C6

Summary

C6 (complement C6, HGNC:1339) is a protein-coding gene on chromosome 5p13.1, encoding Complement component C6 (P13671). 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 a component of the complement cascade. The encoded protein is part of the membrane attack complex that can be incorporated into the cell membrane and cause cell lysis. Mutations in this gene are associated with complement component-6 deficiency. Transcript variants encoding the same protein have been described.

Source: NCBI Gene 729 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complement component 6 deficiency (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 630 total — 37 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 4
• MANE Select transcript: NM_000065

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1339
Approved symbol	C6
Name	complement C6
Location	5p13.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000039537
Ensembl biotype	protein_coding
OMIM	217050
Entrez	729

Gene structure

Transcript identifiers

Ensembl transcripts: 52 — 45 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000263413, ENST00000337836, ENST00000417809, ENST00000433294, ENST00000461473, ENST00000473450, ENST00000475349, ENST00000695764, ENST00000706654, ENST00000706655, ENST00000706656, ENST00000905249, ENST00000905250, ENST00000905251, ENST00000905252, ENST00000905253, ENST00000905254, ENST00000905255, ENST00000905256, ENST00000905257, ENST00000905258, ENST00000905259, ENST00000905260, ENST00000905261, ENST00000905262, ENST00000905263, ENST00000905264, ENST00000905265, ENST00000905266, ENST00000905267, ENST00000905268, ENST00000905269, ENST00000905270, ENST00000905271, ENST00000905272, ENST00000905273, ENST00000905274, ENST00000905275, ENST00000905276, ENST00000905277, ENST00000905278, ENST00000905279, ENST00000905280, ENST00000905281, ENST00000905282, ENST00000942836, ENST00000942837, ENST00000942838, ENST00000942839, ENST00000942840, ENST00000942841, ENST00000942842

RefSeq mRNA: 2 — MANE Select: NM_000065 NM_000065, NM_001115131

CCDS: CCDS3936

Canonical transcript exons

ENST00000337836 — 18 exons

Exon	Start	End
ENSE00000742343	41149241	41149482
ENSE00000742345	41149935	41150025
ENSE00000742356	41160142	41160367
ENSE00000971127	41199768	41199912
ENSE00000971128	41195792	41195933
ENSE00000971129	41186070	41186208
ENSE00001264152	41201558	41201714
ENSE00001527379	41213376	41213532
ENSE00002205138	41203088	41203250
ENSE00003469745	41154972	41155104
ENSE00003524502	41161693	41161859
ENSE00003566748	41181359	41181559
ENSE00003580738	41172225	41172347
ENSE00003598295	41176475	41176715
ENSE00003668669	41159082	41159253
ENSE00003673853	41158674	41158785
ENSE00003684065	41153810	41153998
ENSE00003901464	41142116	41143006

Expression profiles

Bgee: expression breadth ubiquitous, 173 present calls, max score 98.40.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.9926 / max 803.8405, expressed in 95 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
61467	1.3837	55
61466	0.2694	35
61462	0.1279	40
61465	0.0757	17
61464	0.0709	21
61463	0.0593	7
61468	0.0056	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.40	gold quality
liver	UBERON:0002107	98.36	gold quality
heart right ventricle	UBERON:0002080	97.19	gold quality
cardiac muscle of right atrium	UBERON:0003379	96.72	gold quality
right uterine tube	UBERON:0001302	95.81	gold quality
left ventricle myocardium	UBERON:0006566	94.96	gold quality
myocardium	UBERON:0002349	94.90	gold quality
cardiac atrium	UBERON:0002081	94.88	gold quality
right atrium auricular region	UBERON:0006631	94.82	gold quality
body of pancreas	UBERON:0001150	94.13	gold quality
bronchial epithelial cell	CL:0002328	92.94	gold quality
pancreatic ductal cell	CL:0002079	92.50	silver quality
heart left ventricle	UBERON:0002084	89.78	gold quality
cardiac ventricle	UBERON:0002082	89.64	gold quality
heart	UBERON:0000948	89.43	gold quality
epithelium of bronchus	UBERON:0002031	89.13	gold quality
apex of heart	UBERON:0002098	88.98	gold quality
epithelial cell of pancreas	CL:0000083	87.92	gold quality
pancreas	UBERON:0001264	87.61	gold quality
bronchus	UBERON:0002185	87.58	gold quality
gall bladder	UBERON:0002110	87.05	gold quality
calcaneal tendon	UBERON:0003701	86.83	gold quality
synovial joint	UBERON:0002217	84.78	gold quality
subcutaneous adipose tissue	UBERON:0002190	84.33	gold quality
peritoneum	UBERON:0002358	83.36	gold quality
omental fat pad	UBERON:0010414	83.35	gold quality
adipose tissue of abdominal region	UBERON:0007808	83.29	gold quality
caput epididymis	UBERON:0004358	82.53	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.11	gold quality
adipose tissue	UBERON:0001013	82.00	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-8495	yes	181.64
E-ANND-3	yes	9.32

