C2

Summary

C2 (complement C2, HGNC:1248) is a protein-coding gene on chromosome 6p21.33, encoding Complement C2 (P06681). Precursor of the catalytic component of the C3 and C5 convertase complexes, which are part of the complement pathway, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system.

Component C2 is a serum glycoprotein that functions as part of the classical pathway of the complement system. Activated C1 cleaves C2 into C2a and C2b. The serine proteinase C2a then combines with complement factor 4b to create the C3 or C5 convertase. Deficiency of C2 has been reported to associated with certain autoimmune diseases and SNPs in this gene have been associated with altered susceptibility to age-related macular degeneration. This gene localizes within the class III region of the MHC on the short arm of chromosome 6. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described in publications but their full-length sequence has not been determined.

Source: NCBI Gene 717 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complement component 2 deficiency (Strong, GenCC)
• GWAS associations: 68 (top 1% of genes corpus-wide)
• Clinical variants (ClinVar): 542 total — 19 pathogenic, 13 likely-pathogenic (top 6% of genes corpus-wide)
• GTEx eGene: eQTL in 14 tissues, sQTL in 8 (q < 0.05)
• Phenotypes (HPO): 3
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.91 (unconstrained)
• MANE Select transcript: NM_000063

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1248
Approved symbol	C2
Name	complement C2
Location	6p21.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000166278
Ensembl biotype	protein_coding
OMIM	613927
Entrez	717

Gene structure

Transcript identifiers

Ensembl transcripts: 58 — 37 protein_coding, 15 nonsense_mediated_decay, 4 retained_intron, 1 non_stop_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000299367

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 5, TSL 3: 1, TSL 4: 4, TSL 5: 5

ENST00000299367, ENST00000383177, ENST00000411571, ENST00000413154, ENST00000418949, ENST00000442278, ENST00000447952, ENST00000452202, ENST00000452323, ENST00000468407, ENST00000469372, ENST00000482060, ENST00000484636, ENST00000485690, ENST00000486124, ENST00000494905, ENST00000497706, ENST00000695637, ENST00000695638, ENST00000695639, ENST00000695640, ENST00000695644, ENST00000695645, ENST00000695646, ENST00000862556, ENST00000862557, ENST00000862558, ENST00000990543, ENST00000990544, ENST00000990545, ENST00000990546, ENST00000990547, ENST00000990548, ENST00000990550, ENST00000990554, ENST00000990555, ENST00000990556, ENST00000990557, ENST00000990558, ENST00000990559, ENST00000990560, ENST00000990561, ENST00000990564, ENST00000990566, ENST00000990568, ENST00000990569, ENST00000990571, ENST00000990572, ENST00000990573, ENST00001057018, ENST00001057021, ENST00001057023, ENST00001120391, ENST00001120392, ENST00001120393, ENST00001120394, ENST00001125927, ENST00001125928

RefSeq mRNA: 6 — MANE Select: NM_000063 NM_000063, NM_001145903, NM_001178063, NM_001282457, NM_001282458, NM_001282459

CCDS: CCDS4728, CCDS54991, CCDS56416, CCDS75427, CCDS75428

Canonical transcript exons

ENST00000299367 — 18 exons

Exon	Start	End
ENSE00001863951	31927717	31927798
ENSE00003465506	31939231	31939320
ENSE00003510154	31933610	31933783
ENSE00003526031	31934166	31934299
ENSE00003542442	31935923	31936061
ENSE00003542622	31933867	31933965
ENSE00003555157	31945178	31945672
ENSE00003624113	31942959	31943099
ENSE00003625758	31943644	31943809
ENSE00003641559	31944980	31945029
ENSE00003646481	31943917	31943993
ENSE00003649345	31943416	31943527
ENSE00003674113	31943225	31943319
ENSE00003677538	31937319	31937459
ENSE00003681952	31944135	31944226
ENSE00003788330	31944727	31944853
ENSE00003964557	31927955	31928164
ENSE00003964559	31928732	31928917

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 99.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.7629 / max 761.6776, expressed in 1499 samples.

Highest expression (Bgee): liver, lobe of liver, placenta, spleen, upper lobe of left lung.

Genetic regulation across tissues (GTEx eQTL / sQTL)

C2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 14 tissues and its splicing (sQTL) in 8 (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
Cells EBV-transformed lymphocytes	eqtl	1.4e-23	+1.54	6:32633262:A:AT
Adipose Visceral Omentum	sqtl	3.2e-11	-0.72	6:31928196:C:G
Lung	sqtl	6.8e-10	-0.58	6:31928196:C:G
Testis	eqtl	1.6e-09	-0.54	6:31936529:G:A
Brain Nucleus accumbens basal ganglia	eqtl	1.7e-04	+0.35	6:32327642:A:C
Adipose Subcutaneous	eqtl	2.9e-04	+0.13	6:31947158:A:G
Whole Blood	eqtl	8.4e-04	+0.19	6:32390912:A:G
Skin Sun Exposed Lower leg	eqtl	9.0e-04	+0.11	6:32485766:C:G
Breast Mammary Tissue	sqtl	1.1e-03	-0.47	6:31928196:C:G
Artery Aorta	eqtl	1.9e-03	+0.21	6:32752654:G:T
Cells Cultured fibroblasts	eqtl	2.4e-03	+0.13	6:31954477:A:C
Adipose Subcutaneous	sqtl	4.0e-03	-0.46	6:31928196:C:G
Muscle Skeletal	eqtl	7.5e-03	+0.12	6:32731170:G:C
Breast Mammary Tissue	eqtl	8.6e-03	+0.15	6:31947158:A:G
Spleen	sqtl	9.5e-03	-0.72	6:31928196:C:G
Thyroid	eqtl	1.6e-02	+0.15	6:32680723:G:T
Stomach	sqtl	2.7e-02	+0.67	6:31128165:G:A
Colon Transverse	eqtl	3.0e-02	+0.11	6:31484655:C:T
Colon Transverse	sqtl	3.3e-02	-0.57	6:31931842:G:A
Brain Hippocampus	eqtl	3.4e-02	+0.74	6:31793375:G:A

FANTOM5 promoters

9 alternative TSS:

Promoter ID	TPM avg	Samples expressed
67090	6.4129	589
67080	2.8402	1182
67084	0.6145	43
67087	0.4840	147
67088	0.2412	76
67085	0.0734	12
67083	0.0469	12
67086	0.0346	11
67082	0.0152	6

