APOC3

Summary

APOC3 (apolipoprotein C3, HGNC:610) is a protein-coding gene on chromosome 11q23.3, encoding Apolipoprotein C-III (P02656). Component of triglyceride-rich very low density lipoproteins (VLDL) and high density lipoproteins (HDL) in plasma.

This gene encodes a protein component of triglyceride (TG)-rich lipoproteins (TRLs) including very low density lipoproteins (VLDL), high density lipoproteins (HDL) and chylomicrons. The encoded protein plays a role in role in the metabolism of these TRLs through multiple modes. This protein has been shown to promote the secretion of VLDL1, inhibit lipoprotein lipase enzyme activity, and delay catabolism of TRL remnants. Mutations in this gene are associated with low plasma triglyceride levels and reduced risk of ischemic cardiovascular disease, and hyperalphalipoproteinemia, which is characterized by elevated levels of high density lipoprotein (HDL) and HDL cholesterol in human patients. This gene and other related genes comprise an apolipoprotein gene cluster on chromosome 11.

Source: NCBI Gene 345 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cholesterol-ester transfer protein deficiency (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 54
• Clinical variants (ClinVar): 86 total — 2 pathogenic
• Phenotypes (HPO): 3
• Druggable target: yes
• MANE Select transcript: NM_000040

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:610
Approved symbol	APOC3
Name	apolipoprotein C3
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	Apo-CIII, ApoC-III, APOCIII, Apo-C3, ApoC-3
Ensembl gene	ENSG00000110245
Ensembl biotype	protein_coding
OMIM	107720
Entrez	345

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 27 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000227667, ENST00000375345, ENST00000433777, ENST00000470144, ENST00000630701, ENST00000863784, ENST00000863785, ENST00000863786, ENST00000863787, ENST00000863788, ENST00000863789, ENST00000863790, ENST00000863791, ENST00000863792, ENST00000863793, ENST00000863794, ENST00000863795, ENST00000863796, ENST00000863797, ENST00000863798, ENST00000863799, ENST00000863800, ENST00000863801, ENST00000863802, ENST00000863803, ENST00000863804, ENST00000863805, ENST00000863806

RefSeq mRNA: 1 — MANE Select: NM_000040 NM_000040

CCDS: CCDS8377

Canonical transcript exons

ENST00000227667 — 4 exons

Exon	Start	End
ENSE00001413859	116832764	116833072
ENSE00001615517	116829907	116829940
ENSE00003501097	116830570	116830637
ENSE00003643258	116830773	116830896

Expression profiles

Bgee: expression breadth ubiquitous, 156 present calls, max score 99.98.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 58.8372 / max 19828.3420, expressed in 176 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
116842	55.1020	165
116841	3.1326	91
116845	0.2156	22
116847	0.1099	25
116851	0.0607	15
116848	0.0547	18
116843	0.0475	13
116850	0.0429	13
116849	0.0342	15
116844	0.0223	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	99.98	gold quality
right lobe of liver	UBERON:0001114	99.96	gold quality
liver	UBERON:0002107	99.94	gold quality
ileal mucosa	UBERON:0000331	99.44	gold quality
duodenum	UBERON:0002114	96.13	gold quality
small intestine	UBERON:0002108	93.19	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.98	gold quality
jejunum	UBERON:0002115	82.15	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.88	gold quality
amniotic fluid	UBERON:0000173	74.89	silver quality
adult mammalian kidney	UBERON:0000082	74.32	gold quality
colonic epithelium	UBERON:0000397	73.36	gold quality
Brodmann (1909) area 10	UBERON:0013541	71.16	gold quality
kidney	UBERON:0002113	69.09	gold quality
metanephros	UBERON:0000081	66.28	gold quality
left uterine tube	UBERON:0001303	65.31	gold quality
metanephros cortex	UBERON:0010533	64.61	gold quality
body of pancreas	UBERON:0001150	64.08	gold quality
cortex of kidney	UBERON:0001225	63.22	gold quality
intestine	UBERON:0000160	63.08	gold quality
endometrium epithelium	UBERON:0004811	62.49	gold quality
descending thoracic aorta	UBERON:0002345	62.42	gold quality
cerebellar vermis	UBERON:0004720	62.29	gold quality
paraflocculus	UBERON:0005351	62.12	gold quality
frontal pole	UBERON:0002795	62.01	gold quality
middle frontal gyrus	UBERON:0002702	61.96	gold quality
granulocyte	CL:0000094	60.92	gold quality
mucosa of stomach	UBERON:0001199	60.83	gold quality
right lung	UBERON:0002167	60.48	gold quality
body of stomach	UBERON:0001161	60.06	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-HCAD-9	yes	48741.59
E-MTAB-7407	yes	25769.85
E-MTAB-8221	yes	18028.03
E-GEOD-125970	yes	13686.87
E-CURD-98	yes	12582.84
E-ANND-5	yes	842.56
E-MTAB-10553	yes	41.97
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF2, CEBPA, CEBPD, CEBPG, FOXO1, FOXP3, HDAC1, HDAC3, HNF1A, HNF4A, HNF4G, JUN, JUNB, JUND, KAT5, MXD1, NCOA1, NFKB1, NFKB, NR0B1, NR0B2, NR1D1, NR1D2, NR1H4, NR1I3, NR2F1, NR2F2, NR2F6, NR4A1, PITX2, PPARA, PPARGC1A, RARA, RORA, RXRA, SMAD3, SMAD4, SP1, STAT5B, TCF3

