C3

complement C3, the group of Complement system activation components|Receptor ligands|C3 and PZP like, alpha-2-macroglobulin domain containing

Basic information

Region (hg38): 19:6677703-6730562

Links

ENSG00000125730 ∙ NCBI:718 ∙ OMIM:120700 ∙ HGNC:1318 ∙ Uniprot:P01024 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• complement component 3 deficiency (Definitive), mode of inheritance: AR
• complement component 3 deficiency (Supportive), mode of inheritance: AR
• complement component 3 deficiency (Strong), mode of inheritance: AR
• atypical hemolytic-uremic syndrome with C3 anomaly (Strong), mode of inheritance: AD
• C3 glomerulonephritis (Moderate), mode of inheritance: AD
• atypical hemolytic-uremic syndrome with C3 anomaly (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Complement component 3 deficiency, autosomal recessive; Hemolytic uremic syndrome, atypical, susceptibility to, 5	AD/AR	Allergy/Immunology/Infectious; Hematologic; Pharmacogenomic; Renal	In Complement component 3 deficiency, individuals may manifest with frequent infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Individuals may develop renal disease, and awareness may allow early management of renal sequelaentiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; In hemolytic-uremic syndrome, the choice of specific treatment modalities (eg, danazol, plasma exchange, plasma therapy), as well as decision to perform renal transplant, may be dictated by genetic diagnosis, and certain agents/precipitating factors should be avoided (eg, certain medications)	Allergy/Immunology/Infectious; Dermatologic; Hematologic; Ophthalmologic;Renal	4117597; 1976733; 1350678; 1575793; 15781264; 18796626; 19846853; 20807612; 20595690; 22410797

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the C3 gene.

• not provided (855 variants)
• Complement component 3 deficiency (140 variants)
• Age related macular degeneration 9 (138 variants)
• Atypical hemolytic-uremic syndrome with C3 anomaly (133 variants)
• not specified (44 variants)
• Age related macular degeneration 9;Atypical hemolytic-uremic syndrome with C3 anomaly;Complement component 3 deficiency (32 variants)
• Atypical hemolytic-uremic syndrome (32 variants)
• Inborn genetic diseases (21 variants)
• Age related macular degeneration 9;Complement component 3 deficiency;Atypical hemolytic-uremic syndrome with C3 anomaly (17 variants)
• Atypical hemolytic-uremic syndrome with C3 anomaly;Age related macular degeneration 9;Complement component 3 deficiency (17 variants)
• Atypical hemolytic-uremic syndrome with C3 anomaly;Complement component 3 deficiency;Age related macular degeneration 9 (13 variants)
• Complement component 3 deficiency;Atypical hemolytic-uremic syndrome with C3 anomaly;Age related macular degeneration 9 (13 variants)
• Complement component 3 deficiency;Age related macular degeneration 9;Atypical hemolytic-uremic syndrome with C3 anomaly (10 variants)
• C3 deficiency (7 variants)
• Macular degeneration (6 variants)
• Kidney disorder (6 variants)
• C3-related condition (6 variants)
• Focal segmental glomerulosclerosis (2 variants)
• MACULAR DEGENERATION, AGE-RELATED, 9, SUSCEPTIBILITY TO (2 variants)
• C3S/C3F POLYMORPHISM (1 variants)
• Premature ovarian failure (1 variants)
• Familial Atypical Hemolytic-Uremic Syndrome (1 variants)
• Familial hemolytic anemia (1 variants)
• C3 POLYMORPHISM, HAV 4-1 PLUS/MINUS TYPE (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the C3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			13	163	14	190
missense	1	3	310	5	2	321
nonsense	2	3	1			6
start loss						0
frameshift	4	3				7
inframe indel			4			4
splice donor/acceptor (+/-2bp)	1	8	2			11
splice region			28	42	8	78
non coding			12	114	108	234
Total	8	17	342	282	124