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

35 targeting C6, 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-LET-7C-3P	99.95	73.42	2862
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-653-5P	99.46	67.35	1300
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-502-5P	98.77	66.51	906
HSA-MIR-603	98.58	68.28	1603
HSA-MIR-4662B	98.33	66.37	1163
HSA-MIR-4647	98.30	66.41	1139
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-1263	98.13	69.18	459
HSA-MIR-6841-3P	98.08	66.54	604
HSA-MIR-3664-3P	97.85	67.62	1452

Literature-anchored findings (GeneRIF, showing 13)

• The most common defect, which leads to an increased susceptibility to Neisseria meningitidis infections in the Western Cape, is 879delG. (PMID:17257682)
• 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)
• produced by trophoblast cells (PMID:19665237)
• Complement C5b-9 induce a JNK/Bid-dependent and JNK-independent necrotic cell death. (PMID:19864026)
• Genetic polymorphisms in C6 gene do not influence the risk of aspirin hypersensitivity in Korean asthmatic patients. (PMID:21704099)
• Structure of complement C6 suggests a mechanism for initiation and unidirectional, sequential assembly of membrane attack complex (MAC). (PMID:22267737)
• finding of very high serious morbidity in patients with complete C6 deficiency due to meningococcal infections (PMID:22288589)
• Crystal structure of C5b-6 suggests structural basis for priming assembly of the membrane attack complex. (PMID:22500023)
• Complement C5b-9 complex sensitizes 661W photoreceptor cells to both apoptosis and necroptosis. (PMID:25735751)
• recipient C6 rs9200 polymorphism is associated with HCC recurrence after OLT, and improves the predictive value of clinical models. (PMID:27173880)
• Our study provided novel evidence that genetic variations in complement genes C6 and MASP1were associated with preeclampsia risk, and that the risk varied by preeclampsia subtypes (PMID:27405496)
• specific association of NR1I3, C6 and TNN with low hip BMD risk (PMID:28629900)
• Similarities and differences in the structures and proteoform profiles of the complement proteins C6 and C7. (PMID:34241972)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	c6.2	ENSDARG00000057113
danio_rerio	c6.1	ENSDARG00000093052
mus_musculus	C6	ENSMUSG00000022181
rattus_norvegicus	C6	ENSRNOG00000024115

Paralogs (39): CFH (ENSG00000000971), SELE (ENSG00000007908), C8B (ENSG00000021852), SEZ6 (ENSG00000063015), CFHR2 (ENSG00000080910), APOH (ENSG00000091583), SEZ6L (ENSG00000100095), SUSD6 (ENSG00000100647), SRPX (ENSG00000101955), SRPX2 (ENSG00000102359), C7 (ENSG00000112936), C9 (ENSG00000113600), 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 C6 — P13671 (reviewed: P13671)

All UniProt accessions (3): C9JC72, C9JX36, P13671

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. Together with component C5b, involved in MAC complex assembly: complement C5b and C6 associate with the outer leaflet of target cell membrane, reducing the energy for membrane bending.

