C9

Summary

C9 (complement C9, HGNC:1358) is a protein-coding gene on chromosome 5p13.1, encoding Complement component C9 (P02748). 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.

This gene encodes the final component of the complement system. It participates in the formation of the Membrane Attack Complex (MAC). The MAC assembles on bacterial membranes to form a pore, permitting disruption of bacterial membrane organization. Mutations in this gene cause component C9 deficiency.

Source: NCBI Gene 735 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complement component 9 deficiency (Strong, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 434 total — 31 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 4
• Druggable target: yes
• MANE Select transcript: NM_001737

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1358
Approved symbol	C9
Name	complement C9
Location	5p13.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000113600
Ensembl biotype	protein_coding
OMIM	120940
Entrez	735

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 12 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000263408, ENST00000467285, ENST00000509186, ENST00000695880, ENST00000695881, ENST00000695882, ENST00000695883, ENST00000884639, ENST00000884640, ENST00000884641, ENST00000884642, ENST00000884643, ENST00000884644, ENST00000884645, ENST00000884646, ENST00000884647

RefSeq mRNA: 1 — MANE Select: NM_001737 NM_001737

CCDS: CCDS3929

Canonical transcript exons

ENST00000263408 — 11 exons

Exon	Start	End
ENSE00000802116	39306617	39306792
ENSE00000802117	39308230	39308358
ENSE00000802118	39311137	39311377
ENSE00000802119	39315775	39316029
ENSE00001008645	39288723	39288951
ENSE00001143265	39284140	39285233
ENSE00001143272	39364388	39364495
ENSE00003472000	39341146	39341293
ENSE00003574809	39342091	39342196
ENSE00003684175	39341556	39341700
ENSE00003687544	39331676	39331814

Expression profiles

Bgee: expression breadth ubiquitous, 119 present calls, max score 99.08.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 8.0705 / max 4488.9163, expressed in 18 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
61411	19.5228	1432
61400	7.9108	13
61402	0.0843	12
61403	0.0479	5
203533	0.0171	4
61401	0.0104	4

Top tissues by expression

274 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.08	gold quality
liver	UBERON:0002107	97.08	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.01	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.89	gold quality
buccal mucosa cell	CL:0002336	61.81	silver quality
adult mammalian kidney	UBERON:0000082	58.94	gold quality
metanephros cortex	UBERON:0010533	57.06	gold quality
corpus epididymis	UBERON:0004359	53.76	silver quality
kidney	UBERON:0002113	53.70	gold quality
stromal cell of endometrium	CL:0002255	53.25	silver quality
metanephros	UBERON:0000081	52.81	gold quality
right adrenal gland	UBERON:0001233	52.50	gold quality
right adrenal gland cortex	UBERON:0035827	51.88	gold quality
cortex of kidney	UBERON:0001225	51.51	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
right coronary artery	UBERON:0001625	50.21	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
thymus	UBERON:0002370	50.12	gold quality
colonic epithelium	UBERON:0000397	50.02	gold quality
quadriceps femoris	UBERON:0001377	49.82	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
vastus lateralis	UBERON:0001379	49.11	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-130473	yes	757.22
E-HCAD-9	yes	64.25
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

38 targeting C9, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-7844-5P	99.55	68.56	1428
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-4273	99.45	67.93	1206
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-1244	99.33	68.38	832
HSA-MIR-4477B	99.23	70.49	1733
HSA-MIR-4717-3P	99.06	66.34	1072
HSA-MIR-4724-5P	98.87	67.75	1324
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-5197-3P	98.71	67.05	1905
HSA-MIR-8060	98.61	66.93	1187
HSA-MIR-4490	98.51	68.47	943
HSA-MIR-2117	98.48	67.97	1307
HSA-MIR-4257	97.86	68.05	1190
HSA-MIR-4433A-3P	97.75	62.82	1435
HSA-MIR-4678	97.59	68.31	902
HSA-MIR-6069	97.45	65.88	357

Literature-anchored findings (GeneRIF, showing 29)

