APOA5

Summary

APOA5 (apolipoprotein A5, HGNC:17288) is a protein-coding gene on chromosome 11q23.3, encoding Apolipoprotein A-V (Q6Q788). Minor apolipoprotein mainly associated with HDL and to a lesser extent with VLDL.

The protein encoded by this gene is an apolipoprotein that plays an important role in regulating the plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of high density lipoprotein and is highly similar to a rat protein that is upregulated in response to liver injury. Mutations in this gene have been associated with hypertriglyceridemia and hyperlipoproteinemia type 5. This gene is located proximal to the apolipoprotein gene cluster on chromosome 11q23. Alternatively spliced transcript variants encoding the same protein have been identified.

Source: NCBI Gene 116519 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypertriglyceridemia 1 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 227
• Clinical variants (ClinVar): 341 total — 5 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 11
• MANE Select transcript: NM_001371904

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17288
Approved symbol	APOA5
Name	apolipoprotein A5
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	RAP3, APOA-V
Ensembl gene	ENSG00000110243
Ensembl biotype	protein_coding
OMIM	606368
Entrez	116519

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 11 protein_coding

ENST00000227665, ENST00000433069, ENST00000542499, ENST00000673688, ENST00000873020, ENST00000873021, ENST00000873022, ENST00000873023, ENST00000873024, ENST00000873025, ENST00000873026

RefSeq mRNA: 3 — MANE Select: NM_001371904 NM_001166598, NM_001371904, NM_052968

CCDS: CCDS8376

Canonical transcript exons

ENST00000227665 — 3 exons

Exon	Start	End
ENSE00000747556	116791586	116791697
ENSE00001329650	116789367	116791067
ENSE00001941260	116791812	116791879

Expression profiles

Bgee: expression breadth broad, 45 present calls, max score 98.99.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1590 / max 89.2958, expressed in 13 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122422	0.1197	12
122424	0.0237	10
122423	0.0156	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.99	gold quality
liver	UBERON:0002107	97.36	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	78.87	gold quality
nasal cavity epithelium	UBERON:0005384	75.78	gold quality
gingival epithelium	UBERON:0001949	75.62	gold quality
secondary oocyte	CL:0000655	75.16	gold quality
esophagus squamous epithelium	UBERON:0006920	74.93	gold quality
myocardium	UBERON:0002349	74.10	gold quality
deltoid	UBERON:0001476	72.90	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	72.67	gold quality
biceps brachii	UBERON:0001507	72.23	gold quality
gingiva	UBERON:0001828	72.17	gold quality
cardia of stomach	UBERON:0001162	71.77	gold quality
superficial temporal artery	UBERON:0001614	71.64	gold quality
amniotic fluid	UBERON:0000173	71.55	gold quality
oocyte	CL:0000023	71.33	gold quality
body of tongue	UBERON:0011876	71.27	gold quality
cartilage tissue	UBERON:0002418	71.18	gold quality
epithelium of nasopharynx	UBERON:0001951	70.81	gold quality
ventral tegmental area	UBERON:0002691	70.62	gold quality
subthalamic nucleus	UBERON:0001906	70.51	gold quality
mucosa of paranasal sinus	UBERON:0005030	70.51	gold quality
vena cava	UBERON:0004087	70.44	gold quality
tongue	UBERON:0001723	70.42	gold quality
saphenous vein	UBERON:0007318	70.27	gold quality
nipple	UBERON:0002030	70.22	gold quality
cerebellar vermis	UBERON:0004720	70.02	gold quality
dorsal plus ventral thalamus	UBERON:0001897	69.99	gold quality
trabecular bone tissue	UBERON:0002483	69.98	gold quality
pericardium	UBERON:0002407	69.82	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.61

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB3L3, HNF4A, NCOA1, NR1H3, NR1H4, NR4A1, PPARA, PPARGC1A, RORA, SREBF1, SSRP1, USF1, USF2

miRNA regulators (miRDB)

45 targeting APOA5, 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-6825-5P	99.96	69.81	3431
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-6779-5P	99.70	65.76	2363
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-6883-5P	99.69	68.05	3785
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-2355-5P	98.83	65.51	1589
HSA-MIR-7113-3P	98.75	65.71	1120