Subunit / interactions. 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.

Post-translational modifications. All cysteine residues are assumed to be cross-linked to one another. Individual modules containing an even number of conserved cysteine residues are supposed to have disulfide linkages only within the same module.

Disease relevance. Complement component 6 deficiency (C6D) [MIM:612446] A rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections, predominantly by Neisseria gonorrhoeae or Neisseria meningitidis. 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. MAC assembly is also inhibited by clusterin (CLU) chaperones that inhibit polymerization of C9.

Polymorphism. The sequence shown is that of allotype C6 B.

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

RefSeq proteins (2): NP_000056, NP_001108603 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000436	Sushi_SCR_CCP_dom	Domain
IPR000884	TSP1_rpt	Repeat
IPR001862	MAC_perforin	Family
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR002350	Kazal_dom	Domain
IPR003884	FacI_MAC	Domain
IPR020863	MACPF_CS	Conserved_site
IPR020864	MACPF	Domain
IPR023415	LDLR_class-A_CS	Conserved_site
IPR035976	Sushi/SCR/CCP_sf	Homologous_superfamily
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR048828	C6_KAZAL	Domain
IPR048831	C8A_B_C6_EGF-like	Domain

Pfam: PF00057, PF00084, PF00090, PF01823, PF21195, PF21288

UniProt features (174 total): strand 65, disulfide bond 32, helix 29, domain 10, glycosylation site 10, turn 7, binding site 6, region of interest 5, sequence variant 3, sequence conflict 3, transmembrane region 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
7Q6C	X-RAY DIFFRACTION	2.29
3T5O	X-RAY DIFFRACTION	2.87
8B0F	ELECTRON MICROSCOPY	3
7NYD	ELECTRON MICROSCOPY	3.27
8B0G	ELECTRON MICROSCOPY	3.3
8B0H	ELECTRON MICROSCOPY	3.3
4A5W	X-RAY DIFFRACTION	3.5
7NYC	ELECTRON MICROSCOPY	3.54
4E0S	X-RAY DIFFRACTION	4.21
6H03	ELECTRON MICROSCOPY	5.6
6H04	ELECTRON MICROSCOPY	5.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13671-F1	79.72	0.13

Antibody-complex structures (SAbDab): 1 — 7Q6C

Functional residue map

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

Ligand- & substrate-binding residues (6): 156; 159; 161; 163; 169; 170

Disulfide bonds (32): 22–61, 24–65, 35–73, 39–78, 82–117, 93–127, 96–133, 140–151, 146–164, 158–173, 180–218, 399–420, 499–623, 521–570, 523–539, 526–541, 543–552, 577–611, 589–601, 644–686 …

Glycosylation sites (10): 29, 32, 38, 90, 324, 392, 568, 571, 574, 855

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: 179 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, REACTOME_INNATE_IMMUNE_SYSTEM, GRUETZMANN_PANCREATIC_CANCER_DN, GNF2_GSTM1, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GNF2_HPN, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, 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_IN_UTERO_EMBRYONIC_DEVELOPMENT

GO Biological Process (12): in utero embryonic development (GO:0001701), positive regulation of activation of membrane attack complex (GO:0001970), complement activation (GO:0006956), complement activation, classical pathway (GO:0006958), killing of cells of another organism (GO:0031640), positive regulation of angiogenesis (GO:0045766), positive regulation of immune response (GO:0050778), 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 (8): 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), 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	2
immune response	2
cellular anatomical structure	2
chordate embryonic development	1
activation of membrane attack complex	1
regulation of activation of membrane attack complex	1
positive regulation of complement activation	1
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
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	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
innate immune response	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
membrane protein complex	1
transporter complex	1