miRNA regulators (miRDB)

21 targeting APOC3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-2392	99.43	67.50	708
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-8071	95.69	64.93	484
HSA-MIR-5191	95.22	64.69	354

Literature-anchored findings (GeneRIF, showing 40)

• activation of promoter by upstream stimulatory factor and hepatic nuclear factor-4 in presence of initiator-like elements (PMID:11839757)
• Study shows a significant association between rare S2 allele of APOC3 and hypertriglyceridemia in Asian Indians. (PMID:12052247)
• The lipid-interacting properties of the N-terminal domain of human apolipoprotein C-III (apo C-III) were investigated (PMID:12082170)
• Apolipoprotein C-III and E polymorphisms and cardiovascular syndrome, hyperlipidemia, and insulin resistance in renal transplantation (PMID:12118856)
• In a group of healthy adults, this polymorphism was associated with circulating triglycerides, with 55% lower fasting levels in the homozygous wild-type (TT) compared to the homozygous rare allele (GG) genotype. (PMID:12176399)
• SstI polymorphism is associated with insulin sensitivity in young men but not in women (PMID:12189450)
• homozygosity for a ApoC-III gene polymorphism was associated with a significantly increased risk of coronary artery disease, suggesting that it represents an independent genetic susceptibility factor for CAD (PMID:12235176)
• ApoC-III is associated with binding to the vascular proteoglycan biglycan (PMID:12401896)
• Hepatitis B virus (HBV) reduced steady-state levels of apolipoprotein 3 mRNAs in two hepatoma cell lines (PMID:12692252)
• APOC3 worked as LPL-inhibitor of the lipolysis activated by APOC2. The binding density of APOC3 was less for small emulsion surfaces than for large ones. (PMID:12782148)
• associations between the apolipoprotein CIII polymorphism and triacylglycerol concentrations in fasting and postprandial plasma (PMID:14517726)
• apoC-III-rich lipoprotein metabolism and the APOC3 polymorphism have relevant impacts on the coronary artery disease risk of metabolic syndrome patents (PMID:14563827)
• evidence for a pleiotropic effect between HDL, HDL3 and triglycerides at the APOC3 locus (PMID:14569462)
• APOC3, LPL and GpIIIa genes were found to be associated with BP levels. The contributions of these genes, although modest, are consistent with the polygenic nature of blood pressure levels. (PMID:15076187)
• APOA5 and APOC3 independently influence plasma triglyceride concentrations but in an opposing manner. (PMID:15117734)
• S2 allele – a susceptibility marker for high triglycerides levels (PMID:15124908)
• Atorvastatin treatment resulted in a significant dose-dependent reduction in plasma apoC-III in patients with type 2 diabetes. (PMID:15161788)
• Increased hepatic production of VLDL apoC-III may be characteristic of subjects with higher body weights and lower levels of insulin sensitivity and is strongly related to plasma concentration and level of production of VLDL TG. (PMID:15292332)
• Human apoA-I/C-III/A-IV transgenic rabbits may provide a reliable model for studies of the transcriptional regulation of the cluster, and for evaluating the effects of different agents on the expression of the three genes. (PMID:15304365)
• apo C III is an independent risk factor for atherosclerotic diseases in Chinese type 2 diabetes. (PMID:15364160)
• elevated apoCIII concentration was associated with risk factors for cardiovascular disease in normolipidemic type 1 diabetic patients (PMID:15375785)
• This study evaluates in Asian-Indians the association between these polymorphisms with metabolic syndrome and dyslipidemia (PMID:15598690)
• positive association of apoCIII level with microvascular complications of Type 1 diabetes (PMID:15642486)
• the apoCIII enhancer regulates expression of apoAI, apo-CIII, and apoAIV but not apoAV in vivo; the entire cluster has roles in regulating lipid metabolism (PMID:15649902)
