Complement component 9 deficiency

Summary

Complement component 9 deficiency (MONDO:0013445) is a disease caused by C9 (GenCC Strong), with 1 cohort gene.

At a glance

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

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	complement component 9 deficiency
Mondo ID	MONDO:0013445
MeSH	C565165
OMIM	613825
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

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 4b 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

22 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
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
17043	NM_001737.5(C9):c.1280C>G (p.Ser427Ter)	C9	Pathogenic	criteria provided, single submitter
29659	NM_001737.5(C9):c.1583G>A (p.Cys528Tyr)	C9	Pathogenic	no assertion criteria provided
402245	NM_001737.5(C9):c.577del (p.Tyr193fs)	C9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
973622	NM_001737.5(C9):c.375C>A (p.Cys125Ter)	C9	Pathogenic	criteria provided, single submitter
3362573	NM_001737.5(C9):c.184-1G>A	C9	Likely pathogenic	criteria provided, single submitter
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
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	Uncertain significance	criteria provided, single submitter
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
830026	NM_001737.5(C9):c.1677del (p.Lys559fs)	C9	Uncertain significance	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
522196	NM_001737.5(C9):c.133A>T (p.Met45Leu)	C9	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

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.

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

Orphanet rare-disease linkage (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 (full)

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.

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 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)
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

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

Per-gene tissue summary (top 30)

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	965

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
C9	P02748	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Terminal pathway of complement	1	1427.5×	0.001	C9
Regulation of Complement cascade	1	233.1×	0.004	C9

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
cell killing	1	8426.0×	0.001	C9
complement activation, GZMK pathway	1	1296.3×	0.003	C9
complement activation, alternative pathway	1	991.3×	0.003	C9
complement activation	1	624.1×	0.003	C9
complement activation, classical pathway	1	543.6×	0.003	C9
positive regulation of immune response	1	481.5×	0.003	C9
killing of cells of another organism	1	271.8×	0.005	C9
transmembrane transport	1	168.5×	0.007	C9
protein homooligomerization	1	122.1×	0.008	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 (full, sorted 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).

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.