C8G

Summary

C8G (complement C8 gamma chain, HGNC:1354) is a protein-coding gene on chromosome 9q34.3, encoding Complement component C8 gamma chain (P07360). 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 protein encoded by this gene belongs to the lipocalin family. It is one of the three subunits that constitutes complement component 8 (C8), which is composed of a disulfide-linked C8 alpha-gamma heterodimer and a non-covalently associated C8 beta chain. C8 participates in the formation of the membrane attack complex (MAC) on bacterial cell membranes. While subunits alpha and beta play a role in complement-mediated bacterial killing, the gamma subunit is not required for the bactericidal activity.

Source: NCBI Gene 733 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 100 total
• GTEx eGene: eQTL in 19 tissues, sQTL in 3 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.81 (unconstrained)
• MANE Select transcript: NM_000606
• Notable: 100 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1354
Approved symbol	C8G
Name	complement C8 gamma chain
Location	9q34.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000176919
Ensembl biotype	protein_coding
OMIM	120930
Entrez	733

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 16 protein_coding, 11 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000371634

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 3: 3

ENST00000371634, ENST00000465773, ENST00000484376, ENST00000647910, ENST00000649480, ENST00000649755, ENST00000870160, ENST00000870161, ENST00000870162, ENST00000870163, ENST00000870164, ENST00000870165, ENST00000870166, ENST00000870167, ENST00000870168, ENST00000870169, ENST00000870170, ENST00000870171, ENST00000870172, ENST00000978744, ENST00000978745, ENST00000978746, ENST00000978749, ENST00000978750, ENST00000978752, ENST00000978753, ENST00001043835, ENST00001043836, ENST00001105881, ENST00001137001

RefSeq mRNA: 1 — MANE Select: NM_000606 NM_000606

CCDS: CCDS7017

Canonical transcript exons

ENST00000371634 — 7 exons

Exon	Start	End
ENSE00000734162	136945243	136945458
ENSE00000734163	136945634	136945770
ENSE00000734168	136946085	136946192
ENSE00000734170	136946465	136946566
ENSE00001194952	136945929	136945999
ENSE00003686215	136946651	136946689
ENSE00003831539	136946768	136946975

Expression profiles

Bgee: expression breadth ubiquitous, 164 present calls, max score 99.51.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.2664 / max 845.4551, expressed in 59 samples.

Highest expression (Bgee): lobe of liver, liver, primordial germ cell in gonad, duodenum, jejunal mucosa.

Genetic regulation across tissues (GTEx eQTL / sQTL)

C8G is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 19 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 22 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Liver	sqtl	4.7e-37	+0.86	9:136946019:G:T
Testis	sqtl	1.0e-18	+0.93	9:136946019:G:T
Muscle Skeletal	sqtl	1.9e-16	+0.48	9:136946019:G:T
Thyroid	eqtl	9.8e-11	+0.26	9:136933872:G:A
Skin Sun Exposed Lower leg	eqtl	2.8e-07	+0.28	9:136927584:G:C
Skin Not Sun Exposed Suprapubic	eqtl	1.5e-06	+0.28	9:136933872:G:A
Whole Blood	eqtl	1.5e-06	-0.20	9:136964428:G:T
Pituitary	eqtl	4.6e-05	+0.33	9:136926401:A:AGG
Artery Tibial	eqtl	3.4e-03	-0.59	9:136207096:G:A
Liver	eqtl	3.6e-03	+0.24	9:136965502:C:T
Esophagus Gastroesophageal Junction	eqtl	4.1e-03	-0.91	9:136944376:C:T
Esophagus Muscularis	eqtl	4.2e-03	+1.07	9:136877413:G:A
Artery Aorta	eqtl	4.6e-03	+0.30	9:136920601:G:A
Spleen	eqtl	6.2e-03	-0.29	9:136969389:C:T
Heart Atrial Appendage	eqtl	6.5e-03	+0.98	9:137473498:G:A
Adrenal Gland	eqtl	1.4e-02	-1.51	9:137065785:G:A
Esophagus Mucosa	eqtl	1.9e-02	+0.15	9:136932498:A:G
Adipose Subcutaneous	eqtl	2.0e-02	+0.92	9:136877413:G:A
Minor Salivary Gland	eqtl	2.0e-02	+0.46	9:136842005:A:G
Lung	eqtl	2.7e-02	-0.91	9:137437747:A:AC

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
99590	1.3284	48
99592	0.5861	34
99591	0.3292	31
99589	0.0226	9