• Different levels of secreted apoC-III had little effect on LDL and HDL protein degradation by HepG2 cells. Compared to controls, cells under-expressing under-expressing apoC-III demonstrated 70 and 160% higher capacity to take up CE from LDL and HDL. (PMID:15778093)
• Variant alleles of APOE and APOC3 contribute to an unfavorable lipid profile in patients with HIV, who are therefore at high risk for severe ritonavir-associated hypertriglyceridemia. (PMID:15809899)
• Therefore, we conclude that the rare APOC3 G allele may offer some protection against the development of sporadic AD in APOE epsilon4 noncarriers in Chinese. (PMID:15862889)
• APO CIII metabolism is disturbed in type 2 diabetes. (PMID:15864534)
• The APOA5-1131T/C polymorphism but not APOC3-482C/T might contribute to an increased risk of coronary artery disease. (PMID:15924804)
• The association between hepatic lipase T+ genotypes and diabetic nephropathy appeared stronger in diabetic patients with apoC3 -482 non-TT genotypes. (PMID:15983323)
• These results support an exacerbating effect of the APOC3 Sst I single-nucleotide polymorphism on fasting TG levels since a large number of smaller VLDL particles are observed in LPL-deficient men bearing the APOC3 S2 allele. (PMID:16015281)
• haplotypes in the APOC3 gene but not in the apolipoprotein A5 gene increase susceptibility to myocardial infarction (PMID:16192625)
• The APOC3 SstI polymorphism analysis revealed that heterozygous carriers of the S2 allele had higher (P < 0.05) plasma apo C-III and TG concentrations, regardless of gender or dietary period. (PMID:16326171)
• Results show that the S1 allele of APOC3 SstI polymorphism might have a small effect on apoB levels in the Central European Caucasian population with dyslipidemia of metabolic syndrome. (PMID:16343038)
• increased VLDL-apoC-III concentrations resulting from an overproduction of VLDL-apoC-III are strongly associated with the delayed catabolism of triglycerides and apoB in VLDL (PMID:16410456)
• Hypertension was associated with higher ICA IMT only in male carriers of the rare allele of the APOCIII Sst-1 variant (p for the interaction=0.041). (PMID:16430904)
• Results suggest that all apoC-III isoforms, especially the predominant CIII1 and CIII2 isoforms, contribute to hypertriglyceridemia and that ApoC-III2 may play a significant role in the expression of the small, dense LDL phenotype. (PMID:16495512)
• Because modulation of lipoproteins is also seen in genetically altered longevity models, it may be a common pathway influencing lifespan from nematodes to humans (PMID:16602826)
• illustrate the impact of context-dependence on single nucleotide polymorphism selection for prediction of cardiovascular disea risk factor variability (PMID:16705465)
• the variability in APOA1/C3/A4/A5 gene cluster may affect TG and HDL levels in women with type 2 diabetes (PMID:16781717)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Apoc3	ENSMUSG00000032081
rattus_norvegicus	Apoc3	ENSRNOG00000047503

Protein

Protein identifiers

Apolipoprotein C-III — P02656 (reviewed: P02656)

Alternative names: Apolipoprotein C3

All UniProt accessions (4): P02656, A3KPE2, B0YIW2, C9J2Q0

UniProt curated annotations — full annotation on UniProt →

Function. Component of triglyceride-rich very low density lipoproteins (VLDL) and high density lipoproteins (HDL) in plasma. Plays a multifaceted role in triglyceride homeostasis. Intracellularly, promotes hepatic very low density lipoprotein 1 (VLDL1) assembly and secretion; extracellularly, attenuates hydrolysis and clearance of triglyceride-rich lipoproteins (TRLs). Impairs the lipolysis of TRLs by inhibiting lipoprotein lipase and the hepatic uptake of TRLs by remnant receptors. Formed of several curved helices connected via semiflexible hinges, so that it can wrap tightly around the curved micelle surface and easily adapt to the different diameters of its natural binding partners.

Subcellular location. Secreted.