Protein interactions and networks

STRING

698 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C6	CFH	P08603	616
C6	C2	P06681	528
C6	ITIH4	Q14624	500
C6	PGM3	O95394	490
C6	CFI	P05156	480
C6	C7	P10643	465
C6	C3	P01024	459
C6	C9	P02748	456
C6	C8G	P07360	451
C6	C5	P01031	440
C6	GLO1	P78375	435
C6	C1R	P00736	408
C6	CFB	P00751	396
C6	B4E1Z4	B4E1Z4	393
C6	SERPIND1	P05546	389

IntAct

19 interactions, top by confidence:

A	B	Type	Score
C5	C9	psi-mi:“MI:0915”(physical association)	0.550
C6	B3GLCT	psi-mi:“MI:0914”(association)	0.530
NPC2	NME2P1	psi-mi:“MI:0914”(association)	0.530
C6	ABL1	psi-mi:“MI:0915”(physical association)	0.400
C6	FYN	psi-mi:“MI:0915”(physical association)	0.400
C6	GRB2	psi-mi:“MI:0915”(physical association)	0.400
C6	NCK1	psi-mi:“MI:0915”(physical association)	0.400
C6	SART3	psi-mi:“MI:0915”(physical association)	0.370
RYBP	PIPSL	psi-mi:“MI:0914”(association)	0.350
RYBP	FAM186A	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
	C5	psi-mi:“MI:0915”(physical association)	0.320
EPHA1	PIK3R2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (21): C6 (Affinity Capture-MS), C6 (Synthetic Lethality), DPY19L3 (Affinity Capture-MS), ACOT9 (Affinity Capture-MS), B3GALTL (Affinity Capture-MS), C6 (Affinity Capture-MS), C6 (Co-fractionation), C6 (Reconstituted Complex), DPY19L3 (Affinity Capture-MS), ACOT9 (Affinity Capture-MS), B3GALTL (Affinity Capture-MS), C6 (Affinity Capture-MS), C5 (Reconstituted Complex), C6 (Affinity Capture-MS), C6 (Proximity Label-MS)

ESM2 similar proteins: A0A1D5NSM8, A2AVA0, B1AUH1, B3DK56, D3ZHH1, E9Q6D8, G5E8Q8, O18016, O97827, P0C6B8, P13671, P21180, P28175, P35442, P35918, P61134, P61135, P86091, Q03350, Q05793, Q08E66, Q26422, Q29RU4, Q2QI47, Q4LDE5, Q5E9P5, Q5G872, Q5MD89, Q5RDI1, Q6DI48, Q6DIV5, Q6GP28, Q6NZL8, Q6UXH9, Q6YI48, Q7RTY8, Q7TQN3, Q80TS3, Q811M5, Q8BIK6

Diamond homologs: A2AR95, A2ARV4, A4IHY6, C0HL13, E9Q6D8, G3V928, O75074, O75197, O75581, O88204, O88307, O88572, P0DSP1, P13671, P35953, P56677, P61134, P61135, P86091, P98153, P98154, P98155, P98156, P98157, P98158, P98160, P98163, P98164, P98165, P98166, P98167, Q04833, Q06561, Q07954, Q0IIH7, Q14114, Q28832, Q29RU4, Q5HZW5, Q5R662

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
C6	“form complex”	“Membrane attack complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	37
Likely pathogenic	20
Uncertain significance	300
Likely benign	221
Benign	18

