Complement component 4b deficiency

Summary

Complement component 4b deficiency (MONDO:0013720) is a disease caused by C4B (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: C4B (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	complement component 4b deficiency
Mondo ID	MONDO:0013720
OMIM	614379
DOID	DOID:0060298
UMLS	C5779962
MedGen	1830476
GARD	0015797
Is cancer (heuristic)	no

Also known as: C4B classic complement early component deficiency · C4BD · classic complement early component deficiency caused by mutation in C4B · complement component 4b deficiency

Data availability: 5 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 4b 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 4a 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

5 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 1 likely pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
987922	NM_001002029.3:c.(?3231)(3387_?)del	C4B	Pathogenic	criteria provided, single submitter
1299253	NM_001002029.4(C4B):c.3676+1G>A	C4B	Likely pathogenic	criteria provided, single submitter
982136	NM_001002029.4(C4B):c.1040C>A	C4B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1034339	NM_001002029.3(C4B):c.3442G>A (p.Ala1148Thr)	C4B	Uncertain significance	criteria provided, single submitter
3393172	NM_001002029.4(C4B):c.3214C>T (p.Arg1072Trp)	C4B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 6 · 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
C4B	Strong	Autosomal recessive	complement component 4b deficiency	3

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
C4B	Orphanet:169147	Immunodeficiency due to a classical component pathway complement deficiency
C4B	Orphanet:536	Systemic lupus erythematosus

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
C4A	HGNC:1323	ENSG00000244731	P0C0L4	Complement C4-A	gencc,clinvar
C4B	HGNC:1324	ENSG00000224389	P0C0L5	Complement C4-B	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…
C4B	Complement C4-B	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: 2 · 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	2	268.0×	1e-05

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
C4A	Complement	yes		Anaphylatoxin/fibulin, Netrin_domain, Macroglobln_a2
C4B	Complement	yes		Anaphylatoxin/fibulin, Netrin_domain, Macroglobln_a2

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	2
right adrenal gland cortex	2
right lobe of liver	2

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
C4B	134		marker	right lobe of liver, right adrenal gland cortex, liver

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
C4A	222
C4B	55

Intra-cohort edges

A	B	Sources
C4A	C4B	biogrid_interaction, intact

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
C4A	P0C0L4	12
C4B	P0C0L5	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 evidence-associated genes (2 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 2 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	2	1268.9×	3e-06	C4A, C4B
Initial triggering of complement	2	601.0×	8e-06	C4A, C4B
Dengue virus activates/modulates innate and adaptive immune responses	2	335.9×	2e-05	C4A, C4B
Regulation of Complement cascade	2	233.1×	3e-05	C4A, C4B
Post-translational protein phosphorylation	1	50.1×	0.023	C4A
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.023	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 2 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	2	2407.4×	1e-06	C4A, C4B
complement activation, GZMK pathway	2	1296.3×	2e-06	C4A, C4B
complement activation	2	624.1×	6e-06	C4A, C4B
complement activation, classical pathway	2	543.6×	6e-06	C4A, C4B
detection of molecule of bacterial origin	1	2106.5×	7e-04	C4B
inflammatory response	2	37.7×	8e-04	C4A, C4B
opsonization	1	766.0×	0.001	C4B

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
C4B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	C4A, C4B
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
C4A	0	—
C4B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.