Literature-anchored findings (GeneRIF, showing 40)

• an important determinant of plasma triglyceride levels (PMID:11588264)
• Polymorphism in the apoAV gene influences serum TG in populations of different ethnicities (PMID:12417270)
• Two haplotypes are found in 25-50% of subjects, supporting the contribution of common variation to quantitative phenotypes. (PMID:12417524)
• Variation in APOA5 is associated with differences in triglycerides in healthy men. (PMID:12417525)
• Review. APOA5 represents a newly discovered gene involved in triglyceride metabolism in both humans and mice whose mechanism of action remains to be deciphered. (PMID:12615678)
• APOA5 is a highly responsive peroxisome proliferator-activated receptor alpha target gene with a role as a major mediator for how fibrates reduce plasma triglycerides in humans (PMID:12637506)
• ApoAV is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element (PMID:12709436)
• apoA-V is poorly secreted, remains associated with the endoplasmic reticulum, and does not traffic to the Golgi. (PMID:12810715)
• apoA-V may function intracellularly to modulate hepatic VLDL synthesis and/or secretion (PMID:12810715)
• A strong association suggested between T-113C polymorphism in the APOA-V gene and the levels of plasma triglycerides. (PMID:12818421)
• A novel genetic variant in APOA5 is associated with hypertriglyceridemia. (PMID:12915450)
• There is a strong association between the Ser19 to Trp substitution polymorphism in the APOAV gene and extreme concentrations of plasma triglycerides in hypertriglyceridemic patients. (PMID:12920097)
• APOA5 plays a role in the ethnic differences observed for plasma TG and HDL cholesterol concentrations. (PMID:12951359)
• relationship of APOA5 -1131T>C and S19W with lipid subfractions and progression of atherosclerosis (PMID:14729863)
• a major genetic determinant of both LDL particle size and plasma TG levels among ethnic Japanese - data confirm interrelationships that determine CHD risk factors and CHD itself. (PMID:14732475)
• Val153-Met polymorphism in the APOAV gene does not represent an important risk factor for developing the extreme levels of plasma triglycerides. (PMID:15046561)
• APOA5 and APOC3 independently influence plasma triglyceride concentrations but in an opposing manner. (PMID:15117734)
• ApoAIV is a direct target gene of Liver X receptors (LXRs) that may contribute to the antiatherogenic effect of LXR activation (PMID:15131258)
• examination of overexpression on decreased plasma triglyceride levels (PMID:15178420)
• There is a significant correlation between the CC genotype of the APOA5 and the levels of plasma high density lipoprotein-cholosteal in the coronary heart disease group. (PMID:15300628)
• no association between APOA5 gene polymorphisms or haplotypes and coronary artery disease as determined by angiography. (PMID:15306190)
• APOA5 gene expression is regulated by the LXR ligand T0901317 in a negative manner through SREBP-1c. (PMID:15317819)
• APOa5 may have a role in predisposition to cardiovascular disease (PMID:15342688)
• ApoA-V regulates the secretion and/or catabolism of triglyceride-rich lipoproteins. A nonsense mutation in APOA5 gene (Q145X) was found in a boy with hyperchylomicronemia syndrome. This is the first observation of a complete apoA-V deficiency in humans. (PMID:15591215)
• 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)
• APOA5 gene is involved in hypertriglyceridemia associated with hyperinsulinemia. (PMID:15684402)
• Deletion and mutation studies identified three AGGTCA motifs in the ApoAV promoter that mediate RORalpha transactivation (PMID:15781255)
• RORalpha1 and RORalpha4 are transcriptional activators of human APOA5 gene expression (PMID:15790933)
• The V150M polymorphism had an independent influence on 1st and 2nd phase insulin responses. (PMID:15841042)
• S19W and -1131T>C variations in APOA5 gene are associated with and appear to be genetic risk factors for coronary heart disease susceptibility in Chinese. TriglycerideS were significantly higher and HDL cholesterol was decreased in -1131C carriers. (PMID:15877284)
• apoA-V lipid complexes bind heparin and, when present on triglyceride-rich lipoprotein particles, may promote their association with cell surface heparan sulfate proteoglycans (PMID:15878877)
• The APOA5-1131T/C polymorphism but not APOC3-482C/T might contribute to an increased risk of coronary artery disease. (PMID:15924804)
• Asociation of APOA5 single-nucleotide polymorphism with triglyceride levels is not due to the individual effects of any of these SNPs. (PMID:15941721)
• apoA5 - 1131T > C polymorphism is associated with an increased risk of CAD and is also in strong association with serum TG levels. (PMID:15952115)
• data suggest that the APOA5 -1131T–>C polymorphism might play a role in elevated plasma TG levels in type 2 diabetic patients in the Chinese population (PMID:16006256)
• plasma apoAV concentration does not play an acute or a direct role in the regulation of plasma triglycerides in the postprandial state (PMID:16039297)
• HNF-4alpha directly regulates human apoAV promoter through DR1 [a direct repeat separated by one nucleotide (nt)], and via a novel element for HNF-4alpha consisting of an inverted repeat separated by 8 nt (IR8). (PMID:16051671)
• variants of APOA5 gene modulate plasma triglyceride and may use them to predict CAD susceptibility in Taiwanese Chinese. (PMID:16054149)
• genetic variation in the APOA5 gene is an important cofactor in the development of type III hyperlipidemia (PMID:16143024)
• APOA5 c.1259C alleles were associated with higher triglyceride plasma concentrations (PMID:16192625)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Apoa5	ENSMUSG00000032079
rattus_norvegicus	Apoa5	ENSRNOG00000018436