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1032162	NM_000065.5(C6):c.107C>A (p.Ser36Ter)	Pathogenic
1071288	NM_000065.5(C6):c.723del (p.Phe241fs)	Pathogenic
12115	NM_000065.5(C6):c.828del (p.Ser277fs)	Pathogenic
1361000	NM_000065.5(C6):c.1375A>T (p.Lys459Ter)	Pathogenic
1369402	NM_000065.5(C6):c.828dup (p.Ser277fs)	Pathogenic
1385769	NM_000065.5(C6):c.145C>T (p.Gln49Ter)	Pathogenic
1390870	NM_000065.5(C6):c.381C>A (p.Cys127Ter)	Pathogenic
1449532	NM_000065.5(C6):c.2086del (p.Asp696fs)	Pathogenic
1452266	NM_000065.5(C6):c.1251del (p.Glu417fs)	Pathogenic
1923849	NM_000065.5(C6):c.87G>A (p.Trp29Ter)	Pathogenic
1933917	NM_000065.5(C6):c.901C>T (p.Gln301Ter)	Pathogenic
2018397	NM_000065.5(C6):c.277dup (p.Cys93fs)	Pathogenic
2127687	NM_000065.5(C6):c.254del (p.Gly85fs)	Pathogenic
2748896	NM_000065.5(C6):c.420C>A (p.Cys140Ter)	Pathogenic
2755564	NM_000065.5(C6):c.2335C>T (p.Gln779Ter)	Pathogenic
2760122	NM_000065.5(C6):c.894del (p.Phe299fs)	Pathogenic
2794864	NM_000065.5(C6):c.1066C>T (p.Arg356Ter)	Pathogenic
2800265	NM_000065.5(C6):c.2304del (p.Lys768fs)	Pathogenic
2906086	NM_000065.5(C6):c.1816C>T (p.Arg606Ter)	Pathogenic
2969163	NM_000065.5(C6):c.1589del (p.Gly530fs)	Pathogenic
2975647	NM_000065.5(C6):c.2436_2440del (p.Ser813fs)	Pathogenic
2985079	NM_000065.5(C6):c.2416_2422dup (p.Asn808fs)	Pathogenic
29922	NM_000065.5(C6):c.237del (p.Ile80fs)	Pathogenic
2997037	NM_000065.5(C6):c.226C>T (p.Gln76Ter)	Pathogenic
3029906	NM_000065.5(C6):c.1879_1881delinsAT (p.Asp627fs)	Pathogenic
3246425	NC_000005.9:g.(?41199850)(41203332_?)del	Pathogenic
3675425	NM_000065.5(C6):c.184G>T (p.Glu62Ter)	Pathogenic
3721542	NM_000065.5(C6):c.343C>T (p.Gln115Ter)	Pathogenic
3730186	NM_000065.5(C6):c.821_822del (p.Gln274fs)	Pathogenic
4693259	NM_000065.5(C6):c.1912del (p.Glu637_Ile638insTer)	Pathogenic

SpliceAI

3100 predictions. Top by Δscore:

Variant	Effect	Δscore
5:41149361:CAATA:C	acceptor_gain	1.0000
5:41149362:A:T	acceptor_gain	1.0000
5:41149365:A:C	acceptor_gain	1.0000
5:41158669:CTGA:C	donor_loss	1.0000
5:41158670:TGA:T	donor_loss	1.0000
5:41158671:GACCC:G	donor_loss	1.0000
5:41158672:A:C	donor_loss	1.0000
5:41158673:C:G	donor_loss	1.0000
5:41158782:TCCA:T	acceptor_gain	1.0000
5:41158783:CCA:C	acceptor_gain	1.0000
5:41158783:CCAC:C	acceptor_gain	1.0000
5:41158784:CA:C	acceptor_gain	1.0000
5:41158784:CAC:C	acceptor_gain	1.0000
5:41158786:C:CC	acceptor_gain	1.0000
5:41159080:A:AC	donor_gain	1.0000
5:41159081:C:CC	donor_gain	1.0000
5:41159112:T:TA	donor_gain	1.0000
5:41160368:C:CC	acceptor_gain	1.0000
5:41186064:TCATA:T	donor_loss	1.0000
5:41186065:CATAC:C	donor_loss	1.0000
5:41186066:ATAC:A	donor_loss	1.0000
5:41186067:TACC:T	donor_loss	1.0000
5:41186068:A:C	donor_loss	1.0000
5:41186069:C:G	donor_loss	1.0000
5:41195832:T:TA	donor_gain	1.0000
5:41195833:C:A	donor_gain	1.0000
5:41203247:GGCC:G	acceptor_gain	1.0000
5:41203248:GCCC:G	acceptor_loss	1.0000
5:41203250:CCTAA:C	acceptor_loss	1.0000
5:41203251:CTAAA:C	acceptor_loss	1.0000

