Complement component 9 deficiency

Summary

Complement component 9 deficiency (MONDO:0013445) is a disease caused by C9 (GenCC Strong), inherited in an autosomal recessive pattern. Immunodeficiency due to a late component of complement deficiency is a primary immunodeficiency due to an anomaly in either complement components C5, C6, C7, C8 or C9 and is typically characterized by meningitis due to often recurrent meningococcal infections (Orphanet). This page aggregates 1 associated gene.

At a glance

• Causal gene: C9 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 22
• Phenotypes (HPO): 1

Clinical features

Clinical description

Orphanet: Immunodeficiency due to a late component of complement deficiency is a primary immunodeficiency due to an anomaly in either complement components C5, C6, C7, C8 or C9 and is typically characterized by meningitis due to often recurrent meningococcal infections. The prognosis is generally favorable.

Mondo: Any classic complement early component deficiency in which the cause of the disease is a mutation in the C9 gene.

Inheritance: Autosomal recessive

Signs & symptoms

Clinical features (HPO)

1 HPO clinical feature (curated from Orphanet + OMIM; top 1 shown, Orphanet frequencies first):

HPO ID	Term	Frequency
HP:0012308	Decreased circulating complement C9 concentration	—

Identifiers

Disease identifiers

Field	Value
Canonical name	complement component 9 deficiency
Mondo ID	MONDO:0013445
MeSH	C565165
OMIM	613825
Orphanet	169150
DOID	DOID:0060303
UMLS	C3151189
MedGen	462539
GARD	0018292
Is cancer (heuristic)	no

Also known as: C9 classic complement early component deficiency · C9D · classic complement early component deficiency caused by mutation in C9 · complement component 9 deficiency

Data availability: 22 ClinVar variants · 3 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 9 deficiency Also classified under: immunodeficiency due to a late component of complement deficiency

Sibling subtypes (12): C1 inhibitor 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 4b deficiency, complement component 4a deficiency, … (+1 more under the parent term)

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

22 retrieved; paginated sample, class counts are floors:

9 pathogenic/likely pathogenic, 4 conflicting classifications of pathogenicity, 3 uncertain significance, 3 pathogenic, 2 likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17040	NM_001737.5(C9):c.346C>T (p.Arg116Ter)	C9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17041	NM_001737.5(C9):c.162C>A (p.Cys54Ter)	C9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
402245	NM_001737.5(C9):c.577del (p.Tyr193fs)	C9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1029525	NM_001737.5(C9):c.460C>T (p.Arg154Ter)	C9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1033862	NM_001737.5(C9):c.1038_1042delinsT (p.Ser347fs)	C9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1033864	NM_001737.5(C9):c.721del (p.Ser240_Leu241insTer)	C9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324000	NM_001737.5(C9):c.580C>T (p.Arg194Ter)	C9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455046	NM_001737.5(C9):c.1184_1185del (p.Ser395fs)	C9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457531	NM_001737.5(C9):c.1039_1042del (p.Ser347fs)	C9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17043	NM_001737.5(C9):c.1280C>G (p.Ser427Ter)	C9	Pathogenic	criteria provided, single submitter
973622	NM_001737.5(C9):c.375C>A (p.Cys125Ter)	C9	Pathogenic	criteria provided, single submitter
29659	NM_001737.5(C9):c.1583G>A (p.Cys528Tyr)	C9	Pathogenic	no assertion criteria provided
3362573	NM_001737.5(C9):c.184-1G>A	C9	Likely pathogenic	criteria provided, single submitter
17042	NM_001737.5(C9):c.355T>G (p.Cys119Gly)	C9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033863	NM_001737.5(C9):c.409G>A (p.Glu137Lys)	C9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1546178	NM_001737.5(C9):c.1451T>A (p.Met484Lys)	C9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1581502	NM_001737.5(C9):c.1585G>A (p.Ala529Thr)	C9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
830026	NM_001737.5(C9):c.1677del (p.Lys559fs)	C9	Uncertain significance	criteria provided, multiple submitters, no conflicts
1061985	NM_001737.5(C9):c.376G>A (p.Gly126Arg)	C9	Uncertain significance	criteria provided, multiple submitters, no conflicts
2500114	NM_001737.5(C9):c.1346T>C (p.Val449Ala)	C9	Uncertain significance	criteria provided, single submitter
522196	NM_001737.5(C9):c.133A>T (p.Met45Leu)	C9	Likely benign	criteria provided, multiple submitters, no conflicts
1299281	NM_001737.5(C9):c.974C>T (p.Ala325Val)	C9	Likely benign	criteria provided, multiple submitters, no conflicts

Pathogenic / likely-pathogenic variants link to their full per-variant reference — ACMG evidence, calibrated predictors, gnomAD frequency — on Sugi Variant.

