Complement component 4a deficiency

Summary

Complement component 4a deficiency (MONDO:0013721) is a disease caused by C4A (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: C4A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	complement component 4a deficiency
Mondo ID	MONDO:0013721
MeSH	C565167
OMIM	614380
DOID	DOID:0060297
UMLS	C3280642
MedGen	482272
GARD	0015798
Is cancer (heuristic)	no

Also known as: C4A classic complement early component deficiency · C4AD · classic complement early component deficiency caused by mutation in C4A · complement component 4a deficiency

Data availability: 4 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › complement deficiency › classic complement early component deficiency › complement component 4a deficiency

Related subtypes (12): C1 inhibitor deficiency, complement component C1r/C1s deficiency, complement component 2 deficiency, complement component 5 deficiency, complement component 7 deficiency, complement component 6 deficiency, complement component 3 deficiency, complement component C1s deficiency, type II complement component 8 deficiency, type I complement component 8 deficiency, complement component 9 deficiency, complement component 4b deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

4 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029153	NM_007293.3(C4A):c.3059C>T (p.Pro1020Leu)	C4A	Uncertain significance	criteria provided, single submitter
1034372	NM_007293.3(C4A):c.3453T>G (p.His1151Gln)	C4A	Uncertain significance	criteria provided, single submitter
3778969	NM_007293.3(C4A):c.3301C>T (p.Gln1101Ter)	C4A	Uncertain significance	criteria provided, single submitter
17055	NM_007293.3(C4A):c.3694_3695dup (p.Val1233fs)	C4A	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
C4A	Strong	Autosomal recessive	complement component 4a deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
C4A	Orphanet:117	Behçet disease
C4A	Orphanet:169147	Immunodeficiency due to a classical component pathway complement deficiency
C4A	Orphanet:300345	Autosomal systemic lupus erythematosus
C4A	Orphanet:536	Systemic lupus erythematosus

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
C4A	HGNC:1323	ENSG00000244731	P0C0L4	Complement C4-A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
C4A	Complement C4-A	Precursor of non-enzymatic components of the classical, lectin and GZMK complement pathways, which consist in a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune sy…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Complement	1	268.0×	0.004

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
C4A	Complement	yes		Anaphylatoxin/fibulin, Netrin_domain, Macroglobln_a2

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
right adrenal gland cortex	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
C4A	134		marker	right lobe of liver, liver, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
C4A	222

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
C4A	P0C0L4	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Activation of C3 and C5	1	1268.9×	0.005	C4A
Initial triggering of complement	1	601.0×	0.005	C4A
Dengue virus activates/modulates innate and adaptive immune responses	1	335.9×	0.006	C4A
Regulation of Complement cascade	1	233.1×	0.006	C4A
Post-translational protein phosphorylation	1	100.2×	0.012	C4A
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.012	C4A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of apoptotic cell clearance	1	2407.4×	0.002	C4A
complement activation, GZMK pathway	1	1296.3×	0.002	C4A
complement activation	1	624.1×	0.002	C4A
complement activation, classical pathway	1	543.6×	0.002	C4A
inflammatory response	1	37.7×	0.027	C4A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
C4A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	C4A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
C4A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.