• The human complement C9 gene: structural analysis of the 5’ gene region and genetic polymorphism studies. (PMID:11881818)
• C9 binding is dependent on the N-terminal modules (thrombospondin type 1 and low-density lipoprotein receptor class A) of C8 alpha together with the C8 alpha membrane attack complex/perforin domain. (PMID:12463754)
• Founder effect was demonstrated for the R95X mutation of the C9 gene in Japanese (PMID:12596049)
• results indicate that the principal binding site for C9 lies within the MACPF domain of C8alpha (PMID:16618117)
• analysis of the CD59-C9 binding interaction (PMID:16844690)
• Impairment of the mechanisms involved in the regulation of activation of complement system factors C5b-9 may be important in the pathogenesis of endometriosis and endometriosis-associated infertility. (PMID:17482181)
• the amount of C5b-9-AF488 bound to K562 cells after complement activation was highly heterogeneous and inversely correlated with the CD59 level of expression (PMID:17644516)
• Cell cycle induction by C5b-9 in aortic endothelial cells is RGC-32 dependent and this is in part through regulation of Akt and growth factor release. (PMID:19162005)
• Data show that mortalin supports cancer cell resistance to complement-dependent cytotoxicity and suggest consideration of mortalin as a novel target for cancer adjuvant immunotherapy. (PMID:19739077)
• Complement C5b-9 induce a JNK/Bid-dependent and JNK-independent necrotic cell death. (PMID:19864026)
• Data show that C1q, C4, C3, and C9 bind to thrombin receptor-activating peptide-activated platelets in lepirudin-anticoagulated platelet-rich plasma (PRP) and whole blood. (PMID:20139276)
• provided evidence for the recognition of membrane-bound C9 on complement-lysed ghosts by an antibody specific for the helix-turn-helix fold. (PMID:20153530)
• These results suggested that the lack of membrane attack complex because of an Arg95Stop mutation of the complement component 9 gene predisposed patients to pathognomonic glomerulonephritis. (PMID:21057849)
• It was concluded that variations in the complement component 9 gene are unlikely to influence clearance of chronic hepatitis B virus infection and hepatocellular carcinoma occurrence. (PMID:21380615)
• Mapping the intermedilysin-human CD59 receptor interface reveals a deep correspondence with the binding site on CD59 for complement binding proteins C8alpha and C9. (PMID:21507937)
• C9 and fucosylated form could serve as a useful marker for SQLC. (PMID:21840429)
• the haploinsufficiency of C9, a terminal complement complex component, engenders reduced intraocular secretion of VEGF and decreased risk for CNV development. (PMID:22190594)
• Caveolin-1 and dynamin-2 are essential for removal of the complement C5b-9 complex via endocytosis. (PMID:22528500)
• Liver biopsy specimens from chronically hepatitis C virus-infected patients exhibited a lower level of C9 mRNA expression than liver biopsy specimens from unrelated disease or healthy control human liver RNA. (PMID:23487461)
• Borrelial CspA binds the human terminal complement components C7 and C9 and blocks assembly and membrane insertion of the terminal complement complex (TCC). (PMID:23943762)
• Data indicate that complement C9 binds to the ATPase domain of mortalin. (PMID:24719326)
• Complement C5b-9 complex sensitizes 661W photoreceptor cells to both apoptosis and necroptosis. (PMID:25735751)
• Serum-expressed apolipoprotein B-100 protein, C9 Complement, and gelsolin can be used for differential diagnosis of Barrertts esophagus and adenocarcinoma of esophagus. (PMID:26404905)
• Patients with advanced atrophic AMD carried these rare variants more frequently than patients with neovascular AMD (11 of 93 [11.8%] vs 40 of 835 [4.8%]; P = .04). (PMID:26767664)
• Five novel rare genetic variants (p.M45L, p.F62S, p.G126R, p.T170I and p.A529T) in C9 in age-related macular degeneration patients. Those genetic variants affect only the secretion and polymerization of C9, without influencing its classical lytic activity. (PMID:29767720)
• The data supports the assumption that C9 gene expression may stimulate the expression of inflammatory (NLRP3) and angiogenic growth factors (VEGF) in retinal pigment epithelial cells. (PMID:30090015)
• The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade. (PMID:33783477)
• The function of adipsin and C9 protein in the complement system in HIV-associated preeclampsia. (PMID:33881585)
• Hepatitis B virus suppresses complement C9 synthesis by limiting the availability of transcription factor USF-1 and inhibits formation of membrane attack complex: implications in disease pathogenesis. (PMID:36376872)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	c9	ENSDARG00000016319
mus_musculus	C9	ENSMUSG00000022149
rattus_norvegicus	C9	ENSRNOG00000013736