Top tissues by expression

showing 100 of 139 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
liver	UBERON:0002107	99.21	gold quality
right lobe of liver	UBERON:0001114	99.17	gold quality
placenta	UBERON:0001987	96.35	gold quality
spleen	UBERON:0002106	94.06	gold quality
upper lobe of left lung	UBERON:0008952	93.51	gold quality
gall bladder	UBERON:0002110	92.81	gold quality
vermiform appendix	UBERON:0001154	92.07	gold quality
omental fat pad	UBERON:0010414	92.01	gold quality
right lung	UBERON:0002167	91.96	gold quality
lymph node	UBERON:0000029	91.42	gold quality
lung	UBERON:0002048	90.50	gold quality
duodenum	UBERON:0002114	90.48	gold quality
colonic epithelium	UBERON:0000397	90.21	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.87	gold quality
small intestine	UBERON:0002108	89.72	gold quality
adipose tissue	UBERON:0001013	89.05	gold quality
smooth muscle tissue	UBERON:0001135	88.15	gold quality
rectum	UBERON:0001052	86.79	gold quality
subcutaneous adipose tissue	UBERON:0002190	86.64	gold quality
right adrenal gland cortex	UBERON:0035827	86.64	gold quality
right coronary artery	UBERON:0001625	85.43	gold quality
right adrenal gland	UBERON:0001233	85.00	gold quality
left adrenal gland	UBERON:0001234	84.43	gold quality
urinary bladder	UBERON:0001255	84.40	gold quality
monocyte	CL:0000576	84.26	gold quality
left adrenal gland cortex	UBERON:0035825	83.65	gold quality
intestine	UBERON:0000160	83.64	gold quality
leukocyte	CL:0000738	83.62	gold quality
adrenal gland	UBERON:0002369	83.02	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	82.75	gold quality
left coronary artery	UBERON:0001626	82.54	gold quality
transverse colon	UBERON:0001157	82.26	gold quality
apex of heart	UBERON:0002098	81.94	gold quality
thoracic mammary gland	UBERON:0005200	81.93	gold quality
minor salivary gland	UBERON:0001830	81.71	gold quality
colon	UBERON:0001155	81.66	gold quality
adult mammalian kidney	UBERON:0000082	81.57	gold quality
saliva-secreting gland	UBERON:0001044	81.09	gold quality
tonsil	UBERON:0002372	80.91	gold quality
mucosa of transverse colon	UBERON:0004991	80.80	gold quality
mucosa of stomach	UBERON:0001199	80.55	gold quality
myometrium	UBERON:0001296	80.38	gold quality
left uterine tube	UBERON:0001303	80.17	gold quality
fallopian tube	UBERON:0003889	79.65	gold quality
descending thoracic aorta	UBERON:0002345	79.36	gold quality
muscle layer of sigmoid colon	UBERON:0035805	79.31	gold quality
right atrium auricular region	UBERON:0006631	79.09	gold quality
thoracic aorta	UBERON:0001515	78.83	gold quality
kidney	UBERON:0002113	78.69	gold quality
ascending aorta	UBERON:0001496	78.68	gold quality
lower esophagus	UBERON:0013473	78.47	gold quality
lower esophagus muscularis layer	UBERON:0035833	78.47	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	78.33	gold quality
right ovary	UBERON:0002118	77.94	gold quality
prostate gland	UBERON:0002367	77.38	gold quality
endometrium	UBERON:0001295	77.13	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.99	gold quality
metanephros cortex	UBERON:0010533	76.88	gold quality
uterus	UBERON:0000995	76.81	gold quality
skin of leg	UBERON:0001511	76.73	gold quality
esophagus	UBERON:0001043	76.54	gold quality
heart	UBERON:0000948	76.42	gold quality
stomach	UBERON:0000945	76.21	gold quality
fundus of stomach	UBERON:0001160	76.04	gold quality
body of stomach	UBERON:0001161	75.88	gold quality
material anatomical entity	UBERON:0000465	75.81	gold quality
multicellular organism	UBERON:0000468	75.81	gold quality
zone of skin	UBERON:0000014	75.79	gold quality
anatomical system	UBERON:0000467	75.72	gold quality
cortex of kidney	UBERON:0001225	75.70	gold quality
body of uterus	UBERON:0009853	75.67	gold quality
granulocyte	CL:0000094	75.63	gold quality
blood	UBERON:0000178	75.51	gold quality
ovary	UBERON:0000992	75.22	gold quality
muscle tissue	UBERON:0002385	74.77	gold quality
skin of abdomen	UBERON:0001416	74.60	gold quality
esophagus mucosa	UBERON:0002469	74.60	gold quality
lower esophagus mucosa	UBERON:0035834	74.39	gold quality
stromal cell of endometrium	CL:0002255	74.19	gold quality
bone marrow cell	CL:0002092	74.14	gold quality
heart left ventricle	UBERON:0002084	74.06	gold quality
vagina	UBERON:0000996	74.00	gold quality
left ovary	UBERON:0002119	73.95	gold quality
calcaneal tendon	UBERON:0003701	73.67	gold quality
endocervix	UBERON:0000458	73.62	gold quality
synovial membrane of synovial joint	UBERON:0002018	73.52	gold quality
tibial nerve	UBERON:0001323	73.41	gold quality
bone marrow	UBERON:0002371	73.28	gold quality
bone element	UBERON:0001474	73.27	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	73.22	gold quality
adenohypophysis	UBERON:0002196	73.10	gold quality
substantia nigra	UBERON:0002038	72.57	gold quality
popliteal artery	UBERON:0002250	71.31	gold quality
tibial artery	UBERON:0007610	71.31	gold quality
right lobe of thyroid gland	UBERON:0001119	71.23	gold quality
putamen	UBERON:0001874	71.03	gold quality
uterine cervix	UBERON:0000002	70.38	gold quality
nucleus accumbens	UBERON:0001882	70.35	gold quality
caudate nucleus	UBERON:0001873	70.21	gold quality
right uterine tube	UBERON:0001302	70.12	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	25.49
E-MTAB-6678	yes	10.58
E-HCAD-11	yes	7.40
E-MTAB-6142	no	8.40

