C1QA

protein-coding

complement C1q A chain, the group of C1q domain containing|Complement system activation components

Gene summary

This gene encodes the A-chain polypeptide of serum complement subcomponent C1q, which associates with C1r and C1s to yield the first component of the serum complement system. C1q deficiency is associated with lupus erythematosus and glomerulonephritis. C1q is composed of 18 polypeptide chains which include 6 A-chains, 6 B-chains, and 6 C-chains. Each chain contains an N-terminal collagen-like region and a C-terminal C1q globular domain. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

MANE transcript

NM_015991.4

Inheritance

ClinVar variants

P:12U:82B:56

Top phenotype

C1q deficiency 1

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr1:22,635,077-22,639,678

External References & Databases

Ensembl (ENSG00000173372)

Transcript & Mutation Effects

hg38 • Region Span ~4.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

systemic lupus erythematosus related to C1QADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:1060174

Submitter: ClinGen

*C1QA* encodes the A-chain of the complement component C1Q, a core part of the C1 complex—the first component of the classical complement pathway. Together with C1R and C1S, C1Q forms a complex essential for immune defense by binding to pathogens or immune complexes and initiating complement activation. *C1QA* was first reported in relation to autosomal recessive systemic lupus erythematosus (SLE) in 1995 (PMID: 7594474). Twelve variants (4 nonsense, 4 frameshift, 1 splicing and 3 missense) that have been reported in 26 probands in 12 publications (PMIDs: 7594474, 8840296, 9039514, 9225968, 21654842, 26563161, 29739689, 30008451, 35086391, 39196411, 38263665, 22576477) are included in this curation. These variants are identified in both homozygous and compound heterozygous states in affected individuals. All probands exhibit confirmed C1Q deficiency, presenting with SLE or SLE-like clinical features and recurrent infections. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease association is further supported by substantial experimental evidence, including gene expression analyses, animal models, and in vitro functional assays. In affected individuals, C1Q protein is undetectable in serum, and classical pathway hemolytic complement activity (CH50) is absent. Anti-C1Q autoantibodies, which are commonly observed in SLE patients, have been shown to correlate with renal disease activity and serve as a predictive biomarker for lupus nephritis (PMID: 15286009). Moreover, C1QA-deficient mice develop a lupus-like autoimmune phenotype characterized by antinuclear autoantibodies and glomerulonephritis (PMIDs: 9590289, 11859149, 29724957). Mechanistically, C1QA deficiency leads to defective clearance of apoptotic cells, resulting in increased exposure to self-antigens and breakdown of immune tolerance (PMIDs: 9590289, 10934224). Elevated production of interferon-alpha (IFN-α) has also been implicated in disease pathogenesis, representing a potential link between C1Q deficiency and autoimmunity (PMID: 19790049). Notably, C1Q may also limit autoreactivity in CD8+ T cells by modulating mitochondrial metabolism (PMID: 29724957). Bone marrow transplantation restores C1Q production and function in deficient mice (PMIDs: 11564823, 15517607), and treatment with fresh frozen plasma has been utilized to manage SLE associated with C1Q deficiency in human cases (PMID:29113537). In summary, there is **definitive** evidence supporting the relationship between C1QA and autosomal recessive Systemic Lupus Erythematosus. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Monogenic Systemic and Incomplete Lupus Erythematosus GCEP on the meeting date March 12, 2025 (SOP Version 11).

C1Q deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013343

Submitter: Labcorp Genetics (formerly Invitae)

C1Q deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013343

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

C1q deficiency 1AR

Manifestation: Allergy/Immunology/Infectious; Dermatologic; Renal

Intervention: Allergy/Immunology/Infectious

Rationale: While the majority of sequelae may involve autoimmune manifestations (for which treatment with FFP may be beneficial), some individuals have been described with frequent and/or severe infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial

Comments: Individuals are also prone to autoimmune disease (eg, glomerulonephritis, SLE)

Refs: 6445507; 6319055; 7594474; 8840296; 9225968; 10776791; 20560256; 22576477

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to C1QA variants in ClinVar

7 Conditions Cataloged

not providedTotal: 140

Inborn genetic diseasesTotal: 27

C1Q deficiencyTotal: 8

not specifiedTotal: 8

C1QA-related disorderTotal: 3

C1QA-related disordersTotal: 3

C1Q deficiency 1Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015991.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	52 clinvar	1 clinvar	54
missense		2 clinvar	80 clinvar	3 clinvar		85
nonsense	3 clinvar	1 clinvar				4
start loss						0
frameshift	4 clinvar	2 clinvar				6
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	7	5	82	55	1	150

Highest pathogenic variant AF is 0.000025311294

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015991.4	RefSeq	NP_057075.1	2	MANE Select
ENST00000374642.8	Ensembl	ENSP00000363773.3	2	MANE Select
NM_001347465.2	RefSeq	NP_001334394.1	2	Standard
NM_001347466.2	RefSeq	NP_001334395.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Prion diseases - Homo sapiens (human)
Complement and coagulation cascades - Homo sapiens (human)
Pertussis - Homo sapiens (human)
Systemic lupus erythematosus - Homo sapiens (human)
Chagas disease (American trypanosomiasis) - Homo sapiens (human)

Biological Process

proteolysis
complement activation
complement activation, classical pathway
cell-cell signaling
response to iron ion

Molecular Function

serine-type endopeptidase activity
protein binding

Cellular Component

extracellular region
collagen trimer
complement component C1 complex
collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000374642
Coding exons: 2
Length: 3103
Individuals with no LoFs: 125726
Homozygous LoFs: 0
Heterozygous LoFs: 22
Defined: 125748
p: 0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.29	106	151	0.703	0.00000944	1535
Missense (PolyPhen)		18	43.742	0.4115		454
Synonymous	0.554	58	63.6	0.912	0.00000427	528
Loss of Function	1.26	5	9.11	0.549	6.61e-7	81

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000081	0.000079	rare
South Asian	0.00036	0.00036	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: C1q associates with the proenzymes C1r and C1s to yield C1, the first component of the serum complement system. The collagen-like regions of C1q interact with the Ca(2+)-dependent C1r(2)C1s(2) proenzyme complex, and efficient activation of C1 takes place on interaction of the globular heads of C1q with the Fc regions of IgG or IgM antibody present in immune complexes.;
Disease: DISEASE: Complement component C1q deficiency (C1QD) [MIM:613652]: A disorder caused by impaired activation of the complement classical pathway. It generally leads to severe immune complex disease with features of systemic lupus erythematosus and glomerulonephritis. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.383
RVIS EVS: -0.14
RVIS percentile EVS: 43.29

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0298

Gene Damage Prediction

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