Tissue specificity. Liver.

Post-translational modifications. The most abundant glycoforms are characterized by an O-linked disaccharide galactose linked to N-acetylgalactosamine (Gal-GalNAc), further modified with up to 3 sialic acid residues. Less abundant glycoforms are characterized by more complex and fucosylated glycan moieties. O-glycosylated on Thr-94 with a core 1 or possibly core 8 glycan.

Disease relevance. Hyperalphalipoproteinemia 2 (HALP2) [MIM:614028] A condition characterized by high levels of high density lipoprotein (HDL) and increased HDL cholesterol levels. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the apolipoprotein C3 family.

RefSeq proteins (1): NP_000031* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008403	Apo-CIII	Family
IPR038195	Apo_CIII_sf	Homologous_superfamily

Pfam: PF05778

UniProt features (20 total): helix 8, site 3, sequence conflict 2, sequence variant 2, signal peptide 1, chain 1, turn 1, region of interest 1, glycosylation site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2JQ3	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P02656-F1	67.90	0.00

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 (3): 37 (may interact with the ldl receptor); 41 (may interact with the ldl receptor); 44 (may interact with the ldl receptor)

Glycosylation sites (1): 94

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-8963888	Chylomicron assembly
R-HSA-8963901	Chylomicron remodeling
R-HSA-8964058	HDL remodeling
R-HSA-975634	Retinoid metabolism and transport
R-HSA-1430728	Metabolism
R-HSA-174824	Plasma lipoprotein assembly, remodeling, and clearance
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-2187338	Visual phototransduction
R-HSA-382551	Transport of small molecules
R-HSA-6806667	Metabolism of fat-soluble vitamins
R-HSA-8963898	Plasma lipoprotein assembly
R-HSA-8963899	Plasma lipoprotein remodeling
R-HSA-9709957	Sensory Perception

MSigDB gene sets: 226 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, MODULE_172, GOBP_ACYLGLYCEROL_HOMEOSTASIS, GOBP_REGULATION_OF_TRIGLYCERIDE_METABOLIC_PROCESS, GOBP_STEROL_HOMEOSTASIS, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GNF2_GSTM1, GNF2_HPN, HOEGERKORP_CD44_TARGETS_TEMPORAL_DN, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_PROTEIN_LIPID_COMPLEX_ASSEMBLY

GO Biological Process (26): triglyceride metabolic process (GO:0006641), G protein-coupled receptor signaling pathway (GO:0007186), negative regulation of triglyceride catabolic process (GO:0010897), negative regulation of very-low-density lipoprotein particle remodeling (GO:0010903), negative regulation of very-low-density lipoprotein particle clearance (GO:0010916), negative regulation of high-density lipoprotein particle clearance (GO:0010987), negative regulation of low-density lipoprotein particle clearance (GO:0010989), triglyceride catabolic process (GO:0019433), regulation of Cdc42 protein signal transduction (GO:0032489), cholesterol efflux (GO:0033344), phospholipid efflux (GO:0033700), high-density lipoprotein particle remodeling (GO:0034375), very-low-density lipoprotein particle assembly (GO:0034379), chylomicron remnant clearance (GO:0034382), lipoprotein metabolic process (GO:0042157), cholesterol homeostasis (GO:0042632), reverse cholesterol transport (GO:0043691), negative regulation of fatty acid biosynthetic process (GO:0045717), negative regulation of lipid metabolic process (GO:0045833), negative regulation of receptor-mediated endocytosis (GO:0048261), negative regulation of lipid catabolic process (GO:0050995), negative regulation of cholesterol import (GO:0060621), triglyceride homeostasis (GO:0070328), lipid metabolic process (GO:0006629), lipid transport (GO:0006869), lipid catabolic process (GO:0016042)