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	306.4	not detected
Lung	tissue	76.8	not detected
Placenta	tissue	45.6	not detected
Spleen	tissue	42.0	not detected
Adipose tissue	tissue	34.4	not detected
Lymph node	tissue	26.2	not detected
Appendix	tissue	26.1	not detected
Urinary bladder	tissue	22.6	not detected
Smooth muscle	tissue	22.0	not detected
Gallbladder	tissue	21.2	not detected
Small intestine	tissue	19.9	not detected
Duodenum	tissue	15.2	not detected
Colon	tissue	13.8	not detected
Tonsil	tissue	12.8	not detected
Rectum	tissue	12.3	not detected
Adrenal gland	tissue	11.7	not detected
Stomach 1	tissue	11.2	not detected
Spinal cord	tissue	8.6
Cervix	tissue	8.1	not detected
Breast	tissue	7.2	not detected
Esophagus	tissue	7.1	not detected
Superior colliculi	tissue	6.6
Thymus	tissue	5.5
Heart muscle	tissue	5.4	not detected
Vagina	tissue	5.3	not detected
Prostate	tissue	5.0	not detected
Choroid plexus	tissue	4.9
Fallopian tube	tissue	4.7	not detected
Ovary	tissue	4.3	not detected
Substantia nigra	tissue	4.3
Testis	tissue	4.1	not detected
Medulla oblongata	tissue	3.8
Pituitary gland	tissue	3.5
Kidney	tissue	3.5	not detected
Corpus callosum	tissue	3.0
Endometrium 1	tissue	2.9	not detected
Midbrain	tissue	2.9
Thalamus	tissue	2.9
Bone marrow	tissue	2.9	not detected
Pons	tissue	2.7
Skin 1	tissue	2.5	not detected
Tongue	tissue	2.5
Nucleus accumbens	tissue	2.5
Periaqueductal gray	tissue	2.5
Olfactory bulb	tissue	2.5
Salivary gland	tissue	2.4	not detected
Locus coeruleus	tissue	2.3
Frontal cortex	tissue	2.0
Hypothalamus	tissue	2.0
Hippocampus	tissue	2.0	not detected
Epididymis	tissue	1.8	not detected
Hippocampal formation	tissue	1.8
Pancreas	tissue	1.7	not detected
Putamen	tissue	1.6
Septum	tissue	1.6
Entorhinal cortex	tissue	1.4
Ventral forebrain	tissue	1.4
Seminal vesicle	tissue	1.3	not detected
Basal ganglia	tissue	1.3	not detected
Cerebral cortex	tissue	1.2	not detected

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Blood vessel (12.6), Dorsal spinal cord (8.6), Anterior thalamic nucleus, ventral (8.5), Dorsolateral tegmental area (7.8), Nucleus raphe pallidus (7.2).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NKX2-5, TP53

miRNA regulators (miRDB)

Targeting C2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

29 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-6831-5P	98.26	67.20	990
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-4257	97.86	68.05	1190
HSA-MIR-204-3P	97.80	66.84	1656
HSA-MIR-6893-3P	97.79	64.91	1238
HSA-MIR-4646-5P	97.70	66.84	1692
HSA-MIR-3927-3P	97.68	66.76	892
HSA-MIR-512-5P	97.47	66.48	591
HSA-MIR-370-3P	97.09	64.92	1221
HSA-MIR-582-3P	96.69	67.38	1019
HSA-MIR-6753-5P	94.70	64.08	470

Functional genomics

gnomAD constraint: pLI 2.44e-16, LOEUF 0.909, missense Z 2.31 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000299367 — one region, missense o/e 0.84.

Literature-anchored findings (GeneRIF, showing 38)

• C2 microheterogeneity and histocompatibility antigens Class I were studied in an Austrian population. (PMID:12823772)
• study of the formation of high affinity C5 convertase of the classical pathway of complement (PMID:12878586)
• Mannan-binding lectin activates C3 and the alternative complement pathway without involvement of C2 (PMID:16670774)
• a weaker, independent protective effect exists for complement component 2 in age related macular degeneration. (PMID:17576744)
• C2/CFB significantly influences AMD susceptibility and although accounting for effects at this locus does not dramatically increase the overall accuracy of the genetic risk model, the improvement over the CFH-LOC387715 model is statistically significant (PMID:18493315)
• The SNPs rs3753394 and rs800292 of CFH and rs11200638 of HTRA1 are significantly associated with the risk of PCV (polypoidal choroidal vasculopathy) in Chinese patients. (PMID:18515590)
• These data confirm that the classical pathway is vital for complement-mediated phagocytosis of S. pneumoniae and demonstrate why subjects with a C2 deficiency have a marked increase in susceptibility to S. pneumoniae infections. (PMID:18541650)
• In this study, the association of the IVS10 and R32Q variants in the C2 and BF genes in AMD was replicated. Haplotype analysis indicated association of these variants with AMD in an Australian population. (PMID:18806293)
• Because of the high level of linkage disequilibrium within the extended CC2/CFB region, variation within SKIV2L may exert a functional effect in age-related macular degeneration. (PMID:18806297)
• Study provides insights into the genetic pathogenesis of AMD, and C2 has been shown as one of the five genes independently involved in progression from intermediate disease to advanced disease in which blindness is frequent. (PMID:19015224)
• Upon cleavage by C1s, C2a domains undergo conformational rotation while bound to C4b and the released C2b domains may remain folded together as seen in the intact protein. (PMID:19237749)
• Data show that SNPs, and haplotypes risk trends were consistent with those seen in other population studies for CFH, C3, C2, and CFB. (PMID:19259132)
• Our results do not support any major role of the 4 AMD-associated variants in the risk of developing PCV, but favor a predominant association with the RDBP-SKIV2L variants (PMID:19556007)
• The results of the present study provide an independent validation of the association of rs547154 (C2) and rs641153 (CFB) SNPs with reduced risk of AMD in an Indian cohort. (PMID:19696172)
• The polypoidal choroidal vasculopathy (PCV) phenotype in Caucasian patients is associated with the major alleles/genotypes in the age-related macular degeneration (AMD)-associated loci, suggesting that PCV and AMD are genetically similar. (PMID:20378180)
• These data suggest that patients with C2 deficiency are at increased risk of Streptococcus pyogenes infections. (PMID:20417301)
• This study showed that CFH was more likely to be age-related macular(AMD) susceptibility gene, and none of the other C2, CFB, and C3 genes were associated with AMD in a white population. (PMID:20523265)
• These overall results suggest a lack of strong association with the C2 and C7 gene polymorphisms to the susceptibility of systemic lupus erythematosus in the Malaysian population. (PMID:21881993)
• C2/CFB variants play a protective role in the risk of developing neovascular AMD and PCV in the Japanese. (PMID:22232432)
• In conclusion, the genetic effect of C2, CFB and C3 polymorphisms, which are known to be important for AMD in Caucasian, were not significant in the Korean population. (PMID:22273503)
• Results showed that missense mutations in transmembrane protein 2 p.Ser1254Asn, interferon alpha 2 p.Ala120Thr, its regulator NLR family member X1 p.Arg707Cys, and complement component 2 p.Glu318Asp were associated with chronic hepatitis B. (PMID:22610944)
• This meta-analysis provides evidence for an association between C2/CFB polymorphisms and age-related macular degeneration. (PMID:22869612)
• CFH (RS1061170), C2 (RS547154), OR CFB (RS438999) was not associated with early or late AMD. (PMID:23060141)
• Gene variants in CFH and C2/CFB contribute to age related macular degeneration in the Chinese population. (PMID:23233260)
• ARMS2 and C3 are major contributors to advanced age-related macular degeneration in Mexican patients, while the contributions of CFH, C2, and CFB are minor to those of other populations. (PMID:24453474)
• The rs547154, rs641153, and rs12614 SNPs were not associated with age-related macular degeneration development in Greek patients. (PMID:24519512)
• The C2 and CFB gene variants were shown to be associated with polypoidal CNV. Typical PCV was not associated with variants in these genes. (PMID:24965207)
• Inhibition of c3 convertase activity by hepatitis C virus as an additional lesion in the regulation of complement components. (PMID:24983375)
• our data indicate that C2 rs547154 polymorphism plays a protective role in the development of PCV. (PMID:25732348)
• The rs2844455 A allele of C2 is a risk factor for systemic lupus erythematosus development in a Chinese population, whereas the G allele might be a protective factor. (PMID:26176736)
• Solution Structures of Complement C2 and Its C4 Complexes Propose Pathway-specific Mechanisms for Control and Activation of the Complement Proconvertases. (PMID:27252379)
• Vag8 binding to human C1-inhibitor (C1-inh) interferes with the binding of C1-inh to C1s, C1r and MASP-2, resulting in the release of active proteases that subsequently cleave C2 and C4 away from the bacterial surface. (PMID:28742139)
• Logistic regression analyses showed that six C2 single nucleotide polymorphisms had significant associations with the risk of chronic hepatitis B and chronic hepatitis B-related hepatocellular carcinoma among the Korean subjects. Stepwise analysis revealed that causal markers (rs9267665 and rs10947223) were identified among the C2 variants. (PMID:29283494)
• The pooled ORs for rs551397, rs2274700, rs4151667, rs641153, rs1047286, rs9332739, and rs547154 in the heterozygote model were 0.53, 0.53 , 0.54, 0.48, 1.42, 0.50, and 0.52, respectively. We confirmed the protective role of C2/CFB/CFH polymorphisms in the development of Age-Related Macular Degeneration (AMD), and showed single nucleotide polymorphism in C3 was a high-risk factor for AMD (PMID:30179527)
• Hereditary Deficiency of the Second Component of Complement: Early Diagnosis and 21-Year Follow-Up of a Family. (PMID:32164349)
• Complement protein levels and MBL2 polymorphisms are associated with dengue and disease severity. (PMID:32913345)
• Gain-of-Function Mutations R249C and S250C in Complement C2 Protein Increase C3 Deposition in the Presence of C-Reactive Protein. (PMID:34899688)
• Proteomic analysis of diabetes genetic risk scores identifies complement C2 and neuropilin-2 as predictors of type 2 diabetes: the Atherosclerosis Risk in Communities (ARIC) Study. (PMID:36194249)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	C2	ENSMUSG00000024371
rattus_norvegicus	Cfb	ENSRNOG00000051235

