	C06.405.205.731; C06.405.469.432

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression	3
Cyclosporine	decreases expression	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
Estradiol	decreases expression, increases expression	2
Particulate Matter	increases abundance, increases expression, affects cotreatment, decreases abundance	2
dicrotophos	decreases expression	1
2,4,6-tribromophenol	increases expression	1
methyleugenol	decreases expression	1
propionaldehyde	decreases expression	1
bisphenol A	decreases expression	1
decabromobiphenyl ether	increases expression	1
diisononyl phthalate	affects cotreatment, decreases expression	1
sulforaphane	decreases expression	1
lead nitrate	affects cotreatment, decreases expression	1
sodium arsenite	decreases expression	1
tetrabromobisphenol A	increases expression	1
butylbenzyl phthalate	affects cotreatment, decreases expression	1
corosolic acid	increases expression	1
K 7174	decreases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
(+)-JQ1 compound	decreases expression	1
Zoledronic Acid	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Allergens	affects cotreatment, decreases abundance, increases expression, increases abundance	1
Vehicle Emissions	affects cotreatment, decreases abundance, increases expression, increases abundance	1
Cadmium	affects binding	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00167882	PHASE4	COMPLETED	The Influence of 5-Aminosalicylates on Thiopurine Metabolite Levels
NCT00205062	PHASE4	TERMINATED	Positron Emission Tomography (PET)-Computed Tomography (CT) in Inflammatory Bowel Disease (IBD)
NCT00567593	PHASE4	COMPLETED	Gene Regulation by Thiazolidinediones
NCT00746395	PHASE4	COMPLETED	Randomized, Placebo-controlled Trial of Lubiprostone as a Preparation for Capsule Endoscopy
NCT01034358	PHASE4	COMPLETED	Immune Response to the Human Papillomavirus Vaccine in Young Women With Inflammatory Bowel Disease
NCT01056913	PHASE4	COMPLETED	NITI CAR27 (ColonRing) Compression Anastomosis in Colorectal Surgery
NCT01067547	PHASE4	COMPLETED	A Trial of Iron Replacement in Patients With Iron Deficiency.
NCT01341808	PHASE4	COMPLETED	Immunogenicity of Hepatitis A Vaccine in Inflammatory Bowel Disease (IBD) Patients
NCT01908283	PHASE4	COMPLETED	Induction of Immunity Against Streptococcus Pneumoniae in Adults With Inflammatory Bowel Disease
NCT01934088	PHASE4	COMPLETED	Satisfaction With Nurse Administered Propofol Sedation vs. Midazolam With Fentanyl Sedation for Endoscopy
NCT02162862	PHASE4	COMPLETED	Treating Disrupted Sleep in Individuals With Inflammatory Bowel Disease
NCT02248337	PHASE4	COMPLETED	Low Volume Colon Preparation for IBD
NCT02281799	PHASE4	WITHDRAWN	Thiopurine Induced Pancreatitis in IBD Patients
NCT02392286	PHASE4	TERMINATED	Corticosteroid Dosage for Crohn’s Disease Flare
NCT02437591	PHASE4	COMPLETED	Study to Evaluate the Pharmacokinetics of Fidaxomicin in Inflammatory Bowel Disease (IBD) Subjects With Clostridium Difficile Infection (CDI)
NCT02453776	PHASE4	COMPLETED	Precision Dosing of Infliximab Versus Conventional Dosing of Infliximab
NCT02461758	PHASE4	COMPLETED	Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory Bowel Disease Patients
NCT02566889	PHASE4	TERMINATED	An Efficacy and Safety Study of Infliximab Dose Escalation in Pediatric Participants With Inflammatory Bowel Disease
NCT02774057	PHASE4	UNKNOWN	Trial of Captafer® vs. Oral Iron Sulfate in the Treatment of Iron Deficiency Anemia in Patients With IBD
NCT02806206	PHASE4	UNKNOWN	Prucalopride Prior to Small Bowel Capsule Endoscopy
NCT02946203	PHASE4	COMPLETED	Comparison of VoLumen and Breeza Oral Contrast Agents in Pediatric Patients
NCT02994836	PHASE4	COMPLETED	GIS-SUSANTI-TNF-2015 (Anti-TNF Discontinuation )
NCT03220841	PHASE4	UNKNOWN	Stricture Definition and Treatment (STRIDENT) Drug Therapy Study
NCT03351972	PHASE4	COMPLETED	Differences in Preparation for Small Bowel Capsule Endoscopy
NCT03466983	PHASE4	COMPLETED	A Trial Comparing the Incidence of Hypophosphatemia in Relation to Treatment With Iron Isomaltoside and Ferric Carboxymaltose in Subjects With Iron Deficiency Anaemia Due to Inflammatory Bowel Disease
NCT03591770	PHASE4	TERMINATED	Shingrix Vaccine in Patients With Moderate to Severe Ulcerative Colitis on Tofacitinib
NCT03629379	PHASE4	COMPLETED	Response to Ustekinumab for Anti-tnf Induced Psoriasiform Skin Lesions
NCT03723447	PHASE4	COMPLETED	Intraoperative TAP Block With Bupivacaine/Dexamethasone Against Liposomal Bupivacaine (Exparel®)
NCT03798691	PHASE4	COMPLETED	Immunogenicity of Herpes Zoster Subunit Vaccine in Inflammatory Bowel Disease Patients Treated With Vedolizumab
NCT03860012	PHASE4	UNKNOWN	Folic Acid in Pediatric Inflammatory Bowel Disease
NCT03885713	PHASE4	COMPLETED	Identification of Predictive Biomarkers for Response to Biologic Therapies and Tofacitinib in Inflammatory Bowel Disease
NCT03917303	PHASE4	RECRUITING	Control Crohn Safe Trial
NCT04045782	PHASE4	COMPLETED	Evaluation of the Safety and Effectiveness of Switching From Humira® to Imraldi® in Flanders
NCT04304950	PHASE4	COMPLETED	Chronotherapy in Inflammatory Bowel Disease
NCT04626947	PHASE4	TERMINATED	Prevention of Recurrent Clostridium Difficile Infection (CDI) in Patients With Inflammatory Bowel Disease (IBD).
NCT04646187	PHASE4	ENROLLING_BY_INVITATION	De-escalation of Anti-TNF Therapy in Inflammatory Bowel Disease
NCT04835506	PHASE4	ACTIVE_NOT_RECRUITING	Proactive Infliximab Optimization Using a Pharmacokinetic Dashboard Versus Standard of Care in Patients With Inflammatory Bowel Disease: The OPTIMIZE Trial
NCT04982172	PHASE4	COMPLETED	Model-informed Dose De-escalation of Infliximab in Patients With Inflammatory Bowel Diseases
NCT05180175	PHASE4	COMPLETED	The Nordic IBD Treatment Strategy Trial
NCT05280405	PHASE4	UNKNOWN	Early Proactive Therapeutic Drug Monitoring of Infliximab in Children: EPIC Study