Paralogs (3): APOA4 (ENSG00000110244), APOA1 (ENSG00000118137), APOE (ENSG00000130203)

Protein

Protein identifiers

Apolipoprotein A-V — Q6Q788 (reviewed: Q6Q788)

Alternative names: Apolipoprotein A5, Regeneration-associated protein 3

All UniProt accessions (3): Q6Q788, A0A0B4RUS7, A0A669KB69

UniProt curated annotations — full annotation on UniProt →

Function. Minor apolipoprotein mainly associated with HDL and to a lesser extent with VLDL. May also be associated with chylomicrons. Important determinant of plasma triglyceride (TG) levels by both being a potent stimulator of apo-CII lipoprotein lipase (LPL) TG hydrolysis and an inhibitor of the hepatic VLDL-TG production rate (without affecting the VLDL-apoB production rate). Activates poorly lecithin:cholesterol acyltransferase (LCAT) and does not enhance efflux of cholesterol from macrophages. Binds heparin.

Subunit / interactions. Interacts with GPIHBP1. Interacts with SORL1; this interaction leads to APOA5 internalization and sorting either to lysosomes and degradation, or to the trans-Golgi network.

Subcellular location. Secreted. Early endosome. Late endosome. Golgi apparatus. trans-Golgi network.

Tissue specificity. Liver and plasma.

Post-translational modifications. Phosphorylated by FAM20C in the extracellular medium.

Disease relevance. Hypertriglyceridemia 1 (HYTG1) [MIM:145750] A common inherited disorder in which the concentration of very low density lipoprotein (VLDL) is elevated in the plasma. This leads to increased risk of heart disease, obesity, and pancreatitis. Inheritance is autosomal dominant. Disease susceptibility is associated with variants affecting the gene represented in this entry. Hyperlipoproteinemia 5 (HLPP5) [MIM:144650] Characterized by increased amounts of chylomicrons and very low density lipoprotein (VLDL) and decreased low density lipoprotein (LDL) and high density lipoprotein (HDL) in the plasma after a fast. Numerous conditions cause this phenotype, including insulin-dependent diabetes mellitus, contraceptive steroids, alcohol abuse, and glycogen storage disease type 1A (GSD1A). The disease is caused by variants affecting the gene represented in this entry.

Induction. Up-regulated by PPARA agonists, which are used clinically to lower serum TG (such as fibrates).

Polymorphism. Three common alleles are known: allele APOA51, APOA52 and APOA53. The APOA52 haplotype, which consists of 3 non-coding SNPs, is present in approximately 16% of Caucasians and is associated with increased plasma triglyceride concentrations. APOA53 haplotype is defined by the rare Ser-19-Trp substitution. Together, the APOA52 and APOA5*3 haplotypes are found in 25 to 50% of African Americans, Hispanics, and Caucasians.

Miscellaneous. Induced in early phase of liver regeneration.