Genes & proteins

Molecular basis

The molecular function of this disease’s causal gene(s), from UniProt. Attributed to the gene/protein — reporting UniProt’s curation, not an assertion about this disease’s clinical phenotype.

C9 — Complement component C9 (P02748) · GenCC Strong · Belongs to the complement C6/C7/C8/C9 family. Function: Pore-forming component of the membrane attack complex (MAC), a multiprotein complex activated by the complement cascade, which inserts into a target cell membrane and forms a pore, leading to target cell membrane rupture and cell lysis. Localization / cofactor: Secreted UniProt gene–disease: Complement component 9 deficiency (C9D) [MIM:613825] A rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections predominantly by Neisseria gonorrhoeae or Neisseria meningitidis. Some patients may develop …

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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.

1 cohort genes:

Gene	Classification	Inheritance	Disease	Records
C9	Strong	Autosomal recessive	complement component 9 deficiency	3

Orphanet rare-disease linkage (cohort genes)

1 cohort genes:

Gene	Orphanet ID	Rare disease
C9	Orphanet:169150	Immunodeficiency due to a late component of complement deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes

1 cohort genes:

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
C9	HGNC:1358	ENSG00000113600	P02748	Complement component C9	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

1 cohort genes:

Symbol	Protein name	Function (lead sentence)
C9	Complement component C9	Pore-forming component of the membrane attack complex (MAC), a multiprotein complex activated by the complement cascade, which inserts into a target cell membrane and forms a pore, leading to target cell membrane rupture and cell lysis.

Protein-family classification

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

Family distribution

Cohort has 1 family-classified gene — counts only (too few for over-representation statistics).

Family	Genes
Complement	1

Per-gene assignment

1 cohort genes:

Symbol	Family	Druggable?	EC	InterPro (top 3)
C9	Complement	yes		TSP1_rpt, MAC_perforin, LDrepeatLR_classA_rpt

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

3 tissues:

Tissue	Cohort genes
liver	1
male germ line stem cell (sensu Vertebrata) in testis	1
right lobe of liver	1

Per-gene tissue summary

1 cohort genes:

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
C9	119	tissue_specific	marker	right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
C9	759

Structural data

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

Cohort genes with PDB structures

1 cohort genes:

Symbol	UniProt	PDB entries
C9	P02748	9

Alliance gene associations

Curated gene–disease associations from the Alliance of Genome Resources (Disease Ontology) — distinct from the cohort above: implicated (causal/mechanistic) vs biomarker (a marker for the disease).

Implicated genes (1): C9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Cohort has 1 gene with Reactome annotation — too few for over-representation statistics, so the pathways below are membership (what the cohort gene participates in), not enrichment.

Pathways by enrichment

Cohort has 1 annotated gene — membership only (too few for over-representation statistics).

5 pathways:

Pathway	Genes	Sample cohort genes
Terminal pathway of complement	1	C9
Complement cascade	1	C9
Regulation of Complement cascade	1	C9
Innate Immune System	1	C9
Immune System	1	C9

GO biological processes by enrichment

Cohort has 1 annotated gene — membership only (too few for over-representation statistics).

9 GO terms:

GO term	Genes	Sample cohort genes
cell killing	1	C9
complement activation, GZMK pathway	1	C9
complement activation, alternative pathway	1	C9
complement activation	1	C9
complement activation, classical pathway	1	C9
positive regulation of immune response	1	C9
killing of cells of another organism	1	C9
transmembrane transport	1	C9
protein homooligomerization	1	C9

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
C9	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity

1 cohort genes by assay count:

Symbol	Assays	Type breakdown
C9	1	Binding:1

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	C9
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).

1 cohort genes:

Symbol	ChEMBL assays	Drugged partners (top 3)
C9	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.