Paralogs (39): CFH (ENSG00000000971), SELE (ENSG00000007908), C8B (ENSG00000021852), C6 (ENSG00000039537), SEZ6 (ENSG00000063015), CFHR2 (ENSG00000080910), APOH (ENSG00000091583), SEZ6L (ENSG00000100095), SUSD6 (ENSG00000100647), SRPX (ENSG00000101955), SRPX2 (ENSG00000102359), C7 (ENSG00000112936), PAPPA2 (ENSG00000116183), CFHR3 (ENSG00000116785), CR2 (ENSG00000117322), CD46 (ENSG00000117335), CSMD2 (ENSG00000121904), C4BPA (ENSG00000123838), C4BPB (ENSG00000123843), CFHR4 (ENSG00000134365), CFHR5 (ENSG00000134389), F13B (ENSG00000143278), SUSD4 (ENSG00000143502), C8A (ENSG00000157131), SUSD3 (ENSG00000157303), CSMD3 (ENSG00000164796), SVEP1 (ENSG00000165124), C2 (ENSG00000166278), SELP (ENSG00000174175), SEZ6L2 (ENSG00000174938), PRF1 (ENSG00000180644), PAPPA (ENSG00000182752), CSMD1 (ENSG00000183117), SELL (ENSG00000188404), CD55 (ENSG00000196352), CR1L (ENSG00000197721), CR1 (ENSG00000203710), CFB (ENSG00000243649), CFHR1 (ENSG00000244414)

Protein

Protein identifiers

Complement component C9 — P02748 (reviewed: P02748)

All UniProt accessions (4): P02748, A0A8Q3SI37, A0A8Q3SI39, A0A8Q3SI95

UniProt curated annotations — full annotation on UniProt →

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. The MAC is initiated by proteolytic cleavage of C5 into complement C5b in response to the classical, alternative, lectin and GZMK complement pathways. The complement pathways consist in a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system. Constitutes the pore-forming subunit of the MAC complex: during MAC assembly, C9 associates with the C5b8 intermediate complex, and polymerizes to complete the pore.

Subunit / interactions. Homooligomer; about 20 C9 chains oligomerize to give rise to a huge beta-barrel that forms a 100 Angstrom diameter pore in target membranes. Component of the membrane attack complex (MAC), composed of complement C5b, C6, C7, C8A, C8B, C8G and multiple copies of the pore-forming subunit C9.

Subcellular location. Secreted. Target cell membrane.

Tissue specificity. Plasma (at protein level).

Post-translational modifications. Thrombin cleaves factor C9 to produce C9a and C9b. Phosphorylation sites are present in the extracellular medium. Initially, positions and connectivity of disulfide bonds were based on peptide sequencing done for the human protein. The crystal structures for the human and mouse proteins corrected the positions and connectivities of the disulfide bonds. The distance between Cys-57 and Cys-94 in the monomeric mouse protein precludes formation of a disulfide bond, contrary to what is seen in the structure of the human polymeric form of the protein.

Disease relevance. 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 dermatomyositis. Disease susceptibility is associated with variants affecting the gene represented in this entry. Macular degeneration, age-related, 15 (ARMD15) [MIM:615591] A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. Membrane attack complex (MAC) assembly is inhibited by CD59, thereby protecting self-cells from damage during complement activation. CD59 acts by preventing incorporation of the multiple copies of C9 required for complete formation of the osmolytic pore. MAC assembly is also inhibited by clusterin (CLU) chaperones that inhibit polymerization of C9. Specifically inhibited by the antibody aE11, thereby inhibiting MAC assembly.

Similarity. Belongs to the complement C6/C7/C8/C9 family.

RefSeq proteins (1): NP_001728* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000884	TSP1_rpt	Repeat
IPR001862	MAC_perforin	Family
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR020863	MACPF_CS	Conserved_site
IPR020864	MACPF	Domain
IPR023415	LDLR_class-A_CS	Conserved_site
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR036383	TSP1_rpt_sf	Homologous_superfamily