Similarity. Belongs to the apolipoprotein A1/A4/E family.

RefSeq proteins (3): NP_001160070, NP_001358833, NP_443200 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000074	ApoA_E	Family
IPR050163	Apolipoprotein_A1/A4/E	Family

Pfam: PF01442

UniProt features (11 total): sequence variant 4, coiled-coil region 2, modified residue 2, signal peptide 1, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6Q788-F1	72.38	0.27

Functional residue map

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

Post-translational modifications (2): 55, 59

Mutagenesis-validated functional residues (1):

Position	Phenotype
233–234	decreased heparin-binding.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-8963889	Assembly of active LPL and LIPC lipase complexes
R-HSA-8963901	Chylomicron remodeling
R-HSA-1430728	Metabolism
R-HSA-174824	Plasma lipoprotein assembly, remodeling, and clearance
R-HSA-382551	Transport of small molecules
R-HSA-392499	Metabolism of proteins
R-HSA-400206	Regulation of lipid metabolism by PPARalpha
R-HSA-556833	Metabolism of lipids
R-HSA-597592	Post-translational protein modification
R-HSA-8963899	Plasma lipoprotein remodeling

MSigDB gene sets: 205 (showing top): GOBP_ACYLGLYCEROL_HOMEOSTASIS, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_REGULATION_OF_TRIGLYCERIDE_METABOLIC_PROCESS, GOBP_STEROL_HOMEOSTASIS, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, GOBP_GROWTH, GOBP_REGENERATION, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_RECEPTOR_MEDIATED_ENDOCYTOSIS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GGGTGGRR_PAX4_03, GOBP_KETONE_METABOLIC_PROCESS, CAGCTG_AP4_Q5, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (18): triglyceride metabolic process (GO:0006641), lipid transport (GO:0006869), cholesterol metabolic process (GO:0008203), positive regulation of triglyceride catabolic process (GO:0010898), positive regulation of very-low-density lipoprotein particle remodeling (GO:0010902), triglyceride catabolic process (GO:0019433), cholesterol efflux (GO:0033344), phospholipid efflux (GO:0033700), triglyceride-rich lipoprotein particle remodeling (GO:0034370), very-low-density lipoprotein particle clearance (GO:0034447), lipoprotein metabolic process (GO:0042157), tissue regeneration (GO:0042246), cholesterol homeostasis (GO:0042632), positive regulation of fatty acid biosynthetic process (GO:0045723), positive regulation of receptor-mediated endocytosis (GO:0048260), positive regulation of lipid catabolic process (GO:0050996), acylglycerol homeostasis (GO:0055090), triglyceride homeostasis (GO:0070328)

GO Molecular Function (13): phospholipid binding (GO:0005543), heparin binding (GO:0008201), lipid binding (GO:0008289), enzyme binding (GO:0019899), phosphatidylcholine binding (GO:0031210), lipase binding (GO:0035473), low-density lipoprotein particle receptor binding (GO:0050750), phosphatidylcholine-sterol O-acyltransferase activator activity (GO:0060228), lipase activator activity (GO:0060229), lipoprotein lipase activator activity (GO:0060230), lipoprotein particle receptor binding (GO:0070325), cholesterol transfer activity (GO:0120020), protein binding (GO:0005515)