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), 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), SELP (ENSG00000174175), SEZ6L2 (ENSG00000174938), PRF1 (ENSG00000180644), PAPPA (ENSG00000182752), CSMD1 (ENSG00000183117), SELL (ENSG00000188404), CD55 (ENSG00000196352), CR1L (ENSG00000197721), CR1 (ENSG00000203710), CFB (ENSG00000243649), CFHR1 (ENSG00000244414)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88226) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 1 distinct phenotype terms.

Mouse phenotype (MP)	Records
premature death	1

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
Saguinus mystax	O19124	100.0%	Diamond
Saguinus oedipus	O62837	100.0%	Diamond
Gorilla gorilla gorilla	Q864V9	99.6%	Diamond
Pongo pygmaeus	Q8SQ75	99.6%	Diamond
Pan troglodytes	Q8SQ74	99.5%	Diamond
Saimiri sciureus	O62685	89.1%	Diamond
Bos taurus	P81187	85.9%	Diamond
Sus scrofa	Q03710	85.9%	Diamond
Pongo abelii	Q5R4D0	83.0%	Diamond
Equus caballus	Q95LG1	82.2%	Diamond
Chlorocebus aethiops	P79138	81.6%	Diamond
Canis lupus familiaris	P33730	80.6%	Diamond
Danio rerio	A0A1D5NSM8	54.8%	Diamond
Gallus gallus	P81475	44.5%	Diamond
Drosophila melanogaster	Q09101	40.0%	Diamond
Caenorhabditis elegans	Q22328	39.8%	Diamond
Vaccinia virus WR	P68638	100.0%	Diamond
Vaccinia virus Copenhagen	P68639	100.0%	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
C2-AS1	ncRNA	102060414
DXO	protein-coding	1797
CFB	protein-coding	629
SKIC2	protein-coding	6499
NELFE	protein-coding	7936
WHR1	protein-coding	8859
MIR1236	ncRNA	100302242
EHMT2-AS1	ncRNA	107986588
EHMT2	protein-coding	10919
ZBTB12	protein-coding	221527
SNORD52	snoRNA	26797
NEU1	protein-coding	4758
SNHG32	ncRNA	50854
SLC44A4	protein-coding	80736

Protein

Protein identifiers

Complement C2 — P06681 (reviewed: P06681)

Alternative names: C3/C5 convertase

All UniProt accessions (17): A0A8Q3WKM6, A0A8Q3WKM9, A0A8Q3WKN5, A0A8Q3WL70, A2ABG0, B4DQI1, C9JYQ5, E9PDZ0, P06681, F2Z306, F2Z3N2, F8WCJ9, H0Y3H6, H0Y868, Q5JP69, Q5ST52, Q8N6L6

UniProt curated annotations — full annotation on UniProt →

Function. Precursor of the catalytic component of the C3 and C5 convertase complexes, which are part of the complement pathway, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system. Component C2 is part of the classical, lectin and GZMK complement systems. Catalytic component of the complement C3 and C5 convertase complexes. Following complement activation, recruited to the surface of pathogens by complement C4b opsonin to form the C3 convertase, or C3b and C4b opsonins to form the C5 convertase. As part of the C3 convertase, cleaves and activate C3 into C3a anaphylatoxin and C3b opsonin, the next components of the complement pathways. As part of the C5 convertase, cleaves and activate C5 into C5a anaphylatoxin and C5b component of the membrane attack complex.

Subunit / interactions. Serine protease component of the C3 convertase, also named C4bC2b, composed of the serine protease complement C2b and complement C4b. Serine protease component of the C5 convertase, also named C4bC2bC3b, composed of the serine protease complement C2b, complement C3b, as well as complement C4b. (Microbial infection) Interacts with Schistosoma haematobium TOR (via N-terminal extracellular domain). This results in inhibition of the classical and lectin pathway of complement activation, probably due to interference with binding of C2a to C4b such that C3 convertase cannot be formed. This infers resistance to complement-mediated cell lysis, allowing parasite survival and infection.

Subcellular location. Secreted. Cell surface.

Post-translational modifications. Cleaved and activated by different proteases depending on the complement pathway to generate complement C2a and serine protease complement C2b chains. Cleaved and activated by C1S following activation by the classical complement system. Cleaved and activated by MASP2 following activation by the lectin complement system. Cleaved and activated by GZMK following activation by the GZMK complement system.