GO Molecular Function (6): phospholipid binding (GO:0005543), cholesterol binding (GO:0015485), lipase inhibitor activity (GO:0055102), high-density lipoprotein particle receptor binding (GO:0070653), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (8): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), early endosome (GO:0005769), very-low-density lipoprotein particle (GO:0034361), intermediate-density lipoprotein particle (GO:0034363), spherical high-density lipoprotein particle (GO:0034366), chylomicron (GO:0042627), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Plasma lipoprotein remodeling	2
Plasma lipoprotein assembly, remodeling, and clearance	2
Plasma lipoprotein assembly	1
Visual phototransduction	1
Metabolism of fat-soluble vitamins	1
Transport of small molecules	1
Metabolism	1
Sensory Perception	1
Metabolism of vitamins and cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of lipoprotein particle clearance	3
cholesterol transport	2
binding	2
triglyceride-rich plasma lipoprotein particle	2
acylglycerol metabolic process	1
G protein-coupled receptor activity	1
signal transduction	1
regulation of triglyceride catabolic process	1
triglyceride catabolic process	1
negative regulation of lipid catabolic process	1
negative regulation of triglyceride metabolic process	1
regulation of very-low-density lipoprotein particle remodeling	1
very-low-density lipoprotein particle remodeling	1
negative regulation of cellular component organization	1
negative regulation of multicellular organismal process	1
regulation of very-low-density lipoprotein particle clearance	1
very-low-density lipoprotein particle clearance	1
regulation of high-density lipoprotein particle clearance	1
high-density lipoprotein particle clearance	1
regulation of low-density lipoprotein particle clearance	1
low-density lipoprotein particle clearance	1
triglyceride metabolic process	1
acylglycerol catabolic process	1
Cdc42 protein signal transduction	1
regulation of Rho protein signal transduction	1
phospholipid transport	1
plasma lipoprotein particle remodeling	1
plasma lipoprotein particle assembly	1
triglyceride-rich lipoprotein particle clearance	1
protein metabolic process	1
sterol homeostasis	1
fatty acid biosynthetic process	1
regulation of fatty acid biosynthetic process	1
negative regulation of fatty acid metabolic process	1
negative regulation of lipid biosynthetic process	1
lipid metabolic process	1
negative regulation of metabolic process	1
regulation of lipid metabolic process	1
receptor-mediated endocytosis	1
negative regulation of endocytosis	1

Protein interactions and networks

STRING

1802 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APOC3	APOA1	P02647	998
APOC3	APOE	P02649	998
APOC3	APOC2	P02655	997
APOC3	APOA2	P02652	996
APOC3	APOB	P04114	996
APOC3	APOC1	P02654	992
APOC3	APOA4	P06727	982
APOC3	APOA5	Q6Q788	969
APOC3	TLR2	O60603	963
APOC3	LPL	P06858	961
APOC3	CETP	P11597	921
APOC3	LCAT	P04180	849
APOC3	SCARB1	Q8WTV0	836
APOC3	LPA	P08519	811
APOC3	ANGPTL3	Q9Y5C1	802

IntAct

45 interactions, top by confidence:

A	B	Type	Score
APOC3	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
APOC3	GPX8	psi-mi:“MI:0915”(physical association)	0.560
APOC3	FAM209A	psi-mi:“MI:0915”(physical association)	0.560
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
	LECT2	psi-mi:“MI:0915”(physical association)	0.400
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
MEP1B	APOC3	psi-mi:“MI:0915”(physical association)	0.370
APOC3	ARFGAP1	psi-mi:“MI:0915”(physical association)	0.370
APOA1	CNMD	psi-mi:“MI:0914”(association)	0.350
ALB	CNOT1	psi-mi:“MI:0914”(association)	0.350
ALB	F2	psi-mi:“MI:0914”(association)	0.350
ALB	SH3BP5	psi-mi:“MI:0914”(association)	0.350
CHAMP1	F2	psi-mi:“MI:0914”(association)	0.350
RPAP2	APOC3	psi-mi:“MI:0914”(association)	0.350
UTY	KMT2D	psi-mi:“MI:0914”(association)	0.350
TEX101	NDUFA4	psi-mi:“MI:0914”(association)	0.350
TEX101	GGT3P	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
APOC3	EMC8	psi-mi:“MI:0914”(association)	0.350
APOC3	GBA1	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
CASP3	TMEM223	psi-mi:“MI:0914”(association)	0.350
CTNNA1	ILVBL	psi-mi:“MI:0914”(association)	0.350
FOS	ILVBL	psi-mi:“MI:0914”(association)	0.350
GATA2	ILVBL	psi-mi:“MI:0914”(association)	0.350
ATF3	TMEM223	psi-mi:“MI:0914”(association)	0.350

BioGRID (48): APOC3 (Two-hybrid), SOX4 (Affinity Capture-Western), APOC3 (Two-hybrid), APOC3 (Affinity Capture-MS), APOC3 (Affinity Capture-MS), FAM209A (Two-hybrid), ERGIC3 (Two-hybrid), GPX8 (Two-hybrid), APOC3 (Affinity Capture-MS), APOC3 (Affinity Capture-MS), UTY (Affinity Capture-MS), APOC3 (Affinity Capture-MS), RPAP2 (Affinity Capture-MS), F10 (Affinity Capture-MS), APOC3 (Affinity Capture-MS)