Pfam: PF00057, PF00090, PF01823

UniProt features (77 total): strand 18, disulfide bond 11, helix 10, sequence variant 7, mutagenesis site 6, turn 5, domain 4, glycosylation site 4, transmembrane region 4, chain 3, sequence conflict 3, signal peptide 1, site 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
8DE6	ELECTRON MICROSCOPY	3.2
7NYD	ELECTRON MICROSCOPY	3.27
8B0G	ELECTRON MICROSCOPY	3.3
8B0H	ELECTRON MICROSCOPY	3.3
7NYC	ELECTRON MICROSCOPY	3.54
6DLW	ELECTRON MICROSCOPY	3.9
6H03	ELECTRON MICROSCOPY	5.6
6H04	ELECTRON MICROSCOPY	5.6
5FMW	ELECTRON MICROSCOPY	6.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P02748-F1	79.32	0.40

Antibody-complex structures (SAbDab): 1 — 8DE6

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 265–266 (cleavage; by thrombin)

Disulfide bonds (11): 43–78, 54–88, 57–94, 101–112, 107–125, 119–134, 142–181, 380–405, 510–526, 513–528, 530–539

Glycosylation sites (4): 48, 51, 277, 415

Mutagenesis-validated functional residues (6):

Position	Phenotype
86–93	abolished inhibition by the antibody ae11.
86	slightly reduced inhibition by the antibody ae11.
89	reduced inhibition by the antibody ae11.
93	does not affect inhibition by the antibody ae11.
283	creates an artifactual disulfide bond that prevents the conformation change required for oligomerization and pore format
426	creates an artifactual disulfide bond that prevents the conformation change required for oligomerization and pore format

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-166665	Terminal pathway of complement
R-HSA-977606	Regulation of Complement cascade

MSigDB gene sets: 167 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, MODULE_64, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_B_CELL_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_IMMUNE_RESPONSE, MODULE_75, GOBP_COMPLEMENT_ACTIVATION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, KEGG_PRION_DISEASES, GOBP_COMPLEMENT_ACTIVATION_ALTERNATIVE_PATHWAY, HSIAO_LIVER_SPECIFIC_GENES, CAIRO_HEPATOBLASTOMA_DN

GO Biological Process (12): cell killing (GO:0001906), complement activation (GO:0006956), complement activation, alternative pathway (GO:0006957), complement activation, classical pathway (GO:0006958), killing of cells of another organism (GO:0031640), positive regulation of immune response (GO:0050778), protein homooligomerization (GO:0051260), transmembrane transport (GO:0055085), complement activation, GZMK pathway (GO:0160257), immune system process (GO:0002376), immune response (GO:0006955), innate immune response (GO:0045087)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (9): extracellular region (GO:0005576), membrane attack complex (GO:0005579), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), other organism cell membrane (GO:0044218), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), membrane (GO:0016020), transmembrane transporter complex (GO:1902495)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Complement cascade	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
complement activation	3
cellular anatomical structure	3
cellular process	2
innate immune response	2
immune response	2
immune effector process	1
activation of immune response	1
humoral immune response	1
protein activation cascade	1
humoral immune response mediated by circulating immunoglobulin	1
cell killing	1
disruption of cell in another organism	1
positive regulation of immune system process	1
positive regulation of response to stimulus	1
regulation of immune response	1
protein complex oligomerization	1
transport	1
biological_process	1
immune system process	1
response to stimulus	1
defense response to symbiont	1
binding	1
pore complex	1
plasma membrane protein complex	1
membrane	1
cell periphery	1
other organism part	1
extracellular vesicle	1
extracellular region	1
membrane protein complex	1
transporter complex	1

Protein interactions and networks

STRING

926 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C9	VTN	P01141	895
C9	C5	P01031	752
C9	HSPA9	P30036	730
C9	PRF1	P14222	707
C9	CD59	P13987	630
C9	CFB	P00751	622
C9	CFI	P05156	617
C9	C3	P01024	607
C9	TF	P02787	596
C9	C2	P06681	569
C9	APOE	P02649	565
C9	AHSG	P02765	550
C9	CFH	P08603	548
C9	C4A	P01028	507
C9	HSP90AA1	P07900	486

IntAct

18 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
C9	APOE	psi-mi:“MI:0914”(association)	0.560
SOD1	C9	psi-mi:“MI:0915”(physical association)	0.560
C9	APOE	psi-mi:“MI:0915”(physical association)	0.560
C5	C9	psi-mi:“MI:0915”(physical association)	0.550
MPO	C9	psi-mi:“MI:0915”(physical association)	0.400
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
AGPAT1	A2ML1	psi-mi:“MI:0914”(association)	0.350
RHBDD1	A2ML1	psi-mi:“MI:0914”(association)	0.350
UBE2U	IGLL5	psi-mi:“MI:0914”(association)	0.350
KLK10	IGLL5	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
	C5	psi-mi:“MI:0915”(physical association)	0.320