Top tissues by expression

showing 100 of 291 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.51	gold quality
liver	UBERON:0002107	96.45	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.26	gold quality
duodenum	UBERON:0002114	90.42	gold quality
jejunal mucosa	UBERON:0000399	86.48	gold quality
lower esophagus mucosa	UBERON:0035834	86.03	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.11	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.11	gold quality
gastrocnemius	UBERON:0001388	83.81	gold quality
granulocyte	CL:0000094	82.31	gold quality
mucosa of transverse colon	UBERON:0004991	81.64	gold quality
muscle of leg	UBERON:0001383	81.00	gold quality
gall bladder	UBERON:0002110	80.91	gold quality
left testis	UBERON:0004533	79.04	gold quality
right testis	UBERON:0004534	78.93	gold quality
small intestine Peyer’s patch	UBERON:0003454	78.81	gold quality
small intestine	UBERON:0002108	78.56	gold quality
spleen	UBERON:0002106	77.01	gold quality
apex of heart	UBERON:0002098	75.74	gold quality
testis	UBERON:0000473	75.19	gold quality
transverse colon	UBERON:0001157	73.53	gold quality
heart left ventricle	UBERON:0002084	72.84	gold quality
muscle organ	UBERON:0001630	72.68	gold quality
right adrenal gland cortex	UBERON:0035827	72.43	gold quality
right lobe of thyroid gland	UBERON:0001119	72.34	gold quality
left adrenal gland cortex	UBERON:0035825	72.10	gold quality
left lobe of thyroid gland	UBERON:0001120	71.93	gold quality
right hemisphere of cerebellum	UBERON:0014890	71.93	gold quality
cardiac ventricle	UBERON:0002082	71.77	gold quality
adenohypophysis	UBERON:0002196	71.49	gold quality
cerebellar hemisphere	UBERON:0002245	71.13	gold quality
right atrium auricular region	UBERON:0006631	70.90	gold quality
cerebellar cortex	UBERON:0002129	70.88	gold quality
right adrenal gland	UBERON:0001233	70.82	gold quality
pituitary gland	UBERON:0000007	70.59	gold quality
popliteal artery	UBERON:0002250	70.33	gold quality
tibial artery	UBERON:0007610	70.32	gold quality
thyroid gland	UBERON:0002046	70.02	gold quality
esophagus mucosa	UBERON:0002469	69.97	gold quality
adrenal cortex	UBERON:0001235	69.95	gold quality
metanephros cortex	UBERON:0010533	69.88	gold quality
left adrenal gland	UBERON:0001234	69.62	gold quality
right frontal lobe	UBERON:0002810	69.30	gold quality
cardiac atrium	UBERON:0002081	69.09	gold quality
stromal cell of endometrium	CL:0002255	68.77	gold quality
cerebellum	UBERON:0002037	68.20	gold quality
right lung	UBERON:0002167	68.19	gold quality
heart	UBERON:0000948	68.05	gold quality
aorta	UBERON:0000947	67.87	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	67.87	gold quality
body of stomach	UBERON:0001161	67.75	gold quality
ectocervix	UBERON:0012249	67.58	gold quality
leukocyte	CL:0000738	67.49	gold quality
esophagus	UBERON:0001043	67.49	gold quality
intestine	UBERON:0000160	67.40	gold quality
left uterine tube	UBERON:0001303	67.36	gold quality
monocyte	CL:0000576	67.30	gold quality
tibial nerve	UBERON:0001323	67.23	gold quality
minor salivary gland	UBERON:0001830	67.21	gold quality
mononuclear cell	CL:0000842	67.14	gold quality
rectum	UBERON:0001052	67.14	gold quality
skin of abdomen	UBERON:0001416	67.07	gold quality
right uterine tube	UBERON:0001302	67.00	gold quality
adrenal gland	UBERON:0002369	66.97	gold quality
skin of leg	UBERON:0001511	66.52	gold quality
left coronary artery	UBERON:0001626	66.32	gold quality
body of uterus	UBERON:0009853	66.12	gold quality
right coronary artery	UBERON:0001625	65.89	gold quality
jejunum	UBERON:0002115	65.86	gold quality
upper lobe of left lung	UBERON:0008952	65.82	gold quality
cingulate cortex	UBERON:0003027	65.75	gold quality
lower esophagus	UBERON:0013473	65.66	gold quality
omental fat pad	UBERON:0010414	65.60	gold quality
lower esophagus muscularis layer	UBERON:0035833	65.56	gold quality
Brodmann (1909) area 9	UBERON:0013540	65.55	gold quality
amygdala	UBERON:0001876	65.54	gold quality
peritoneum	UBERON:0002358	65.53	gold quality
anterior cingulate cortex	UBERON:0009835	65.44	gold quality
body of pancreas	UBERON:0001150	65.41	gold quality
spinal cord	UBERON:0002240	65.13	gold quality
endocervix	UBERON:0000458	65.01	gold quality
putamen	UBERON:0001874	65.00	gold quality
thoracic aorta	UBERON:0001515	64.97	gold quality
ascending aorta	UBERON:0001496	64.94	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	64.94	gold quality
coronary artery	UBERON:0001621	64.87	gold quality
colon	UBERON:0001155	64.83	gold quality
adult mammalian kidney	UBERON:0000082	64.79	gold quality
adipose tissue of abdominal region	UBERON:0007808	64.23	gold quality
muscle layer of sigmoid colon	UBERON:0035805	64.15	gold quality
large intestine	UBERON:0000059	64.10	gold quality
nucleus accumbens	UBERON:0001882	63.80	gold quality
caudate nucleus	UBERON:0001873	63.77	gold quality
mouth mucosa	UBERON:0003729	63.69	gold quality
descending thoracic aorta	UBERON:0002345	63.66	gold quality
vagina	UBERON:0000996	63.50	gold quality
saliva-secreting gland	UBERON:0001044	63.50	gold quality
upper lobe of lung	UBERON:0008948	63.44	gold quality
anatomical system	UBERON:0000467	63.42	gold quality
lymph node	UBERON:0000029	63.32	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-HCAD-9	yes	57.40
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enriched