ESM2 similar proteins: A0A096P2H4, A0A0D9S1R9, A0A1A6FVD4, A0A2U3Y4D7, A0A2Y9GHM8, A0A2Y9HRM2, G3HPD1, G3V8D4, G5BQH4, P02655, P02656, P0DKU5, P0DKV7, P0DKV9, P0DKW0, P0DKY1, P0DM92, P0DMN9, P0DMP9, P0DN28, P0DN40, P0DOC1, P0DP52, P0DP84, P0DSP0, P0DTQ5, P0DTQ6, P0DTR9, P0DTS4, P0DTS5, P0DUP3, P0DUP4, P0DUX6, P0DUX7, P0DUX8, P0DUX9, P0DUY0, P0DUY1, P12278, P12279

Diamond homologs: A0A2Y9HRM2, G5BQH4, P02656, P06759, P0DMP9, P0DN28, P0DSP0, P0DTS4, P0DTS5, P12279, P18659, P19035, P27917, P33622, Q9Z2R5

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
APOC3	“down-regulates activity”	LPL
PPARGC1A	“up-regulates quantity by expression”	APOC3	“transcriptional regulation”
NCOA1	“up-regulates quantity by expression”	APOC3	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	38
Likely benign	22
Benign	12

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
17902	NM_000040.3(APOC3):c.280A>G (p.Thr94Ala)	Pathogenic
17903	NM_000040.3(APOC3):c.232A>G (p.Lys78Glu)	Pathogenic

SpliceAI

486 predictions. Top by Δscore:

Variant	Effect	Δscore
11:116830638:G:GG	donor_gain	1.0000
11:116830768:CTCA:C	acceptor_loss	1.0000
11:116830770:CAG:C	acceptor_loss	1.0000
11:116830771:A:AG	acceptor_gain	1.0000
11:116830771:AGG:A	acceptor_loss	1.0000
11:116830772:G:A	acceptor_loss	1.0000
11:116830772:G:GG	acceptor_gain	1.0000
11:116830772:GGA:G	acceptor_gain	1.0000
11:116830893:CCAG:C	donor_loss	1.0000
11:116830895:AGGTA:A	donor_loss	1.0000
11:116830897:GTAC:G	donor_loss	1.0000
11:116830898:T:G	donor_loss	1.0000
11:116830634:GCCC:G	donor_gain	0.9900
11:116830771:AG:A	acceptor_gain	0.9900
11:116830772:GG:G	acceptor_gain	0.9900
11:116830772:GGAGC:G	acceptor_gain	0.9900
11:116830850:G:GT	donor_gain	0.9900
11:116829936:TCCAG:T	donor_loss	0.9800
11:116829937:CCAG:C	donor_loss	0.9800
11:116829938:CAGG:C	donor_loss	0.9800
11:116829939:AGGT:A	donor_loss	0.9800
11:116829940:GGTAA:G	donor_loss	0.9800
11:116829941:GTAAT:G	donor_loss	0.9800
11:116829942:T:G	donor_loss	0.9800
11:116830769:TCAGG:T	acceptor_gain	0.9700
11:116830770:CAGG:C	acceptor_gain	0.9700
11:116830771:AGGA:A	acceptor_gain	0.9700
11:116830772:GGAG:G	acceptor_gain	0.9700
11:116832752:T:A	acceptor_gain	0.9700
11:116832756:T:A	acceptor_gain	0.9700

AlphaMissense

638 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:116830845:C:A	A43D	0.988
11:116830832:G:C	A39P	0.983
11:116830844:G:C	A43P	0.982
11:116830833:C:A	A39D	0.980
11:116830892:G:C	A59P	0.968
11:116830893:C:A	A59D	0.967
11:116832770:G:C	W62C	0.967
11:116832770:G:T	W62C	0.967
11:116830853:G:C	A46P	0.962
11:116832804:T:A	W74R	0.932
11:116832804:T:C	W74R	0.932
11:116832814:T:A	V77D	0.932
11:116830857:T:C	L47P	0.914
11:116832768:T:A	W62R	0.899
11:116832768:T:C	W62R	0.899
11:116830611:C:A	A10D	0.891
11:116832793:T:C	L70P	0.888
11:116832793:T:G	L70R	0.881
11:116832839:G:C	W85C	0.878
11:116832839:G:T	W85C	0.878
11:116830884:C:A	A56D	0.876
11:116830836:C:T	T40I	0.868
11:116832772:T:A	V63E	0.862
11:116830620:C:A	A13E	0.856
11:116830812:T:A	M32K	0.854
11:116830812:T:G	M32R	0.848
11:116832793:T:A	L70Q	0.845
11:116830614:T:G	L11R	0.837
11:116830608:T:A	V9D	0.836
11:116830813:G:A	M32I	0.827