BioGRID (21): C9 (Two-hybrid), APOE (Affinity Capture-MS), CST6 (Affinity Capture-MS), C9 (Reconstituted Complex), C9 (Affinity Capture-MS), C9 (Reconstituted Complex), C9 (Affinity Capture-MS), CD59 (Reconstituted Complex), APOE (Affinity Capture-MS), C9 (Affinity Capture-MS), C9 (Affinity Capture-MS), C9 (Affinity Capture-MS), C9 (Affinity Capture-MS), C9 (Affinity Capture-MS), C9 (Affinity Capture-MS)

ESM2 similar proteins: A0A0D3QS97, A1L314, D3YXF5, E7F0Z8, O75339, P02748, P06682, P06683, P07357, P07358, P10643, P10820, P35763, P48747, P48770, P51578, P55314, P79755, P98136, P98137, Q2KJC3, Q2M385, Q3MHN2, Q3V5L5, Q5RBP9, Q62930, Q64663, Q66K08, Q66S13, Q66S17, Q66S21, Q66S25, Q6UX71, Q765H6, Q8BG22, Q8BH35, Q8K182, Q8L612, Q8N2E2, Q90X85

Diamond homologs: P02748, P06682, P06683, P07357, P48747, P48770, P56677, P79755, Q04833, Q0IIH7, Q3MHN2, Q5RAD0, Q62930, Q924X6, Q9NZR2, P55314, P61134, P61135, P98136, Q8BH35, Q8K182, P0DSP1, P35950, P98165, Q28832, Q5R662, Q8BUJ9, Q95209, Q9Y561, H9J9M0, P35446, Q29RU4, Q8VCC9, Q9GLX9, Q9HCB6, Q9W770, G3V928, P98155, P98156, P98157

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
C9	“form complex”	“Membrane attack complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

434 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	31
Likely pathogenic	7
Uncertain significance	195
Likely benign	156
Benign	14

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074589	NM_001737.5(C9):c.787del (p.Ser263fs)	Pathogenic
1352973	NM_001737.5(C9):c.488T>G (p.Leu163Ter)	Pathogenic
1368067	NM_001737.5(C9):c.1073dup (p.Ile359fs)	Pathogenic
1371814	NM_001737.5(C9):c.803del (p.Gly268fs)	Pathogenic
1385789	NM_001737.5(C9):c.1336C>T (p.Arg446Ter)	Pathogenic
1451163	NM_001737.5(C9):c.1321A>T (p.Lys441Ter)	Pathogenic
1452941	NM_001737.5(C9):c.1419del (p.Ser474fs)	Pathogenic
1457056	NM_001737.5(C9):c.898G>T (p.Glu300Ter)	Pathogenic
17043	NM_001737.5(C9):c.1280C>G (p.Ser427Ter)	Pathogenic
1924368	NM_001737.5(C9):c.423dup (p.Cys142fs)	Pathogenic
1927393	NM_001737.5(C9):c.46del (p.Glu15_Ile16insTer)	Pathogenic
1957236	NM_001737.5(C9):c.1373G>A (p.Trp458Ter)	Pathogenic
1963532	NM_001737.5(C9):c.214C>T (p.Gln72Ter)	Pathogenic
2033505	NM_001737.5(C9):c.415del (p.Arg139fs)	Pathogenic
2057844	NM_001737.5(C9):c.256C>T (p.Arg86Ter)	Pathogenic
2114100	NM_001737.5(C9):c.1189G>T (p.Gly397Ter)	Pathogenic
2701350	NM_001737.5(C9):c.858_863del (p.Tyr286_Ser288delinsTer)	Pathogenic
2730113	NM_001737.5(C9):c.851del (p.Leu284fs)	Pathogenic
2771601	NM_001737.5(C9):c.143G>A (p.Trp48Ter)	Pathogenic
29659	NM_001737.5(C9):c.1583G>A (p.Cys528Tyr)	Pathogenic
2997144	NM_001737.5(C9):c.852del (p.Leu284fs)	Pathogenic
3638707	NM_001737.5(C9):c.191C>G (p.Ser64Ter)	Pathogenic
3645357	NM_001737.5(C9):c.275_276del (p.Glu92fs)	Pathogenic
3681705	NM_001737.5(C9):c.887del (p.His296fs)	Pathogenic
3684939	NM_001737.5(C9):c.449_450del (p.Glu149_Ser150insTer)	Pathogenic
3715577	NM_001737.5(C9):c.122_134del (p.Ile41fs)	Pathogenic
3721558	NM_001737.5(C9):c.291dup (p.Glu98Ter)	Pathogenic
4702380	NM_001737.5(C9):c.651C>G (p.Tyr217Ter)	Pathogenic
4780004	NM_001737.5(C9):c.274G>T (p.Glu92Ter)	Pathogenic
58094	GRCh38/hg38 5p13.2-13.1(chr5:37016043-39383281)x3	Pathogenic