GO Cellular Component (11): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), early endosome (GO:0005769), late endosome (GO:0005770), endoplasmic reticulum lumen (GO:0005788), Golgi apparatus (GO:0005794), very-low-density lipoprotein particle (GO:0034361), high-density lipoprotein particle (GO:0034364), chylomicron (GO:0042627), extracellular vesicle (GO:1903561), endosome (GO:0005768)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Metabolism of proteins	2
Plasma lipoprotein remodeling	2
Regulation of lipid metabolism by PPARalpha	1
Post-translational protein modification	1
Transport of small molecules	1
Metabolism of lipids	1
Metabolism	1
Plasma lipoprotein assembly, remodeling, and clearance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
enzyme activator activity	2
endosome	2
endomembrane system	2
plasma lipoprotein particle	2
acylglycerol metabolic process	1
transport	1
lipid localization	1
sterol metabolic process	1
secondary alcohol metabolic process	1
regulation of triglyceride catabolic process	1
triglyceride catabolic process	1
positive regulation of lipid catabolic process	1
positive regulation of triglyceride metabolic process	1
regulation of very-low-density lipoprotein particle remodeling	1
very-low-density lipoprotein particle remodeling	1
positive regulation of cellular component organization	1
positive regulation of multicellular organismal process	1
triglyceride metabolic process	1
acylglycerol catabolic process	1
cholesterol transport	1
phospholipid transport	1
plasma lipoprotein particle remodeling	1
plasma lipoprotein particle clearance	1
protein metabolic process	1
regeneration	1
developmental growth	1
sterol homeostasis	1
fatty acid biosynthetic process	1
regulation of fatty acid biosynthetic process	1
positive regulation of fatty acid metabolic process	1
positive regulation of lipid biosynthetic process	1
receptor-mediated endocytosis	1
positive regulation of endocytosis	1
regulation of receptor-mediated endocytosis	1
positive regulation of catabolic process	1
lipid catabolic process	1
positive regulation of lipid metabolic process	1
regulation of lipid catabolic process	1
lipid homeostasis	1

Protein interactions and networks

STRING

1856 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APOA5	APOC2	P02655	979
APOA5	APOC3	P02656	969
APOA5	APOB	P04114	935
APOA5	APOE	P02649	930
APOA5	RAP2A	P10114	885
APOA5	LMF1	Q96S06	881
APOA5	LPL	P06858	880
APOA5	GPIHBP1	Q8IV16	873
APOA5	ANGPTL3	Q9Y5C1	865
APOA5	APOA2	P02652	855
APOA5	BUD13	Q9BRD0	828
APOA5	ZPR1	O75312	809
APOA5	APOC1	P02654	778
APOA5	CETP	P11597	774
APOA5	APOM	O95445	773

IntAct

47 interactions, top by confidence:

A	B	Type	Score
YIF1A	APOA5	psi-mi:“MI:0915”(physical association)	0.560
APOA5	ACSF2	psi-mi:“MI:0915”(physical association)	0.560
APOA5	TMEM19	psi-mi:“MI:0915”(physical association)	0.560
BMP10	APOA5	psi-mi:“MI:0915”(physical association)	0.560
TMEM120B	APOA5	psi-mi:“MI:0915”(physical association)	0.560
APOA5	MYG1	psi-mi:“MI:0915”(physical association)	0.560
APOA5	CMTM6	psi-mi:“MI:0915”(physical association)	0.560
TTPA	APOA5	psi-mi:“MI:0915”(physical association)	0.560
APOA5	CMTM3	psi-mi:“MI:0915”(physical association)	0.560
APOA5	CMTM5	psi-mi:“MI:0915”(physical association)	0.560
APOA5	MORN4	psi-mi:“MI:0915”(physical association)	0.560
APOA5	SELENOS	psi-mi:“MI:0915”(physical association)	0.560
APOA5	TMEM43	psi-mi:“MI:0915”(physical association)	0.560
APOA5	FAM20C	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
LPL	APOA5	psi-mi:“MI:0407”(direct interaction)	0.440
APOA5	FAS	psi-mi:“MI:0915”(physical association)	0.370
APOA5	RAB5B	psi-mi:“MI:0915”(physical association)	0.370
APOA5	SMARCD1	psi-mi:“MI:0915”(physical association)	0.370
	APOA5	psi-mi:“MI:0915”(physical association)	0.370
APOA5	YIF1A	psi-mi:“MI:0915”(physical association)	0.000
BMP10	APOA5	psi-mi:“MI:0915”(physical association)	0.000
TMEM120B	APOA5	psi-mi:“MI:0915”(physical association)	0.000
MYG1	APOA5	psi-mi:“MI:0915”(physical association)	0.000
APOA5	CMTM6	psi-mi:“MI:0915”(physical association)	0.000
TTPA	APOA5	psi-mi:“MI:0915”(physical association)	0.000
CMTM3	APOA5	psi-mi:“MI:0915”(physical association)	0.000
CMTM5	APOA5	psi-mi:“MI:0915”(physical association)	0.000
MORN4	APOA5	psi-mi:“MI:0915”(physical association)	0.000
SELENOS	APOA5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (16): APOA5 (Two-hybrid), VIMP (Two-hybrid), TTPA (Two-hybrid), TMEM19 (Two-hybrid), C12orf10 (Two-hybrid), CMTM3 (Two-hybrid), BMP10 (Two-hybrid), CMTM5 (Two-hybrid), ACSF2 (Two-hybrid), TMEM43 (Two-hybrid), MORN4 (Two-hybrid), YIF1A (Two-hybrid), TMEM120B (Two-hybrid), FAS (Two-hybrid), RAB5B (Two-hybrid)