Disease relevance. Macular degeneration, age-related, 14 (ARMD14) [MIM:615489] 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 may be associated with variants affecting the gene represented in this entry. Haplotype analyzes have identified a statistically significant common risk haplotype and two protective haplotypes. CFB variant His-9 and C2 variant Asp-318, as well as CFB variant Gln-32 and a variant in intron 10 of C2, confer a significantly reduced risk of AMD. Complement component 2 deficiency (C2D) [MIM:217000] A rare defect of the complement classical pathway associated with the development of autoimmune disorders, mainly systemic lupus erythematosus. Skin and joint manifestations are common and renal disease is relatively rare. Patients with complement component 2 deficiency are also reported to have recurrent invasive infections. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The MIDAS-like motif in the VWFA domain binds divalent metal cations.

Miscellaneous. C2 is a major histocompatibility complex class-III protein.

Similarity. Belongs to the peptidase S1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
P06681-1	1	yes
P06681-2	2
P06681-3	3

RefSeq proteins (6): NP_000054, NP_001139375, NP_001171534, NP_001269386, NP_001269387, NP_001269388 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000436	Sushi_SCR_CCP_dom	Domain
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR002035	VWF_A	Domain
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR011360	Compl_C2_B	Family
IPR018114	TRYPSIN_HIS	Active_site
IPR033116	TRYPSIN_SER	Active_site
IPR035976	Sushi/SCR/CCP_sf	Homologous_superfamily
IPR036465	vWFA_dom_sf	Homologous_superfamily
IPR043504

Pfam: PF00084, PF00089, PF00092

UniProt features (129 total): strand 43, helix 25, disulfide bond 11, glycosylation site 8, binding site 6, sequence variant 6, domain 5, mutagenesis site 5, sequence conflict 5, chain 3, active site 3, turn 3, splice variant 3, signal peptide 1, site 1, short sequence motif 1

Structure

Experimental structures (PDB)

14 structures by resolution:

PDB	Title	Method	Resolution (Å)
3ERB	The Crystal Structure of C2b, a Fragment of Complement Component C2 produced during …	X-RAY DIFFRACTION	1.8
8ACF	Structure of the argX-117 in complex with a complement C2 fragment at low pH	X-RAY DIFFRACTION	1.8
8ACI	Structure of ARG-117 Fab in complex with a fragment of complement C2, neutral pH	X-RAY DIFFRACTION	1.85
2ODP	Complement component C2a, the catalytic fragment of C3- and C5-convertase of human …	X-RAY DIFFRACTION	1.9
2I6Q	Complement component C2a	X-RAY DIFFRACTION	2.1
2ODQ	Complement component C2a, the catalytic fragment of C3- and C5-convertase of human …	X-RAY DIFFRACTION	2.3
2I6S	Complement component C2a	X-RAY DIFFRACTION	2.7
9U60	C3 convertases zymogen C4b2 in loading state	ELECTRON MICROSCOPY	2.9
9U5Z	C3 convertases zymogen C4b2 in activation state	ELECTRON MICROSCOPY	3.1
9U61	CP/MBL pathways C3 convertase C4b2a and C3 complex	ELECTRON MICROSCOPY	3.1
9QJ5	Structure of the Complement classical and lectin pathway proconvertase, C4b2	ELECTRON MICROSCOPY	3.5
9QK2	Structure of the Complement classical and lectin pathway C3 convertase in complex with …	ELECTRON MICROSCOPY	3.5
9QJ4	Structure of the Complement classical and lectin pathway proconvertase, C4b2	ELECTRON MICROSCOPY	3.9
9QPY	Structure of the Complement classical and lectin pathway C3 convertase	ELECTRON MICROSCOPY	4.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P06681-F1	88.61	0.66

Antibody-complex structures (SAbDab)

3 antibodies co-crystallized with this protein: 8ACF, 8ACI, EMPASIPRUBART

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Serine-type peptidases, Predicted secreted proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, Potential drug targets, Human disease related genes, Primary immunodeficiency, Eye disease

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH supported

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 (4)

Position	Role
507	charge relay system
561	charge relay system
679	charge relay system
243–244	cleavage; by c1s, masp2 and gzmk

Ligand- & substrate-binding residues (6)

Position	Role
262	Mg(2+)
262	Mn(2+)
264	Mg(2+)
264	Mn(2+)
337	Mg(2+)
337	Mn(2+)

Disulfide bonds (11)

Type	Positions
Disulfide bond	24–64, 51–84, 89–131, 117–144, 151–191, 177–204, 463–581, 492–508, 584–600, 638–665, 675–705

Glycosylation sites (8)

Type	Positions
N-linked (glcnac…) asparagine	29, 112, 290, 333, 467, 471, 621
N-linked (glcnac…) (complex) asparagine	651

Mutagenesis-validated functional residues (5)

Position	Phenotype
261	prolonged activity and half-life.
263	prolonged activity and half-life.
344	promotes partial resistance to degradation, slightly increasing half-life of the protein.
347	promotes resistance to degradation, increasing half-life of the protein.
348	promotes partial resistance to degradation, slightly increasing half-life of the protein.

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 6; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

6 pathways:

ID	Pathway	Evidence
R-HSA-174577	Activation of C3 and C5	curated
R-HSA-166663	Initial triggering of complement	curated
R-HSA-977606	Regulation of Complement cascade	curated
R-HSA-166658	Complement cascade	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—

MSigDB gene sets: 259 (showing top): MODULE_172, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, MODULE_45, GOCC_CELL_SURFACE, GOBP_APOPTOTIC_CELL_CLEARANCE, GOBP_VESICLE_MEDIATED_TRANSPORT, GAURNIER_PSMD4_TARGETS, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_B_CELL_MEDIATED_IMMUNITY, YAN_ESCAPE_FROM_ANOIKIS, PICCALUGA_ANGIOIMMUNOBLASTIC_LYMPHOMA_UP, GOBP_REGULATION_OF_IMMUNE_RESPONSE, MODULE_75

GO Biological Process (8): proteolysis (GO:0006508), complement activation (GO:0006956), complement activation, classical pathway (GO:0006958), response to bacterium (GO:0009617), complement activation, GZMK pathway (GO:0160257), positive regulation of apoptotic cell clearance (GO:2000427), immune system process (GO:0002376), innate immune response (GO:0045087)

GO Molecular Function (6): serine-type endopeptidase activity (GO:0004252), metal ion binding (GO:0046872), protein binding (GO:0005515), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (4): extracellular region (GO:0005576), cell surface (GO:0009986), extracellular exosome (GO:0070062), symbiont cell surface (GO:0106139)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Complement cascade	3
Innate Immune System	1
Immune System	1

GO top-level categories

27 GO namespaces:

Category	Terms
complement activation	2
cellular anatomical structure	2
protein metabolic process	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
response to other organism	1
innate immune response	1
apoptotic cell clearance	1
positive regulation of phagocytosis	1
regulation of apoptotic cell clearance	1
biological_process	1
immune response	1
defense response to symbiont	1
endopeptidase activity	1
serine-type peptidase activity	1
cation binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
serine hydrolase activity	1
catalytic activity	1
extracellular vesicle	1
other organism part	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 5 of 19 annotations. The rest are phylogenetic / computational / electronic (IEA).