SpliceAI

1899 predictions. Top by Δscore:

Variant	Effect	Δscore
5:39288849:CA:C	donor_gain	1.0000
5:39288949:CAG:C	acceptor_gain	1.0000
5:39306611:TCTTA:T	donor_loss	1.0000
5:39306612:CTTA:C	donor_loss	1.0000
5:39306613:TTA:T	donor_loss	1.0000
5:39306614:TACT:T	donor_loss	1.0000
5:39306615:A:AC	donor_gain	1.0000
5:39306615:A:C	donor_loss	1.0000
5:39306616:C:CG	donor_gain	1.0000
5:39306616:CT:C	donor_gain	1.0000
5:39306616:CTT:C	donor_gain	1.0000
5:39306616:CTTT:C	donor_gain	1.0000
5:39306618:TTTTG:T	donor_gain	1.0000
5:39306788:GTTTA:G	acceptor_gain	1.0000
5:39306789:TTTA:T	acceptor_gain	1.0000
5:39306790:TTA:T	acceptor_gain	1.0000
5:39306791:TA:T	acceptor_gain	1.0000
5:39306792:AC:A	acceptor_loss	1.0000
5:39306793:C:CC	acceptor_gain	1.0000
5:39306793:CTG:C	acceptor_loss	1.0000
5:39306812:T:C	acceptor_gain	1.0000
5:39311250:C:CA	donor_gain	1.0000
5:39315842:C:A	donor_gain	1.0000
5:39316030:C:CC	acceptor_gain	1.0000
5:39331669:GACTT:G	donor_loss	1.0000
5:39331670:ACTT:A	donor_loss	1.0000
5:39331671:CTT:C	donor_loss	1.0000
5:39331672:TTA:T	donor_loss	1.0000
5:39331673:TACT:T	donor_loss	1.0000
5:39331674:A:AC	donor_gain	1.0000

AlphaMissense

3694 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:39331749:C:G	C181S	0.998
5:39331750:A:T	C181S	0.998
5:39342121:C:A	W51C	0.998
5:39342121:C:G	W51C	0.998
5:39306659:C:A	W458C	0.997
5:39306659:C:G	W458C	0.997
5:39331697:G:C	N198K	0.997
5:39331697:G:T	N198K	0.997
5:39341248:C:G	C125S	0.996
5:39341249:A:T	C125S	0.996
5:39341696:C:G	R63P	0.996
5:39342130:C:A	W48C	0.996
5:39342130:C:G	W48C	0.996
5:39331749:C:T	C181Y	0.995
5:39341197:C:G	C142S	0.995
5:39341198:A:T	C142S	0.995
5:39288839:C:G	C510S	0.994
5:39288840:A:T	C510S	0.994
5:39331749:C:A	C181F	0.994
5:39341247:G:C	C125W	0.994
5:39341248:C:T	C125Y	0.994
5:39341564:C:G	C107S	0.994
5:39341565:A:T	C107S	0.994
5:39342123:A:G	W51R	0.994
5:39342123:A:T	W51R	0.994
5:39288752:C:G	C539S	0.993
5:39288753:A:T	C539S	0.993
5:39331750:A:G	C181R	0.993
5:39341266:C:G	C119S	0.993
5:39341267:A:T	C119S	0.993

dbSNP variants (sampled 300 via entrez): RS1000001174 (5:39303071 C>G,T), RS1000030496 (5:39328371 A>G), RS1000031318 (5:39291849 G>A), RS1000064277 (5:39333583 C>T), RS1000071635 (5:39333456 T>TATCCCAGTG), RS1000140935 (5:39286203 C>T), RS1000167921 (5:39311070 G>A,C), RS1000178721 (5:39333736 C>A,G,T), RS1000257459 (5:39285891 G>A,C), RS1000284596 (5:39322756 T>C), RS1000349677 (5:39339945 C>A,T), RS1000474146 (5:39287564 G>A,T), RS1000474773 (5:39287818 T>C), RS1000510224 (5:39335289 G>A), RS1000519334 (5:39348516 A>G)