dbSNP variants (sampled 300 via entrez): RS1000014830 (11:116832120 A>T), RS1001379094 (11:116828168 A>G), RS1001906500 (11:116833285 G>A), RS1003641037 (11:116829594 C>T), RS1003735822 (11:116829343 G>T), RS1003741928 (11:116828732 T>G), RS1003851423 (11:116832660 T>C,G), RS1004032421 (11:116828951 C>T), RS1005843444 (11:116829627 C>T), RS1006098606 (11:116830352 G>C), RS1006205509 (11:116829870 G>A), RS1006592772 (11:116828426 C>T), RS1007619351 (11:116830986 G>A), RS1007949836 (11:116829220 G>A,C), RS1008107783 (11:116828177 T>A,C)

Disease associations

OMIM: gene MIM:107720 | disease phenotypes: MIM:608446, MIM:614028, MIM:143470, MIM:611040, MIM:613148, MIM:615607, MIM:615615, MIM:615617

GenCC curated gene-disease

Disease	Classification	Inheritance
cholesterol-ester transfer protein deficiency	Supportive	Autosomal dominant
apolipoprotein c-III deficiency	Limited	Autosomal dominant

Mondo (9): myocardial infarction, susceptibility to (MONDO:0012039), apolipoprotein c-III deficiency (MONDO:0013534), cholesterol-ester transfer protein deficiency (MONDO:0007744), isolated microphthalmia 5 (MONDO:0012605), inflammatory bowel disease 28 (MONDO:0013153), combined immunodeficiency due to CD3gamma deficiency (MONDO:0014276), immunodeficiency 18 (MONDO:0014278), immunodeficiency 19 (MONDO:0014280), RASopathy (MONDO:0021060)

Orphanet (5): Combined immunodeficiency due to CD3gamma deficiency (Orphanet:169082), Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections syndrome (Orphanet:238569), Microphthalmia-retinitis pigmentosa-foveoschisis-optic disc drusen syndrome (Orphanet:251279), RASopathy (Orphanet:536391), OBSOLETE: Cholesterol-ester transfer protein deficiency (Orphanet:79506)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0003563	Decreased LDL cholesterol concentration
HP:0012153	Hypotriglyceridemia
HP:0012184	Increased HDL cholesterol concentration

GWAS associations

54 associations (top):

Study	Trait	p-value
GCST000131_3	LDL cholesterol	3.000000e-11
GCST000138_5	Triglycerides	2.000000e-17
GCST000139_1	Triglycerides	1.000000e-26
GCST000282_1	LDL cholesterol	5.000000e-13
GCST000285_3	Cholesterol, total	7.000000e-07
GCST000286_6	Triglycerides	4.000000e-62
GCST000289_6	Triglycerides	5.000000e-13
GCST000290_3	HDL cholesterol	1.000000e-12
GCST000300_1	Triglycerides	3.000000e-29
GCST000583_1	Hematological and biochemical traits	9.000000e-10
GCST000584_2	Triglycerides	1.000000e-49
GCST000755_1	HDL cholesterol	5.000000e-47
GCST000758_19	Triglycerides	7.000000e-240
GCST000759_31	LDL cholesterol	1.000000e-26
GCST000760_51	Cholesterol, total	6.000000e-57
GCST000805_4	HDL cholesterol	2.000000e-11
GCST000807_7	LDL cholesterol	2.000000e-06
GCST000809_11	Triglycerides	4.000000e-21
GCST000998_20	Coronary heart disease	1.000000e-17
GCST001230_3	Triglycerides	2.000000e-86
GCST001392_8	Lipid metabolism phenotypes	8.000000e-20
GCST001639_26	Metabolite levels	8.000000e-20
GCST001905_3	Hypertriglyceridemia	5.000000e-35
GCST002321_16	Lipid traits	2.000000e-59
GCST002746_1	Lipoprotein (a) - cholesterol levels	5.000000e-09
GCST003215_2	HDL cholesterol	2.000000e-85
GCST003217_6	Triglycerides	4.000000e-213
GCST003364_2	Triglyceride levels	1.000000e-30
GCST004207_23	HDL cholesterol	3.000000e-20
GCST004232_3	HDL cholesterol levels	3.000000e-71