56 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	126.5	not detected
Duodenum	tissue	29.3	not detected
Small intestine	tissue	16.8	not detected
Corpus callosum	tissue	5.4
Spinal cord	tissue	4.1
Medulla oblongata	tissue	3.4
Midbrain	tissue	2.7
Substantia nigra	tissue	2.7
Thalamus	tissue	2.4
Superior colliculi	tissue	2.4
Gallbladder	tissue	2.3	not detected
Pons	tissue	2.1
Putamen	tissue	2.0
Ventral forebrain	tissue	2.0
Periaqueductal gray	tissue	2.0
Olfactory bulb	tissue	1.8
Frontal cortex	tissue	1.7
Cerebral cortex	tissue	1.6	not detected
Amygdala	tissue	1.6
Hypothalamus	tissue	1.6
Cerebellum	tissue	1.6	not detected
Hippocampal formation	tissue	1.6
Retrosplenial cortex	tissue	1.6
Insular cortex	tissue	1.6
Basal ganglia	tissue	1.5	not detected
Septum	tissue	1.5
Retrosplenial and cingulate cortex	tissue	1.4
Temporal cortex	tissue	1.4
Motor cortex	tissue	1.3
Entorhinal cortex	tissue	1.3
Somatosensory cortex	tissue	1.3
Occipital cortex	tissue	1.3
Prefrontal cortex	tissue	1.2
Stomach 1	tissue	1.2	not detected
Colon	tissue	1.2	not detected
Caudate putamen	tissue	1.0
Epididymis	tissue	0.9	not detected
Testis	tissue	0.5	medium
Spleen	tissue	0.5	not detected
Pituitary gland	tissue	0.4
Heart muscle	tissue	0.3	not detected
Rectum	tissue	0.3	not detected
Locus coeruleus	tissue	0.3
Hippocampus	tissue	0.3	not detected
Adrenal gland	tissue	0.3	not detected
Postcentral gyrus	tissue	0.3
Vagina	tissue	0.2	not detected
Esophagus	tissue	0.2	not detected
Skeletal muscle	tissue	0.2	not detected
Nucleus accumbens	tissue	0.2
Thymus	tissue	0.2
Lymph node	tissue	0.1	not detected
Seminal vesicle	tissue	0.1	not detected
Choroid plexus	tissue	0.1
Kidney	tissue	0.1	not detected
Tonsil	tissue	0.1	not detected

Brain sub-regions (HPA Brain Atlas): detected in 177; highest nTPM — White matter (5.4), Ventral spinal cord (4.1), Dorsal spinal cord (3.4), Dorsal hippocampus (1.6), Ventral hippocampus (1.5).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting C8G by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

4 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-6801-3P	98.04	64.64	805
HSA-MIR-6810-3P	97.96	64.57	1023
HSA-MIR-4329	97.68	66.26	1003

Functional genomics

gnomAD constraint: pLI 4.73e-18, LOEUF 1.81, missense Z -1.14 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000371634 — one region, missense o/e 1.12.