Disease associations

OMIM: gene MIM:120940 | disease phenotypes: MIM:613825, MIM:615591

GenCC curated gene-disease

Disease	Classification	Inheritance
complement component 9 deficiency	Strong	Autosomal recessive

Mondo (2): complement component 9 deficiency (MONDO:0013445), age related macular degeneration 15 (MONDO:0014266)

Orphanet (0):

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000608	Macular degeneration
HP:0003581	Adult onset
HP:0012308	Decreased circulating complement C9 concentration

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000649_22	Chronic kidney disease	1.000000e-07
GCST003219_21	Advanced age-related macular degeneration	1.000000e-14
GCST004867_32	Systemic lupus erythematosus	8.000000e-06
GCST006585_1728	Blood protein levels	7.000000e-10
GCST006585_1729	Blood protein levels	6.000000e-10
GCST006585_2841	Blood protein levels	5.000000e-09
GCST008513_9	Health literacy	8.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:1001492	atrophic macular degeneration
EFO:0010104	health literacy measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C565165	C9 Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295693 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.30	IC50	500	nM	CHEMBL4238111
6.30	IC50	500	nM	CHEMBL4242254
6.30	IC50	500	nM	AURINTRICARBOXYLIC ACID

PubChem BioAssay actives

3 with measured affinity, of 3 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
5-[(3-carboxy-4-hydroxyphenyl)-(3-carboxy-4-oxocyclohexa-2,5-dien-1-ylidene)methyl]-2-hydroxybenzoic acid	1393236: Inhibition of C9 binding to C5b678 in zymogen activated human serum assessed as suppression of human erythrocyte lysis after 1 hr by ELISA	ic50	0.5000	uM
5-[bis(3-carboxy-4-hydroxyphenyl)methyl]-3-[(Z)-(3-carboxy-4-oxocyclohexa-2,5-dien-1-ylidene)methyl]-2-hydroxybenzoic acid	1393236: Inhibition of C9 binding to C5b678 in zymogen activated human serum assessed as suppression of human erythrocyte lysis after 1 hr by ELISA	ic50	0.5000	uM
5-[[5-[bis(3-carboxy-4-hydroxyphenyl)methyl]-3-carboxy-2-hydroxyphenyl]methyl]-3-[(Z)-(3-carboxy-4-hydroxyphenyl)-(3-carboxy-4-oxocyclohexa-2,5-dien-1-ylidene)methyl]-2-hydroxybenzoic acid	1393236: Inhibition of C9 binding to C5b678 in zymogen activated human serum assessed as suppression of human erythrocyte lysis after 1 hr by ELISA	ic50	0.5000	uM

CTD chemical–gene interactions

45 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
fluxapyroxad	decreases expression	1
ginger extract	increases abundance, affects cotreatment, affects expression	1
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, decreases expression	1
bisphenol A	affects cotreatment, affects expression, increases abundance	1
chlortoluron	decreases expression	1
hydroxyhydroquinone	increases expression	1
perfluorooctanoic acid	decreases expression	1
ochratoxin A	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
perfluorooctane sulfonic acid	increases expression	1
tebuconazole	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Olanzapine	affects phosphorylation	1
Fulvestrant	increases methylation	1
Bosentan	affects expression	1
Arsenic	affects expression, increases abundance	1
Cacodylic Acid	affects expression, increases abundance	1
Chenodeoxycholic Acid	affects cotreatment, decreases expression	1
Cholic Acids	affects cotreatment, affects expression	1
Copper	affects binding	1
Deoxycholic Acid	affects cotreatment, decreases expression	1
Glycochenodeoxycholic Acid	affects cotreatment, decreases expression	1
Glycocholic Acid	affects cotreatment, decreases expression	1
Glycodeoxycholic Acid	decreases expression, affects cotreatment	1
Gold	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4229706	Binding	Inhibition of C9 binding to C5b678 in zymogen activated human serum assessed as suppression of human erythrocyte lysis after 1 hr by ELISA	Chemical Approaches to Modulating Complement-Mediated Diseases. — J Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.