AlphaMissense

6164 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:41203135:C:A	W32C	0.997
5:41203135:C:G	W32C	0.997
5:41159225:C:A	W571C	0.996
5:41159225:C:G	W571C	0.996
5:41159216:C:A	W574C	0.994
5:41159216:C:G	W574C	0.994
5:41199776:C:G	C146S	0.994
5:41199777:A:T	C146S	0.994
5:41203144:C:A	W29C	0.994
5:41203144:C:G	W29C	0.994
5:41154997:C:A	W692C	0.993
5:41154997:C:G	W692C	0.993
5:41160306:A:G	L507P	0.993
5:41195888:C:G	C164S	0.993
5:41195889:A:T	C164S	0.993
5:41149254:C:A	W870C	0.992
5:41149254:C:G	W870C	0.992
5:41159234:C:A	W568C	0.992
5:41159234:C:G	W568C	0.992
5:41155016:C:G	C686S	0.990
5:41155017:A:T	C686S	0.990
5:41176559:C:A	G362W	0.990
5:41161737:A:G	W472R	0.989
5:41161737:A:T	W472R	0.989
5:41176668:G:C	F325L	0.989
5:41176668:G:T	F325L	0.989
5:41176670:A:G	F325L	0.989
5:41195887:A:C	C164W	0.989
5:41199775:A:C	C146W	0.989
5:41199777:A:G	C146R	0.989

dbSNP variants (sampled 300 via entrez): RS1000011097 (5:41190075 G>A), RS1000048884 (5:41174539 T>C), RS1000053375 (5:41208267 A>T), RS1000076474 (5:41178230 C>T), RS1000090327 (5:41249377 AAAT>A), RS1000138092 (5:41261238 A>T), RS1000141344 (5:41249635 T>C), RS1000151404 (5:41222383 G>T), RS1000171898 (5:41228391 T>C,G), RS1000176901 (5:41239467 T>G), RS1000248201 (5:41211052 T>C), RS1000248822 (5:41239298 G>T), RS1000249225 (5:41153688 G>C), RS1000281741 (5:41260307 T>C), RS1000306527 (5:41205732 C>A,G,T)

Disease associations

OMIM: gene MIM:217050 | disease phenotypes: MIM:612446

GenCC curated gene-disease

Disease	Classification	Inheritance
complement component 6 deficiency	Strong	Autosomal recessive

Mondo (2): complement component 6 deficiency (MONDO:0012908), immunodeficiency due to a late component of complement deficiency (MONDO:0015700)

Orphanet (1): Immunodeficiency due to a late component of complement deficiency (Orphanet:169150)

HPO phenotypes

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

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0005381	Recurrent meningococcal disease
HP:0025434	Reduced circulating CH50 activity
HP:0033059	Decreased circulating complement C6 concentration

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001738_11	Response to fenofibrate (adiponectin levels)	5.000000e-06
GCST010002_23	Refractive error	2.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Cyclosporine	decreases expression	2
bisphenol F	affects cotreatment, decreases expression	1
methyleugenol	decreases expression	1
propionaldehyde	decreases expression	1
bisphenol A	affects cotreatment, decreases expression	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
bisphenol S	affects cotreatment, decreases methylation	1
Olanzapine	affects phosphorylation	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	decreases expression	1
Chlorpromazine	affects expression, affects cotreatment	1
Cholic Acids	affects cotreatment, affects expression	1
Copper	affects binding	1
Dexamethasone	decreases expression, increases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Indomethacin	increases expression, affects cotreatment, decreases expression	1
Mercury	affects expression	1
Nickel	affects binding	1
Silicon Dioxide	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	decreases methylation, decreases expression	1
Zinc	affects binding	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression, increases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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