Literature-anchored findings (GeneRIF, showing 9)

• Binding of C8 gamma subunit to C8 beta is dependent on the thrombospondin type 1 module + low-density lipoprotein receptor class A module + membrane attack complex/perforin domain of C8 beta. (PMID:12220191)
• C8 alpha and C8 beta have correspondingly similar roles in MAC-mediated lysis of erythrocytes and bacterial killing. C8 gamma is not required for complement-mediated killing of Gram-negative bacteria. (PMID:12413696)
• results indicate that the principal binding site for C9 lies within the MACPF domain of C8alpha; they also suggest this site and the binding sites for C8beta and C8gamma are distinct (PMID:16618117)
• One can predict that the indel segment of C8alpha assumes a conformation that allows for multiple points of contact with C8gamma. (PMID:16935577)
• structure of a C8gamma.laurate complex revealed Y83 and Y131 can move to allow penetration of hydrocarbon chain of laurate into the lower cavity. A Y83W mutation blocked access but had no effect on the ability of C8gamma to enhance C8 cytolytic activity (PMID:17452033)
• Results describe the crystal structure of the human C8 alpha MACPF domain disulfide-linked to C8 gamma (alphaMACPF-gamma) at 2.15 A resolution. (PMID:18440555)
• C8gamma binds an indel peptide of C8alpha sequence and forms a non-covalent complex. (PMID:19048311)
• These data provide a detailed specification of co-occurring C8 proteoforms, including experimental evidence on N-glycosylation, C-mannosylation, and O-glycosylation. (PMID:29532326)
• Elevated complement component 8 gamma levels in astrocyte-derived exosomes are associated with cognitive impairment in obstructive sleep apnea patients without dementia. (PMID:36509166)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	c8g	ENSDARG00000032098
mus_musculus	C8g	ENSMUSG00000015083
rattus_norvegicus	C8g	ENSRNOG00000028701

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Oryctolagus cuniculus	Q28679	76.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
FBXW5	protein-coding	54461
TRAF2	protein-coding	7186
EDF1	protein-coding	8721
LCN12	protein-coding	286256
PTGDS	protein-coding	5730
MIR4479	ncRNA	100616480
LINC02692	ncRNA	101928638
MAMDC4	protein-coding	158056

Protein

Protein identifiers

Complement component C8 gamma chain — P07360 (reviewed: P07360)

All UniProt accessions (3): A0A3B3ITK5, A0A3B3ITY0, P07360

UniProt curated annotations — full annotation on UniProt →

Function. 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. C8G, together with C8A and C8B, inserts into the target membrane, but does not form pores by itself. During MAC assembly, associates with C5b, C6 and C7 to form the C5b8 intermediate complex that inserts into the target membrane and traverses the bilayer increasing membrane rigidity.

Subunit / interactions. Heterotrimer of 3 chains: alpha (C8A), beta (C8B) and gamma (C8G); the alpha and gamma chains are disulfide bonded. 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.

Activity regulation. Membrane attack complex (MAC) assembly is inhibited by CD59, thereby protecting self-cells from damage during complement activation. MAC assembly is also inhibited by clusterin (CLU) chaperones that inhibit polymerization of C9.

Similarity. Belongs to the calycin superfamily. Lipocalin family.

RefSeq proteins (1): NP_000597* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000566	Lipocln_cytosolic_FA-bd_dom	Domain
IPR002968	A1-microglobln	Family
IPR012674	Calycin_sf	Homologous_superfamily
IPR022272	Lipocalin_CS	Conserved_site
IPR043245	C8G	Family

Pfam: PF00061

UniProt features (28 total): strand 11, helix 9, sequence variant 3, disulfide bond 2, signal peptide 1, chain 1, modified residue 1

Structure

Experimental structures (PDB)

15 structures by resolution:

PDB	Title	Method	Resolution (Å)
1LF7	Crystal Structure of Human Complement Protein C8gamma at 1.2 A Resolution	X-RAY DIFFRACTION	1.2
2OVA	X-ray structure of Human Complement Protein C8gamma Y83W Mutant	X-RAY DIFFRACTION	1.5
2OVD	Crystal Structure of Human Complement Protein C8gamma with Laurate	X-RAY DIFFRACTION	1.8
2QOS	Crystal structure of complement protein C8 in complex with a peptide containing the C8 …	X-RAY DIFFRACTION	1.81
1IW2	X-ray structure of Human Complement Protein C8gamma at pH=7.O	X-RAY DIFFRACTION	1.9
2OVE	Crystal Structure of Recombinant Human Complement Protein C8gamma	X-RAY DIFFRACTION	2
2RD7	Human Complement Membrane Attack Proteins Share a Common Fold with Bacterial Cytolysins	X-RAY DIFFRACTION	2.15
3OJY	Crystal Structure of Human Complement Component C8	X-RAY DIFFRACTION	2.51
8B0F	CryoEM structure of C5b8-CD59	ELECTRON MICROSCOPY	3
7NYD	cryoEM structure of 2C9-sMAC	ELECTRON MICROSCOPY	3.27
8B0G	2C9, C5b9-CD59 structure	ELECTRON MICROSCOPY	3.3
8B0H	2C9, C5b9-CD59 cryoEM structure	ELECTRON MICROSCOPY	3.3
7NYC	cryoEM structure of 3C9-sMAC	ELECTRON MICROSCOPY	3.54
6H03	OPEN CONFORMATION OF THE MEMBRANE ATTACK COMPLEX	ELECTRON MICROSCOPY	5.6
6H04	Closed conformation of the Membrane Attack Complex	ELECTRON MICROSCOPY	5.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07360-F1	90.06	0.78