Variants in C3

This is a list of pathogenic ClinVar variants found in the C3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
19-6677788-G-A			Benign (Jun 18, 2021)
19-6677887-T-C			Uncertain significance (Nov 01, 2022)
19-6677923-C-A			Uncertain significance (Oct 13, 2023)
19-6677927-G-A		Atypical hemolytic-uremic syndrome with C3 anomaly;Age related macular degeneration 9;Complement component 3 deficiency	Conflicting classifications of pathogenicity (Sep 27, 2023)
19-6677933-C-T		Age related macular degeneration 9 • Complement component 3 deficiency • Atypical hemolytic-uremic syndrome with C3 anomaly	Conflicting classifications of pathogenicity (Jul 23, 2022)
19-6677939-T-C			Likely benign (Mar 17, 2023)
19-6677952-T-C			Uncertain significance (Jan 19, 2024)
19-6677963-G-A			Likely benign (Sep 07, 2022)
19-6677967-T-G			Uncertain significance (Oct 27, 2022)
19-6677968-C-G		Age related macular degeneration 9;Atypical hemolytic-uremic syndrome with C3 anomaly;Complement component 3 deficiency	Uncertain significance (May 17, 2022)
19-6677969-G-A			Likely benign (Apr 18, 2022)
19-6677974-C-T			Uncertain significance (Aug 20, 2022)
19-6677978-G-A		Complement component 3 deficiency • Age related macular degeneration 9 • Atypical hemolytic-uremic syndrome with C3 anomaly • not specified	Benign (Feb 01, 2024)
19-6677982-C-T		not specified	Uncertain significance (May 04, 2022)
19-6677987-C-G			Uncertain significance (Nov 22, 2022)
19-6677996-A-G		Atypical hemolytic-uremic syndrome with C3 anomaly • Age related macular degeneration 9 • Complement component 3 deficiency • not specified • Kidney disorder • Atypical hemolytic-uremic syndrome with C3 anomaly;Complement component 3 deficiency;Age related macular degeneration 9 • C3-related disorder	Benign/Likely benign (Jan 20, 2024)
19-6678004-T-A			Likely pathogenic (Jan 01, 2023)
19-6678007-C-A		Age related macular degeneration 9 • Atypical hemolytic-uremic syndrome with C3 anomaly • Complement component 3 deficiency	Uncertain significance (Dec 16, 2022)
19-6678012-A-C			Uncertain significance (Jan 09, 2024)
19-6678019-T-G		Age related macular degeneration 9 • Complement component 3 deficiency • Atypical hemolytic-uremic syndrome with C3 anomaly • Age related macular degeneration 9;Atypical hemolytic-uremic syndrome with C3 anomaly;Complement component 3 deficiency • not specified	Conflicting classifications of pathogenicity (Jan 29, 2024)
19-6678024-C-A			Uncertain significance (Nov 13, 2021)
19-6678024-C-T			Uncertain significance (Oct 17, 2022)
19-6678031-G-C			Likely benign (Sep 07, 2022)
19-6678041-A-G			Likely benign (Jul 17, 2022)
19-6678132-C-A			Likely benign (Aug 11, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
C3	protein_coding	protein_coding	ENST00000245907	41	52859

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.904	0.0958	125706	0	42	125748	0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.75	720	960	0.750	0.0000648	10871
Missense in Polyphen		160	271.92	0.5884		3068
Synonymous	-1.59	442	401	1.10	0.0000297	3245
Loss of Function	7.01	19	91.3	0.208	0.00000513	1036