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0004574	total cholesterol measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004529	lipid measurement
EFO:0004723	coronary artery calcification
EFO:0006925	lipoprotein A measurement
EFO:0004309	platelet count
EFO:0007985	platelet crit
EFO:0004340	body mass index
EFO:0009188	Red cell distribution width

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
C566270	Apolipoprotein C-III Deficiency (supp.)
C567728	Inflammatory Bowel Disease 28, Autosomal Recessive (supp.)
C567024	Microphthalmia, Posterior, With Retinitis Pigmentosa, Foveoschisis, And Optic Disc Drusen (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523160 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2854116	Toxicity	3	ritonavir	HIV infectious disease;Hyperlipidemias
rs2854117	Toxicity	3	ritonavir	HIV infectious disease;Hyperlipidemias
rs5128	Toxicity	3	ritonavir	HIV infectious disease;Hyperlipidemias
rs5128	Metabolism/PK	3	olanzapine

PharmGKB variants

7 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4520	APOC3		0.00	0
rs5128	APOC3	3	2.50	2	ritonavir;olanzapine
rs2542051	APOC3		0.00	0
rs2542052	APOC3		0.00	0
rs2854116	APOC3	3	2.50	1	ritonavir
rs2854117	APOA4, APOC3	3	4.25	1	ritonavir
rs779597455	APOC3		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, affects cotreatment, affects expression, decreases expression	8
sodium arsenite	decreases methylation, decreases reaction, decreases expression, increases expression	3
Valproic Acid	affects expression, decreases expression	3
benzo(b)fluoranthene	affects cotreatment, decreases expression, affects expression	2
Acetaminophen	decreases expression	2
Bezafibrate	decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	decreases expression, affects expression	2
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	affects expression	1
deoxynivalenol	decreases expression	1
fluoranthene	affects expression, affects cotreatment	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
tetramethylpyrazine	decreases expression	1
butyraldehyde	decreases expression	1
linalool	decreases expression	1
1,2,5,6-dibenzanthracene	affects expression, affects cotreatment	1
periodate-oxidized adenosine	affects expression	1
benz(a)anthracene	affects cotreatment, decreases expression	1
chrysene	decreases expression, affects cotreatment	1
benazol P	decreases expression	1
transplatin	decreases expression	1
1-methylphenanthrene	affects cotreatment, affects expression	1
dibenzo(a,l)pyrene	affects cotreatment, affects expression	1
corosolic acid	increases expression	1
K 7174	decreases expression	1
obeticholic acid	decreases expression	1
muraglitazar	affects cotreatment, increases expression	1
tesaglitazar	affects cotreatment, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4315655	Binding	Inhibition of human APOC3 at 40 uM relative to control	Multigram scale synthesis of polycyclic lactones and evaluation of antitumor and other biological properties. — Eur J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01916512	Not specified	UNKNOWN	Relationship Between CETP Deficiency and Atherosclerosis in Patients With Hyperalphalipoproteinemia
NCT04888936	Not specified	RECRUITING	Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies
NCT05761314	Not specified	RECRUITING	Solid Tumors in RASopathies
NCT06331117	Not specified	UNKNOWN	Effect of RAS/MAPK Pathway Hyperactivation on Growth’ and Bone’ Profile of the RASopathies
NCT06355622	Not specified	UNKNOWN	Prevalence and Characterization of Pain in RASopathies
NCT06489067	Not specified	RECRUITING	Study of the Thyroid Function and Echostructural Morphology in Patients Affected With Rasopathies (ECORAS2023)
NCT06776380	Not specified	RECRUITING	Pubertal Development in Patients with RASopathies
NCT07005297	Not specified	NOT_YET_RECRUITING	Clinical Genetics Branch Eligibility Screening Survey
NCT07344480	Not specified	RECRUITING	Retrospective Natural History Study of RASopathy-associated Cardiomyopathy (RAS-CM)
NCT07464821	Not specified	RECRUITING	National Multicentre Study on Lipid Profile in Noonan Syndrome and Related Disorders: Trends by Age, Gender and Genotype