C4A

complement C4A (Rodgers blood group), the group of Complement system activation components|Blood group antigens|C3 and PZP like, alpha-2-macroglobulin domain containing

Basic information

Region (hg38): 6:31982057-32002681

Links

ENSG00000244731 ∙ NCBI:720 ∙ OMIM:120810 ∙ HGNC:1323 ∙ Uniprot:P0C0L4 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• complement component 4a deficiency (Moderate), mode of inheritance: AR
• complement component 4a deficiency (Strong), mode of inheritance: AR
• systemic lupus erythematosus (Supportive), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Blood group, Chido/Rodgers system	BG	Hematologic	Variants associated with a blood group may be important in specific situations (eg, related to transfusion)	Allergy/Immunology/Infectious; Hematologic	4190973; 6932037; 7451653; 2862466; 3260957; 2551816; 2295875; 2243578; 2289315; 2384609; 8473511; 7706484; 22387014; 29928053

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the C4A gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the C4A 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			1		1	2
missense			31	4	1	36
nonsense						0
start loss						0
frameshift					1	1
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region					1	1
non coding				1	3	4
Total	0	0	32	5	6

Variants in C4A

This is a list of pathogenic ClinVar variants found in the C4A region.

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

Position	Type	Phenotype	Significance	ClinVar
6-31984403-C-A		not specified	Benign (-)
6-31984478-G-A		not specified	Benign (-)
6-31991937-C-A		not specified	Benign (-)
6-31994269-A-G		Inborn genetic diseases	Likely benign (Jan 04, 2022)
6-31994331-G-T			Uncertain significance (Sep 16, 2018)
6-31994504-G-A		Inborn genetic diseases	Uncertain significance (Nov 27, 2024)
6-31994510-G-A		Inborn genetic diseases	Uncertain significance (Apr 06, 2023)
6-31994546-G-A		Inborn genetic diseases	Uncertain significance (Jan 22, 2024)
6-31994573-C-A		Inborn genetic diseases	Uncertain significance (Oct 11, 2024)
6-31994594-G-A		Inborn genetic diseases	Uncertain significance (Apr 26, 2024)
6-31994600-T-C		Inborn genetic diseases	Uncertain significance (Aug 21, 2024)
6-31994616-C-T		Inborn genetic diseases	Uncertain significance (Apr 17, 2023)
6-31994627-G-A		Inborn genetic diseases	Uncertain significance (Sep 27, 2022)
6-31994646-T-G		Inborn genetic diseases	Uncertain significance (Dec 05, 2022)
6-31994649-C-T		Inborn genetic diseases	Uncertain significance (Jan 07, 2025)
6-31994682-C-T		Inborn genetic diseases	Uncertain significance (Feb 06, 2024)
6-31995127-A-C		Inborn genetic diseases	Likely benign (Mar 31, 2022)
6-31995249-T-C		not specified	Benign/Likely benign (-)
6-31995444-C-T		Complement component 4a deficiency	Uncertain significance (Jun 03, 2020)
6-31995528-T-G		Inborn genetic diseases	Uncertain significance (Sep 22, 2023)
6-31995727-C-T		Inborn genetic diseases	Uncertain significance (Apr 26, 2024)
6-31995741-T-A		Inborn genetic diseases	Uncertain significance (Jan 07, 2025)
6-31995749-C-T		Inborn genetic diseases	Uncertain significance (Sep 14, 2023)
6-31995764-C-A			Uncertain significance (Feb 01, 2024)
6-31995779-G-A		Inborn genetic diseases	Uncertain significance (Jun 24, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
C4A	protein_coding	protein_coding	ENST00000428956	41	20658

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.54e-11	0.0568	124261	3	28	124292	0.000125

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.92	130	208	0.625	0.0000124	11177
Missense in Polyphen		35	62.201	0.56269		3004
Synonymous	1.41	76	93.3	0.815	0.00000601	3601
Loss of Function	0.135	17	17.6	0.965	8.23e-7	1030

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000320	0.000320
Ashkenazi Jewish	0.00	0.00
East Asian	0.000168	0.000163
Finnish	0.000160	0.0000925
European (Non-Finnish)	0.0000792	0.0000631
Middle Eastern	0.000168	0.000163
South Asian	0.000295	0.000294
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Non-enzymatic component of C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. Covalently binds to immunoglobulins and immune complexes and enhances the solubilization of immune aggregates and the clearance of IC through CR1 on erythrocytes. C4A isotype is responsible for effective binding to form amide bonds with immune aggregates or protein antigens, while C4B isotype catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens.
• Disease: DISEASE: Complement component 4A deficiency (C4AD) [MIM:614380]: A rare defect of the complement classical pathway associated with the development of autoimmune disorders, mainly systemic lupus with or without associated glomerulonephritis. {ECO:0000269|PubMed:8473511}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. {ECO:0000269|PubMed:10092831, ECO:0000269|PubMed:17503323}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Interindividual copy-number variation (CNV) of complement component C4 and associated polymorphisms result in different susceptibilities to SLE. The risk of SLE susceptibility has been shown to be significantly increased among subjects with only two copies of total C4. A high copy number is a protective factor against SLE.
• Pathway: Complement and coagulation cascades - Homo sapiens (human);Pertussis - Homo sapiens (human);Systemic lupus erythematosus - Homo sapiens (human);Staphylococcus aureus infection - Homo sapiens (human);Allograft Rejection;Human Complement System;Complement Activation;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Post-translational protein phosphorylation;Post-translational protein modification;Metabolism of proteins;Innate Immune System;Immune System;Activation of C3 and C5;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;Complement cascade (Consensus)

Haploinsufficiency Scores

• pHI: 0.185
• ghis: 0.453

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.600

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: C4b
• Phenotype: immune system phenotype; renal/urinary system phenotype; digestive/alimentary phenotype; hematopoietic system 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); 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); liver/biliary system phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: proteolysis;inflammatory response;complement activation;complement activation, classical pathway;negative regulation of endopeptidase activity;regulation of complement activation;post-translational protein modification;cellular protein metabolic process;innate immune response;positive regulation of apoptotic cell clearance
• Cellular component: extracellular region;extracellular space;endoplasmic reticulum lumen;plasma membrane;cell junction;axon;dendrite;neuronal cell body;synapse;extracellular exosome;blood microparticle
• Molecular function: complement component C1q binding;serine-type endopeptidase activity;endopeptidase inhibitor activity