Human Protein Atlas

Protein class: Predicted secreted proteins, Plasma proteins, Human disease related genes, Primary immunodeficiency

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH approved

Functional residue map

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

Post-translational modifications (1)

Type	Positions
Pyrrolidone carboxylic acid	21

Disulfide bonds (2)

Type	Positions
Interchain (with c-194 in c8-alpha chain)	60
Disulfide bond	96–188

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 5; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

5 pathways:

ID	Pathway	Evidence
R-HSA-977606	Regulation of Complement cascade	curated
R-HSA-166665	Terminal pathway of complement	curated
R-HSA-166658	Complement cascade	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—

MSigDB gene sets: 141 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GNF2_GSTM1, GNF2_HPN, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, SHEPARD_BMYB_MORPHOLINO_DN, GOBP_B_CELL_MEDIATED_IMMUNITY, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_REGULATION_OF_IMMUNE_RESPONSE, MODULE_75, GOBP_COMPLEMENT_ACTIVATION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, KEGG_PRION_DISEASES, GOBP_COMPLEMENT_ACTIVATION_ALTERNATIVE_PATHWAY, GNF2_LCAT

GO Biological Process (9): 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), transmembrane transport (GO:0055085), complement activation, GZMK pathway (GO:0160257), immune system process (GO:0002376), innate immune response (GO:0045087)

GO Molecular Function (3): retinol binding (GO:0019841), protein binding (GO:0005515), wide pore channel activity (GO:0022829)

GO Cellular Component (6): extracellular region (GO:0005576), membrane attack complex (GO:0005579), plasma membrane (GO:0005886), other organism cell membrane (GO:0044218), extracellular exosome (GO:0070062), blood microparticle (GO:0072562)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Complement cascade	2
Innate Immune System	1
Immune System	1

GO top-level categories

30 GO namespaces:

Category	Terms
complement activation	3
innate immune response	2
immune response	2
cellular anatomical structure	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
transport	1
cellular process	1
biological_process	1
defense response to symbiont	1
retinoid binding	1
vitamin binding	1
alcohol binding	1
binding	1
channel activity	1
pore complex	1
plasma membrane protein complex	1
membrane	1
cell periphery	1
other organism part	1
extracellular vesicle	1
extracellular region	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 18 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
complement activation	BP	direct assay
complement activation, GZMK pathway	BP	direct assay
killing of cells of another organism	BP	direct assay
blood microparticle	CC	high-throughput assay
extracellular exosome	CC	high-throughput assay
membrane attack complex	CC	direct assay
other organism cell membrane	CC	direct assay
plasma membrane	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 516 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C8G	C8A	P07357	966
C8G	C8B	P07358	942
C8G	LCN1	P31025	789
C8G	PAEP	P09466	738
C8G	PTGDS	P41222	692
C8G	ORM1	P02763	637
C8G	LCN2	P30150	561
C8G	C4BPA	P04003	554
C8G	HLA-DRB5	Q30154	552
C8G	C1R	P00736	549
C8G	C4BPB	P20851	547
C8G	C4A	P01028	538
C8G	C1S	P09871	514
C8G	PGM1	P36871	506
C8G	CFB	P00751	499

IntAct

Human interaction partners of C8G in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
UBQLN2	physical association	0.560	3
SEC24B	association	0.350	2

BioGRID (14 interactions; top human partners by supporting records): EDEM2 (Affinity Capture-MS; 2 records), S1PR2 (Affinity Capture-MS; 2 records), SEC24B (Affinity Capture-MS; 2 records), SH3GL1 (Affinity Capture-MS; 2 records), TMEM2 (Affinity Capture-MS; 2 records), AGPAT1 (Affinity Capture-MS), C8A (Reconstituted Complex), RHBDD1 (Affinity Capture-MS), UBQLN2 (Two-hybrid)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
C8G	“form complex”	“Membrane attack complex”	binding

Disease & clinical

Genetic variants

Variant evidence for C8G: 100 ClinVar records (0 pathogenic / likely pathogenic); 1 GWAS association.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	45
Likely benign	42
Benign	3