5 experimentally-supported GO terms:

GO term	NS	Evidence
complement activation	BP	direct assay
complement activation, GZMK pathway	BP	direct assay
positive regulation of apoptotic cell clearance	BP	mutant phenotype
extracellular exosome	CC	high-throughput assay
symbiont cell surface	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 696 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C2	CFH	P08603	844
C2	DXO	O77932	737
C2	CFHR3	Q02985	733
C2	C3	P01024	719
C2	ARMS2	P0C7Q2	719
C2	CFHR1	Q03591	711
C2	CFI	P05156	701
C2	HMCN1	Q96RW7	687
C2	FBLN5	Q9UBX5	623
C2	C4A	P01028	622
C2	SKIC2	Q15477	621
C2	WHR1	P49842	617
C2	C4A	P01028	604
C2	C9	P02748	587
C2	C5	P01031	555

IntAct

Human interaction partners of C2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

11 partners by confidence:

Partner	Interaction type	MIscore	Records
SEC11C	physical association	0.560	5
CREB3	physical association	0.560	3
EBP	physical association	0.560	3
ERGIC3	physical association	0.560	3
FAM209A	physical association	0.560	3
MUC1	physical association	0.560	3
SLC10A1	physical association	0.560	3
SLC35C2	physical association	0.560	3
STOM	physical association	0.560	3
C1S	protein cleavage	0.440	1
CD55	physical association	0.400	2

BioGRID (14 interactions; top human partners by supporting records): C4B (Reconstituted Complex; 2 records), CD55 (Affinity Capture-MS; 2 records), CREB3 (Two-hybrid), EBP (Two-hybrid), ERGIC3 (Two-hybrid), FAM209A (Two-hybrid), HNRNPH1 (Affinity Capture-RNA), MUC1 (Two-hybrid), SEC11C (Two-hybrid), SLC10A1 (Two-hybrid), SLC35C2 (Two-hybrid), STOM (Two-hybrid)

SIGNOR signaling

showing 4 of 7 signaling interactions:

A	Effect	B	Mechanism
MASP2	“up-regulates activity”	C2	cleavage
MASP1	“up-regulates activity”	C2	cleavage
C2	“form complex”	“C3 convertase complex”	binding
“Complement C1 complex”	“up-regulates activity”	C2	cleavage

Disease & clinical

Genetic variants

Variant evidence for C2: 542 ClinVar records (32 pathogenic / likely pathogenic); 68 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	13
Uncertain significance	246
Likely benign	191
Benign	3

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 32 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
3381002	NM_000063.6(C2):c.1829_1832del (p.Lys610fs)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
591016	NM_000063.6(C2):c.1102C>T (p.Arg368Ter)	Pathogenic	criteria provided, single submitter	2
2054147	NM_000063.6(C2):c.275_276del (p.Pro92fs)	Pathogenic	criteria provided, single submitter	2
636724	NM_000063.6(C2):c.1482_1483delinsC (p.Ala495fs)	Pathogenic	criteria provided, single submitter	1
1452098	NM_000063.6(C2):c.37del (p.Leu13fs)	Pathogenic	criteria provided, single submitter	1
2750154	NM_000063.6(C2):c.917del (p.Met306fs)	Pathogenic	criteria provided, single submitter	1
2818188	NM_000063.6(C2):c.970G>T (p.Glu324Ter)	Pathogenic	criteria provided, single submitter	1
2842298	NM_000063.6(C2):c.1654C>T (p.Gln552Ter)	Pathogenic	criteria provided, single submitter	1
2870130	NM_000063.6(C2):c.795_796del (p.Ser266fs)	Pathogenic	criteria provided, single submitter	1
2876427	NM_000063.6(C2):c.630T>A (p.Tyr210Ter)	Pathogenic	criteria provided, single submitter	1
2965736	NM_000063.6(C2):c.768C>G (p.Tyr256Ter)	Pathogenic	criteria provided, single submitter	1
3257316	NM_000063.6(C2):c.1215T>A (p.Tyr405Ter)	Pathogenic	criteria provided, single submitter	1
3393189	NM_000063.6(C2):c.1902+1G>A	Pathogenic	criteria provided, single submitter	1
3720679	NM_000063.6(C2):c.235_236del (p.Leu79fs)	Pathogenic	criteria provided, single submitter	1
4712064	NM_000063.6(C2):c.1790del (p.Gly597fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore C2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 33 predictions of 1,513):

Position(s)	Effect	Δscore	Sites
6:31933865–31933866	acceptor_loss	1.0000	6
6:31933966–31933967	donor_loss	1.0000	5
6:31934274	donor_gain	1.0000
6:31937307	acceptor_gain	1.0000
6:31937311	acceptor_gain	1.0000
6:31939321–31939322	donor_loss	1.0000	3
6:31942957–31942958	acceptor_loss	1.0000	6
6:31943100–31943101	donor_loss	1.0000	5
6:31943320–31943321	donor_loss	1.0000	4
6:31943784	donor_gain	1.0000

AlphaMissense

1,269 missense substitutions predicted likely pathogenic (of 4,972 scored), across 349 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
D561	8	0.978	0.994
D260	8	0.957	0.972
D727	8	0.928	0.962
H507	8	0.925	0.965
D211	8	0.912	0.950
D376	8	0.911	0.966
F749	8	0.894	0.984
F733	8	0.893	0.978
D407	8	0.856	0.912
H435	8	0.838	0.941
H603	8	0.751	0.935
C581	7	0.993	0.997
C508	7	0.992	0.995
C584	7	0.989	0.996
C144	7	0.987	0.994
C131	7	0.984	0.995
C492	7	0.984	0.992
C665	7	0.984	0.995
W197	7	0.983	0.999
C191	7	0.982	0.995

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Liver Hepatocellular Carcinoma)

Disease associations

OMIM: gene MIM:613927 | disease phenotypes: MIM:217000, MIM:615489

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
complement component 2 deficiency	Strong	Autosomal recessive	2

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (2 panels, 2 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

2 panels:

Panel	Rating
COVID-19 research	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green

Mondo (2): complement component 2 deficiency (MONDO:0009006), age related macular degeneration 14 (MONDO:0014207)

HPO phenotypes

3 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000979	Purpura
HP:0002725	Systemic lupus erythematosus

GWAS associations

showing 30 of 68 associations:

Study	Trait	p-value
GCST003219_18	Advanced age-related macular degeneration	1e-103
GCST001884_13	Age-related macular degeneration	4e-89
GCST004133_55	Ulcerative colitis	5e-65
GCST004131_25	Inflammatory bowel disease	2e-31
GCST001100_11	Age-related macular degeneration	2e-23
GCST000652_8	Age-related macular degeneration	3e-21
GCST002463_14	Systemic lupus erythematosus	8e-21
GCST000653_7	Age-related macular degeneration	2e-20
GCST004521_4	Autism spectrum disorder or schizophrenia	8e-20
GCST010723_2	Early age-related macular degeneration	1e-18
GCST004521_71	Autism spectrum disorder or schizophrenia	6e-18
GCST004521_265	Autism spectrum disorder or schizophrenia	3e-17
GCST004863_141	Mosquito bite size	1e-16
GCST004521_214	Autism spectrum disorder or schizophrenia	2e-16
GCST004521_85	Autism spectrum disorder or schizophrenia	5e-16
GCST012227_641	Hip circumference adjusted for BMI	1e-15
GCST90020024_409	A body shape index	2e-15
GCST004521_268	Autism spectrum disorder or schizophrenia	3e-15
GCST004521_269	Autism spectrum disorder or schizophrenia	3e-15
GCST004521_87	Autism spectrum disorder or schizophrenia	5e-15
GCST004521_220	Autism spectrum disorder or schizophrenia	1e-14
GCST012230_525	Waist-to-hip ratio adjusted for BMI	2e-14
GCST004521_124	Autism spectrum disorder or schizophrenia	4e-14
GCST005195_41	Coronary artery disease	3e-13
GCST004521_89	Autism spectrum disorder or schizophrenia	5e-13
GCST005196_199	Coronary artery disease	6e-13
GCST012228_424	Waist-hip index	1e-12
GCST004521_168	Autism spectrum disorder or schizophrenia	2e-12
GCST004521_128	Autism spectrum disorder or schizophrenia	4e-12
GCST008746_16	Estimated glomerular filtration rate in diabetes	5e-12

EFO canonical traits (from GWAS)

12 canonical traits:

EFO ID	Trait name
EFO:1001492	atrophic macular degeneration
EFO:0005243	myeloperoxidase measurement
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0008336	disease progression measurement
EFO:0006781	coffee consumption measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0009130	clostridium difficile infection
EFO:0004531	urate measurement
EFO:0009749	age at first sexual intercourse measurement
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295701 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL4247125	IC50	28000 nM

ChEMBL bioactivities

3 potent at pChembl≥5 of 4 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.48	IC50	330	nM	CHEMBL4247125
6.30	IC50	500	nM	CHEMBL4247125
5.14	IC50	7300	nM	CHEMBL4247125

PubChem BioAssay actives

3 with measured affinity, of 4 total; 1 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
(2S)-2-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methylpentanamide	1393232: Competitive/reversible inhibition of human C2 using Ac-SHLGLAR-pNA as substrate	ic50	0.3300	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	affects expression, affects methylation, decreases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	2
Smoke	decreases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
propionaldehyde	increases expression	1
bisphenol A	increases expression	1
beta-lapachone	decreases expression, increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	decreases expression	1
aflatoxin B2	decreases methylation	1
chromium hexavalent ion	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Aripiprazole	affects cotreatment, increases expression	1
Fulvestrant	increases methylation	1
Acetaminophen	decreases expression	1
Glyphosate	increases expression	1
Air Pollutants, Occupational	increases expression	1
Allergens	affects cotreatment, increases expression	1
Vehicle Emissions	affects cotreatment, increases expression	1
Benzene	increases expression	1
Calcitriol	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Methapyrilene	decreases methylation	1
Nickel	increases expression	1
Ozone	increases expression, affects cotreatment	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4229702	Binding	Competitive/reversible inhibition of human C2 using Ac-SHLGLAR-pNA as substrate	Chemical Approaches to Modulating Complement-Mediated Diseases. — *J Med Chem*

Clinical trials (associated diseases)

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

showing 60 of 299 trials:

NCT	Phase	Status	Title
NCT02574403	Phase 4	COMPLETED	Study Assessing an Algorithm-based Strategy of Eculizumab Discontinuation in Children and Adults With aHUS
NCT07308574	Phase 4	RECRUITING	Post-Marketing Clinical Study of Ravulizumab in Participants With Clinical aHUS
NCT01129557	Phase 4	TERMINATED	Aldosterone Breakthrough During Diovan, Tekturna, and Combination Therapy in Patients With Proteinuric Kidney Disease
NCT02399462	Phase 4	WITHDRAWN	Acthar for Treatment of Post-transplant FSGS
NCT02585804	Phase 4	COMPLETED	Treating to Reduce Albuminuria and Normalize Hemodynamic Function in Focal ScLerosis With dApagliflozin Trial Effects
NCT02633046	Phase 4	COMPLETED	Acthar for Treatment-Resistant or Treatment-Intolerant Proteinuria
NCT07219121	Phase 4	ACTIVE_NOT_RECRUITING	Sparsentan in Posttransplant Immunoglobulin A Nephropathy or Focal Segmental Glomerulosclerosis
NCT00312351	Phase 4	TERMINATED	A Clinical Trial to Explore the Safety and Efficacy of Three Different Doses of Pegaptanib Sodium in Patients With Wet Age-Related Macular Degeneration (AMD)
NCT00324116	Phase 4	COMPLETED	Evaluation Of Safety And Efficacy Of 0.3 Mg/Eye Macugen In Patients With Small Age-Related Macular Degeneration Lesions
NCT00327470	Phase 4	TERMINATED	An Open Label Trial to Investigate Macugen for the Preservation of Visual Function in Subjects With Neovascular AMD
NCT00533520	Phase 4	COMPLETED	Evaluation of Dosing Interval of Higher Doses of Ranibizumab
NCT00813891	Phase 4	UNKNOWN	Efficacy of Ranibizumab in Combination With Photodynamic Therapy for Wet Age-Related Macular Degeneration
NCT01006538	Phase 4	COMPLETED	Macular EpiRetinal Brachytherapy Versus Lucentis® Only Treatment (MERLOT)
NCT01213667	Phase 4	UNKNOWN	Genetics in Non-response to Anti-VEGF Treatment in Exudative AMD
NCT01831947	Phase 4	COMPLETED	Efficacy Study of Ranibizumab on Patients With Age-related Macular Degeneration.
NCT02581891	Phase 4	COMPLETED	Managing Neovascular (Known as Wet) Age-related Macular Degeneration Over 2 Years Using Different Treatment Schedules of 2 mg Intravitreal Aflibercept Injected in the Eye
NCT02689518	Phase 4	COMPLETED	EAGLE: Evaluating Genotypes Using Intravitreal Aflibercept Injection
NCT03804099	Phase 4	COMPLETED	Effect Aflibercept on Ocular Perfusion
NCT07367282	Phase 4	RECRUITING	Evaluate the Efficacy of Faricimab in Patients With Neovascular Age-related Macular Degeneration
NCT07779356	Phase 4	COMPLETED	Patient Comfort Following Intravitreal Injections Using Iheezo Versus Standard Anesthesia
NCT02949128	Phase 3	COMPLETED	Study of ALXN1210 in Complement Inhibitor Treatment-Naïve Adult and Adolescent Participants With Atypical Hemolytic Uremic Syndrome (aHUS)
NCT03131219	Phase 3	COMPLETED	Study of Ravulizumab in Children and Adolescents With Atypical Hemolytic Uremic Syndrome (aHUS)
NCT03205995	Phase 3	TERMINATED	Safety and Efficacy Study of OMS721 in Patients With Atypical Hemolytic Uremic Syndrome
NCT04861259	Phase 3	ACTIVE_NOT_RECRUITING	A Study Evaluating the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Crovalimab in Adult and Adolescent Participants With Atypical Hemolytic Uremic Syndrome (aHUS)
NCT04889430	Phase 3	COMPLETED	Efficacy and Safety of Iptacopan (LNP023) in Adult Patients With Atypical Hemolytic Uremic Syndrome Naive to Complement Inhibitor Therapy
NCT04958265	Phase 3	ACTIVE_NOT_RECRUITING	A Study Evaluating the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Crovalimab in Pediatric Participants With Atypical Hemolytic Uremic Syndrome (aHUS)
NCT05795140	Phase 3	RECRUITING	Evaluate Long-term Safety, Tolerability and Efficacy of Iptacopan in Study Participants With aHUS
NCT05935215	Phase 3	RECRUITING	Efficacy and Safety of Switching From Anti-C5 Antibody Treatment to Iptacopan Treatment in Study Participants With Atypical Hemolytic Uremic Syndrome (aHUS)
NCT01164098	Phase 3	TERMINATED	Rituximab to Prevent Recurrence of Proteinuria
NCT02683889	Phase 3	COMPLETED	Use of Acthar in Patients With FSGS That Will be Undergoing Renal Transplantation
NCT03298698	Phase 3	UNKNOWN	Efficacy of Rituximab in Comparison to Continued Corticosteroid Treatment in Idiopathic Nephrotic Syndrome
NCT03493685	Phase 3	COMPLETED	Study of Sparsentan in Patients With Primary Focal Segmental Glomerulosclerosis (FSGS)
NCT05183646	Phase 3	RECRUITING	A Study of the Efficacy and Safety of DMX-200 in Patients With FSGS Who Are Receiving an ARB
NCT07220083	Phase 3	RECRUITING	A Study to Find Out if BI 764198 Helps Adults and Adolescents With a Kidney Condition Called Focal Segmental Glomerulosclerosis (FSGS)
NCT00000145	Phase 3	COMPLETED	Age-Related Eye Disease Study (AREDS)
NCT00000150	Phase 3	COMPLETED	Submacular Surgery Trials (SST)
NCT00000152	Phase 3	UNKNOWN	Randomized Trial of Beta-Carotene and Macular Degeneration
NCT00000158	Phase 3	UNKNOWN	Macular Photocoagulation Study (MPS)
NCT00000161	Phase 3	UNKNOWN	Randomized Trials of Vitamin Supplements and Eye Disease
NCT00000162	Phase 3	COMPLETED	Branch Vein Occlusion Study
NCT00000167	Phase 3	COMPLETED	Complications of Age-Related Macular Degeneration Prevention Trial
NCT00041483	Phase 3	COMPLETED	Phase 3 Study to Evaluate Anecortave Acetate vs. Visudyne for the Treatment of the Wet Form of AMD
NCT00042211	Phase 3	COMPLETED	Preventing Depression in Patients With Macular Degeneration
NCT00050479	Phase 3	COMPLETED	Laser and Medical Treatment of Diabetic Macular Edema
NCT00051129	Phase 3	COMPLETED	Anecortave Acetate in Subfoveal Choroidal Neovascularization (CNV) Due to Wet Age-Related Macular Degeneration (AMD)
NCT00056836	Phase 3	COMPLETED	A Study to Evaluate rhuFab V2 in Subjects With Minimally Classic or Occult Subfoveal Neovascular Macular Degeneration
NCT00058994	Phase 3	COMPLETED	An Evaluation of Safety and Efficacy of Anecortave Acetate Versus Placebo in Patients With Subfoveal CNV Due to Exudative AMD
NCT00061594	Phase 3	COMPLETED	A Study to Compare rhuFab V2 With Verteporfin Photodynamic in Treating Subfoveal Neovascular Macular Degeneration
NCT00065728	Phase 3	TERMINATED	Open-Label Posterior Juxtascleral Injections of Anecortave Acetate 15mg Dose for Long Term Use in Patients With AMD
NCT00078221	Phase 3	UNKNOWN	Rheopheresis Blood Filtration Study for the Treatment of Dry Age-Related Macular Degeneration (AMD)
NCT00090623	Phase 3	COMPLETED	A Study of rhuFab V2 (Ranibizumab) in Subjects With Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (AMD)
NCT00095433	Phase 3	COMPLETED	Extension Study of rhuFab V2 in Subjects With Neovascular Age-Related Macular Degeneration (AMD)
NCT00100009	Phase 3	COMPLETED	Triamcinolone Acetonide Plus Laser Therapy to Treat Age-Related Macular Degeneration
NCT00121407	Phase 3	COMPLETED	Visudyne® in Occult (VIO)
NCT00150202	Phase 3	COMPLETED	Clinical Study Of EYE001 For Wet-Type AMD (Age-Related Macular Degeneration)
NCT00157976	Phase 3	UNKNOWN	Double-Masked Study of Photrex (Rostaporfin) Photodynamic Therapy in the Treatment of Age-Related Macular Degeneration
NCT00242580	Phase 3	COMPLETED	A Safety and Efficacy Study Comparing the Combination Treatments of Verteporfin Therapy Plus One of Two Different Doses of Intravitreal Triamcinolone Acetonide and the Verteporfin Therapy Plus Intravitreal Pegaptanib
NCT00299507	Phase 3	COMPLETED	Anecortave Acetate in Patients With Exudative Age-related Macular Degeneration (AMD)
NCT00436553	Phase 3	COMPLETED	Efficacy/Safety of Verteporfin Photodynamic Therapy and Ranibizumab Compared With Ranibizumab in Patients With Subfoveal Choroidal Neovascularization
NCT00454389	Phase 3	UNKNOWN	A Study of Strontium90 Beta Radiation With Lucentis to Treat Age-Related Macular Degeneration