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000391	0.000391
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000238	0.000237
Middle Eastern	0.000109	0.000109
South Asian	0.0000980	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: C3 plays a central role in the activation of the complement system. Its processing by C3 convertase is the central reaction in both classical and alternative complement pathways. After activation C3b can bind covalently, via its reactive thioester, to cell surface carbohydrates or immune aggregates.; FUNCTION: C3-beta-c: Acts as a chemoattractant for neutrophils in chronic inflammation. {ECO:0000250}.
• Disease: DISEASE: Complement component 3 deficiency (C3D) [MIM:613779]: A rare defect of the complement classical pathway. Patients develop recurrent, severe, pyogenic infections because of ineffective opsonization of pathogens. Some patients may also develop autoimmune disorders, such as arthralgia and vasculitic rashes, lupus-like syndrome and membranoproliferative glomerulonephritis. {ECO:0000269|PubMed:7961791}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Macular degeneration, age-related, 9 (ARMD9) [MIM:611378]: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. {ECO:0000269|PubMed:17634448, ECO:0000269|PubMed:24036952}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Hemolytic uremic syndrome atypical 5 (AHUS5) [MIM:612925]: An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. {ECO:0000269|PubMed:18796626, ECO:0000269|PubMed:20513133}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Other genes may play a role in modifying the phenotype.; DISEASE: Note=Increased levels of C3 and its cleavage product ASP, are associated with obesity, diabetes and coronary heart disease. Short-term endurance training reduces baseline ASP levels and subsequently fat storage.
• Pathway: Complement and coagulation cascades - Homo sapiens (human);Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human);Pertussis - Homo sapiens (human);Legionellosis - Homo sapiens (human);Systemic lupus erythematosus - Homo sapiens (human);Phagosome - Homo sapiens (human);Chagas disease (American trypanosomiasis) - Homo sapiens (human);Staphylococcus aureus infection - Homo sapiens (human);Tuberculosis - Homo sapiens (human);Leishmaniasis - Homo sapiens (human);Viral carcinogenesis - Homo sapiens (human);Herpes simplex infection - Homo sapiens (human);Allograft Rejection;Human Complement System;Dengue-2 Interactions with Complement and Coagulation Cascades;TYROBP Causal Network;Complement Activation;Complement and Coagulation Cascades;Signaling by GPCR;Neutrophil degranulation;Signal Transduction;alternative complement pathway;classical complement pathway;lectin induced complement pathway;Post-translational protein phosphorylation;Post-translational protein modification;Metabolism of proteins;Innate Immune System;Immune System;Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell;Activation of C3 and C5;Adaptive Immune System;Peptide ligand-binding receptors;Class A/1 (Rhodopsin-like receptors);GPCR ligand binding;Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs);Initial triggering of complement;Regulation of Complement cascade;G alpha (i) signalling events;Complement cascade;Alternative complement activation;GPCR downstream signalling;Validated nuclear estrogen receptor alpha network;Validated nuclear estrogen receptor beta network;Beta2 integrin cell surface interactions (Consensus)

Intolerance Scores

• loftool: 0.335
• rvis_EVS: -1.69
• rvis_percentile_EVS: 2.62

Haploinsufficiency Scores

• hipred: Y
• hipred_score: 0.640
• ghis: 0.520

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.961

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: C3
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; skeleton phenotype; renal/urinary system phenotype; digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; reproductive system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); embryo phenotype

Zebrafish Information Network

• Gene name: c3a.1
• Affected structure: whole organism
• Phenotype tag: abnormal
• Phenotype quality: malformed

Gene ontology

• Biological process: positive regulation of type IIa hypersensitivity;positive regulation of protein phosphorylation;positive regulation of activation of membrane attack complex;proteolysis;fatty acid metabolic process;phagocytosis, engulfment;inflammatory response;immune response;complement activation;complement activation, alternative pathway;complement activation, classical pathway;signal transduction;G protein-coupled receptor signaling pathway;response to bacterium;positive regulation of vascular endothelial growth factor production;positive regulation of glucose transmembrane transport;regulation of triglyceride biosynthetic process;positive regulation of lipid storage;negative regulation of endopeptidase activity;regulation of complement activation;neutrophil degranulation;post-translational protein modification;cellular protein metabolic process;positive regulation of G protein-coupled receptor signaling pathway;positive regulation of angiogenesis;regulation of immune response;positive regulation of phagocytosis, engulfment;amyloid-beta clearance;cell surface receptor signaling pathway involved in cell-cell signaling;positive regulation of apoptotic cell clearance
• Cellular component: extracellular region;extracellular space;endoplasmic reticulum lumen;plasma membrane;protein-containing complex;secretory granule lumen;azurophil granule lumen;extracellular exosome;blood microparticle
• Molecular function: serine-type endopeptidase activity;endopeptidase inhibitor activity;signaling receptor binding;protein binding;C5L2 anaphylatoxin chemotactic receptor binding