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 35 predictions of 533):

Position(s)	Effect	Δscore	Sites
9:136946193–136946194	donor_loss	1.0000	5
9:136946567–136946568	donor_loss	1.0000	3
9:136945456	donor_gain	0.9900
9:136945459–136945460	donor_loss	0.9900	5
9:136946000–136946001	donor_loss	0.9900	5
9:136946072	acceptor_gain	0.9900
9:136946077	acceptor_gain	0.9900
9:136946083–136946084	acceptor_loss	0.9900	6
9:136946463–136946464	acceptor_loss	0.9900	6
9:136946567	donor_loss	0.9900	2

AlphaMissense

230 missense substitutions predicted likely pathogenic (of 1,284 scored), across 78 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
C96	7	0.944	0.965
C188	7	0.936	0.969
W51	7	0.928	0.984
F165	7	0.909	0.973
F112	7	0.897	0.947
F187	7	0.876	0.974
F182	7	0.873	0.962
W97	7	0.830	0.974
G49	6	0.824	0.942
C60	6	0.783	0.865
F47	5	0.929	0.940
F42	5	0.906	0.929
Y151	5	0.854	0.944
K149	5	0.831	0.944
F194	5	0.831	0.902
D131	5	0.737	0.755
Y185	5	0.729	0.927
P183	5	0.700	0.801
F135	4	0.884	0.934
G110	4	0.857	0.878

HPA cancer prognostics

RNA cancer specificity: Cancer enriched (Liver Hepatocellular Carcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	favorable	0.000325

Disease associations

OMIM: gene MIM:120930 | disease phenotypes:

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (1 panels, 1 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

1 panels:

Panel	Rating
COVID-19 research	green

GWAS associations

1 associations:

Study	Trait	p-value
GCST90013442_14	Keratoconus	1e-11

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	decreases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
aristolochic acid I	increases expression	1
methyleugenol	decreases expression	1
pirinixic acid	decreases expression, increases activity, affects binding	1
decabromobiphenyl ether	decreases expression	1
tributyltin	affects binding, decreases reaction	1
tris(2-butoxyethyl) phosphate	affects expression	1
dibutyldichlorotin	affects binding, affects reaction, increases abundance	1
1-anilino-8-naphthalenesulfonate	affects binding	1
triphenyltin	increases abundance, decreases reaction, affects binding, affects reaction	1
11-(dansylamino)undecanoic acid	affects binding	1
di-n-butyltin	affects binding, affects reaction, increases abundance	1
diphenyltin	increases abundance, affects binding, affects reaction	1
di-n-butylphosphoric acid	affects expression	1
diphenyltin chloride	affects binding, affects reaction, increases abundance	1
triphenyllead chloride	affects binding, decreases reaction	1
abrine	increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
Rosiglitazone	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Troglitazone	decreases expression	1
Acetaminophen	decreases expression	1
Cadmium	affects binding	1
Estradiol	decreases expression	1
Nickel	affects binding	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 250 trials:

NCT	Phase	Status	Title
NCT00001542	Phase 4	COMPLETED	Fluconazole Prophylaxis of Thrush in AIDS
NCT00144157	Phase 4	COMPLETED	Open Label Study of NVP+CBV Treatment in Women Who Have Received sdNVP for the pMTCT of HIV
NCT00162643	Phase 4	UNKNOWN	PI Vs. NNRTI Based Therapy for HIV Advanced Disease
NCT00273988	Phase 4	COMPLETED	Pharmacokinetic Study of Interaction Between Nevirapine and Methadone in HIV-1 Infected, Opioid-dependent Adults
NCT00981318	Phase 4	TERMINATED	Pilot Assessment of Lopinavir/Ritonavir and Maraviroc
NCT01086878	Phase 4	COMPLETED	Safety of Cotrimoxazole in HIV- and HAART-exposed Infants
NCT01090102	Phase 4	COMPLETED	Mesalamine to Reduce T Cell Activation in HIV Infection
NCT01147042	Phase 4	TERMINATED	Biochemical Response to Interferon-Gamma in Subjects With Specific Gene Mutation in Chronic Granulomatous Disease
NCT01230580	Phase 4	UNKNOWN	Protease Inhibitor Monotherapy Versus Ongoing Triple-therapy in the Long Term Management of HIV Infection (PIVOT)
NCT01465958	Phase 4	COMPLETED	Pharmacokinetics, Safety, and Tolerability of Subcutaneous GAMUNEX-C in Pediatric Subjects With Primary Immunodeficiency
NCT02274662	Phase 4	COMPLETED	Expanded Access Protocol Thymus Transplantation
NCT02348177	Phase 4	COMPLETED	Pharmacokinetics of Lopinavir/Ritonavir Superboosting in Infants and Young Children Co-infected With HIV and TB
NCT02396979	Phase 4	COMPLETED	Intervention of HIV, Drug Use and the Criminal Justice System in Malaysia
NCT02490956	Phase 4	UNKNOWN	Diagnostic Immunization With Rabies Vaccine in Patients With PID
NCT02503293	Phase 4	COMPLETED	A Study to Compare Quality of Life and Satisfaction in Primary Immunodeficient Patients Treated With Subcutaneous Injections of Gammanorm® 165 mg/mL Administered With Two Different Delivery Devices: Injections Using Pump or Rapid Push
NCT02881437	Phase 4	COMPLETED	IgG Level in Primary Immunodeficiency Switching From Standard SCIG to Every Other Week HyQvia
NCT03033745	Phase 4	COMPLETED	Safety and Tolerability of Higher Infusion Parameters of IgPro20 (Hizentra) in Subjects With Primary Immunodeficiency (PID)
NCT03677557	Phase 4	UNKNOWN	Safety, Tolerability, Patient Satisfaction and Cost of 16.5% Subcutaneous Immunoglobulin (Cutaquig®) Treatment
NCT04192487	Phase 4	COMPLETED	Effects of Crofelemer on the Gut Microbiome in Healthy Volunteers and in HIV+ Patients With Non-Infectious Diarrhea
NCT04566692	Phase 4	COMPLETED	A Study to Evaluate IGSC 20% Biweekly Dosing in Treatment-Experienced Participants and Loading/Maintenance Dosing in Treatment-Naïve Participants With Primary Immunodeficiency
NCT05493969	Phase 4	UNKNOWN	Efficacy and Tolerability of DTG Plus 3TC in HIV Infected Adults With Virologically Suppression and TDF Toxicity
NCT06576024	Phase 4	COMPLETED	Immunogenicity and Safety of Inactivated Hepatitis A Vaccine in HIV-infected People
NCT06634641	Phase 4	RECRUITING	Clozapine-related Immunodeficiency in Parkinsons Disease
NCT07076446	Phase 4	COMPLETED	An Open-label, Multicenter Study to Assess the Pharmacokinetics (PK), Safety, and Tolerability of Subcutaneous IgPro20 in Immunoglobulin (IG) Treatment-naïve Participants With Primary Immunodeficiency (PID)
NCT00000118	Phase 3	COMPLETED	Ganciclovir Implant Study for Cytomegalovirus Retinitis
NCT00000134	Phase 3	COMPLETED	Studies of the Ocular Complications of AIDS (SOCA)–Cytomegalovirus Retinitis Retreatment Trial (CRRT)
NCT00000590	Phase 3	COMPLETED	Anti-HIV Immunoglobulin (HIVIG) in Prevention of Maternal-Fetal HIV Transmission (Pediatric ACTG Protocol 185)
NCT00001267	Phase 3	COMPLETED	A Randomized Pilot Study for the Treatment of AIDS or AIDS Related Complex With an Alternating or Simultaneous Combination Regimen of AZT and 2’,3’-Dideoxyinosine
NCT00001646	Phase 3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00144183	Phase 3	COMPLETED	A Study of Single Dose Nevirapine (NVP) Combined With Combivir® for the Prevention of Mother to Child Transmission (pMTCT) - Treatment Options Preservation Study (TOPS)
NCT00243568	Phase 3	WITHDRAWN	Vicriviroc, a CCR5 Inhibitor, Added to an Optimized Antiretroviral Therapy for Previously Treated HIV (VICTOR-E2) (Study P04285
NCT00278954	Phase 3	COMPLETED	Efficacy, Safety and Pharmacokinetics of Gammaplex in Primary Immunodeficiency Diseases.
NCT00474370	Phase 3	COMPLETED	Vicriviroc in HIV-Treatment Experienced Subjects (Study P04889AM8)(COMPLETED)
NCT00478231	Phase 3	COMPLETED	Multicenter, Safety Study Of Maraviroc
NCT00523211	Phase 3	COMPLETED	Vicriviroc in HIV-Treatment Experienced Subjects (Study P04405AM5)
NCT00698334	Phase 3	COMPLETED	Efficacy of Thrice Weekly Directly Observed Treatment, Short-course (DOTS) in HIV-associated Tuberculosis
NCT00966160	Phase 3	COMPLETED	CD4 Cell Recovery in HIV-1 Patients Comparing 2 Treatment Regimes
NCT01363011	Phase 3	COMPLETED	Cobicistat-containing Highly Active Antiretroviral Regimens in HIV-1 Infected Patients With Mild to Moderate Renal Impairment
NCT01440569	Phase 3	COMPLETED	Safety and Efficacy of Cobicistat-boosted Darunavir in HIV Infected Adults
NCT01475838	Phase 3	COMPLETED	Study to Evaluate Switching From Regimens Consisting of a Ritonavir-boosted Protease Inhibitor Plus Emtricitabine/Tenofovir Fixed-Dose Combination to the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF Single-Tablet Regimen in Virologically Suppressed, HIV-1 Infected Patients
NCT01495702	Phase 3	COMPLETED	Study to Evaluate Switching From Regimens Consisting of a Nonnucleoside Reverse Transcriptase Inhibitor Plus Emtricitabine and Tenofovir DF to the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF Single-Tablet Regimen in Virologically Suppressed, HIV-1 Infected Patients
NCT01533259	Phase 3	COMPLETED	Open-Label Pilot Study to Evaluate Switching From a Regimen Consisting of Raltegravir Plus Emtricitabine/Tenofovir DF Fixed-Dose Combination to the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF Single-Tablet Regimen in Virologically Suppressed, HIV-1 Infected Patients
NCT01581593	Phase 3	COMPLETED	Efficacy and Safety Study of Kedrion IVIG 10% to Treat Subjects With Primary Immunodeficiency (PID)
NCT01705574	Phase 3	COMPLETED	Safety and Efficacy of E/C/F/TDF Versus RTV-Boosted ATV Plus FTC/TDF in HIV-1 Infected, Antiretroviral Treatment-Naive Women
NCT01967940	Phase 3	COMPLETED	Efficacy of Tenofovir Alafenamide Versus Placebo Added to a Failing Regimen Followed by Treatment With Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Plus Atazanavir in HIV-1 Positive, Antiretroviral Treatment-Experienced Adults
NCT01968551	Phase 3	COMPLETED	Phase 3 Open-Label Study to Evaluate Switching From Optimized Stable Antiretroviral Regimens Containing Darunavir to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Fixed Dose Combination (FDC) Plus Darunavir (DRV) in Treatment Experienced HIV-1 Positive Adults
NCT01985373	Phase 3	COMPLETED	Pharmacokinetics and Safety of IVIG Nanogam 100 mg/ml
NCT02269163	Phase 3	COMPLETED	Study of ProMetic BioTherapeutics Immune Globulin Intravenous (Human) 10%
NCT02604810	Phase 3	COMPLETED	Safety and Pharmacokinetics of IGSC 20% in Subjects With Primary Immunodeficiency
NCT02806986	Phase 3	COMPLETED	Efficacy, Pharmacokinetics, Safety, and Tolerability of IGSC 20% in Subjects With Primary Immunodeficiency
NCT03814798	Phase 3	WITHDRAWN	Study Evaluating IGSC 20% Flexible Dosing in Treatment-Experienced and Treatment-Naive Subjects With Primary Immunodeficiency
NCT03907241	Phase 3	COMPLETED	CLINICAL PHASE III STUDY TO MONITOR THE SAFETY, TOLERABILITY AND EFFICACY OF SUBCUTANEOUS HUMAN IMMUNOGLOBULIN (OCTANORM) IN PATIENTS WITH PRIMARY IMMUNODEFICIENCY DISEASES, INCLUDING (BUT NOT LIMITED TO) THOSE WHO HAVE COMPLETED THE SCGAM-01 TRIAL
NCT04561115	Phase 3	COMPLETED	A Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Immune Globulin (Human) 10% (Gamunex-C) PEG Process (IVIG-PEG) Compared to Gamunex-C in Participants With Primary Humoral Immunodeficiency
NCT04738812	Phase 3	COMPLETED	Determination of Adequate Tuberculosis Regimen in Patients Hospitalized With HIV-associated Severe Immune Suppression
NCT04836260	Phase 3	UNKNOWN	Preemptive Use of Convalescent Plasma for High-risk Patients With COVID-19
NCT06954441	Phase 3	RECRUITING	V-IMMUNE: A Novel Immunoglobulin Therapy for Immunodeficiency
NCT06980480	Phase 3	RECRUITING	A Study of Gammagard Liquid (Immune Globulin Infusion, 10%) to Prevent Infections in Adults With Multiple Myeloma
NCT00000587	Phase 2	COMPLETED	Erythropoietin for Anemia Due to Zidovudine in Human Immunodeficiency Virus Infection
NCT00001354	Phase 2	COMPLETED	Interleukin-2 Therapy for HIV Infection - Supplemental Procedures
NCT00001475	Phase 2	COMPLETED	Home Treatment of HIV-Infected Patients With Interleukin-2 With or Without a Tumor Necrosis Factor Antagonist