ESM2 similar proteins: A0A0D9S1R0, A0A2Y9GHM3, A0A2Y9HKE5, A0A6P3R0Z0, L5KM50, P05770, P0DKW5, P0DKW8, P0DKY2, P0DML7, P0DML8, P0DML9, P0DMM0, P0DMM1, P0DN38, P0DN39, P0DN41, P0DO94, P0DOC3, P0DSO9, P0DTS2, P0DTS3, P0DTS6, P0DTT1, P0DTT2, P0DUI5, P0DUI6, P0DUI7, P0DUI8, P0DUI9, P0DUJ0, P0DUJ2, P0DUP8, P0DUZ4, P0DUZ6, P0DUZ7, P10517, P18287, P18649, P18650

Diamond homologs: A0A2Y9HKE5, P0DSO9, P0DTS2, P0DTS3, P0DTS6, Q28758, Q6Q788, Q8C7G5, Q9QUH3, A0A2U3YVN9, A0A2Y9HKB5, E2RE76, M3W955, O46409, P02651, P06727, P06728, P08226, P0DSO8, P0DTS0, P0DTS1, P0DUY7, P33621, Q32PJ2

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
APOA5	“up-regulates activity”	LPL	binding
PPARGC1A	“up-regulates quantity by expression”	APOA5	“transcriptional regulation”
NCOA1	“up-regulates quantity by expression”	APOA5	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	7
Uncertain significance	193
Likely benign	96
Benign	13

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
2587093	NM_001371904.1(APOA5):c.42dup (p.Leu15fs)	Pathogenic
381733	NM_001371904.1(APOA5):c.289C>T (p.Gln97Ter)	Pathogenic
3884283	NM_001371904.1(APOA5):c.562A>T (p.Lys188Ter)	Pathogenic
4404	NM_001371904.1(APOA5):c.415C>T (p.Gln139Ter)	Pathogenic
995944	NM_001371904.1(APOA5):c.579_592del (p.Tyr194fs)	Pathogenic
1678124	NM_001371904.1(APOA5):c.847C>T (p.Gln283Ter)	Likely pathogenic
1742314	NM_001371904.1(APOA5):c.466G>T (p.Glu156Ter)	Likely pathogenic
1760482	NM_001371904.1(APOA5):c.775A>T (p.Arg259Ter)	Likely pathogenic
1775030	NM_001371904.1(APOA5):c.154G>T (p.Glu52Ter)	Likely pathogenic
2434519	NM_001371904.1(APOA5):c.117_120del (p.Arg40fs)	Likely pathogenic
3066069	NM_001371904.1(APOA5):c.681C>A (p.Cys227Ter)	Likely pathogenic
4075749	NM_001371904.1(APOA5):c.667C>T (p.Arg223Cys)	Likely pathogenic

SpliceAI

304 predictions. Top by Δscore:

Variant	Effect	Δscore
11:116791584:A:AC	donor_gain	1.0000
11:116791585:C:CC	donor_gain	1.0000
11:116791585:CG:C	donor_gain	1.0000
11:116791065:GTC:G	acceptor_gain	0.9900
11:116791066:TC:T	acceptor_gain	0.9900
11:116791067:CC:C	acceptor_gain	0.9900
11:116791067:CCTG:C	acceptor_loss	0.9900
11:116791068:C:CC	acceptor_gain	0.9900
11:116791068:CTG:C	acceptor_loss	0.9900
11:116791069:T:C	acceptor_loss	0.9900
11:116791577:GGCAC:G	donor_loss	0.9900
11:116791578:GCAC:G	donor_loss	0.9900
11:116791579:CACTC:C	donor_loss	0.9900
11:116791580:AC:A	donor_loss	0.9900
11:116791581:CT:C	donor_loss	0.9900
11:116791582:TCA:T	donor_loss	0.9900
11:116791583:CACG:C	donor_loss	0.9900
11:116791584:ACG:A	donor_gain	0.9900
11:116791584:ACGCG:A	donor_loss	0.9900
11:116791585:C:CA	donor_loss	0.9900
11:116791585:CGC:C	donor_gain	0.9900
11:116791585:CGCG:C	donor_gain	0.9900
11:116791585:CGCGG:C	donor_gain	0.9900
11:116791696:CG:C	acceptor_gain	0.9900
11:116791698:C:CC	acceptor_gain	0.9900
11:116791694:AACG:A	acceptor_gain	0.9800
11:116791696:CGCTG:C	acceptor_loss	0.9800
11:116791698:C:A	acceptor_loss	0.9800
11:116791807:CCCA:C	donor_loss	0.9800
11:116791808:CCA:C	donor_loss	0.9800

AlphaMissense

2405 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:116790333:A:G	F299S	0.969
11:116790332:G:C	F299L	0.968
11:116790332:G:T	F299L	0.968
11:116790334:A:G	F299L	0.968
11:116790365:G:C	F288L	0.958
11:116790365:G:T	F288L	0.958
11:116790367:A:G	F288L	0.958
11:116790366:A:G	F288S	0.945
11:116790514:C:G	A239P	0.936
11:116790525:A:G	L235P	0.935
11:116790492:A:G	I246T	0.931
11:116790843:A:G	L129P	0.924
11:116790342:A:T	I296K	0.921
11:116790855:A:G	L125S	0.920
11:116790185:C:A	W348C	0.916
11:116790185:C:G	W348C	0.916
11:116790333:A:C	F299C	0.910
11:116790342:A:C	I296R	0.906
11:116790321:A:T	I303N	0.897
11:116790525:A:T	L235H	0.895
11:116790822:A:G	L136P	0.892
11:116790189:A:G	L347P	0.889
11:116790603:A:G	L209P	0.875
11:116790366:A:C	F288C	0.868
11:116790909:A:G	L107P	0.866
11:116790789:A:G	L147P	0.862
11:116790569:G:C	S220R	0.859
11:116790569:G:T	S220R	0.859
11:116790571:T:G	S220R	0.859
11:116790492:A:C	I246S	0.856

dbSNP variants (sampled 300 via entrez): RS1000014881 (11:116793828 G>A), RS1000069861 (11:116790917 C>G), RS1000497657 (11:116793618 G>A), RS1001851290 (11:116792999 C>T), RS1001924963 (11:116792797 C>A), RS1002945690 (11:116792577 A>G), RS1003758326 (11:116789799 G>A,C,T), RS1004075805 (11:116793277 C>T), RS1004176481 (11:116793112 T>C), RS1004346195 (11:116793494 C>A), RS1005842551 (11:116790044 C>G), RS1006106594 (11:116788995 C>A), RS1006283533 (11:116794382 A>G), RS1007529615 (11:116789717 C>A,T), RS1007560678 (11:116789376 A>T)

Disease associations

OMIM: gene MIM:606368 | disease phenotypes: MIM:144650, MIM:145750, MIM:238600

GenCC curated gene-disease

Disease	Classification	Inheritance
hypertriglyceridemia 1	Definitive	Autosomal dominant
hyperlipoproteinemia type V	Strong	Semidominant

Mondo (6): hyperlipoproteinemia type V (MONDO:0007762), hypertriglyceridemia 1 (MONDO:0007788), hypertriglyceridemia (MONDO:0005347), hyperlipoproteinemia (MONDO:0037748), dementia (MONDO:0001627), familial lipoprotein lipase deficiency (MONDO:0009387)

Orphanet (4): Familial apolipoprotein A5 deficiency (Orphanet:530849), Familial lipoprotein lipase deficiency (Orphanet:309015), Familial chylomicronemia syndrome (Orphanet:444490), OBSOLETE: Hyperlipoproteinemia type 5 (Orphanet:70470)

HPO phenotypes

11 total (13 of 11 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000819	Diabetes mellitus
HP:0001039	Atheroeruptive xanthoma
HP:0001952	Glucose intolerance
HP:0002155	Hypertriglyceridemia
HP:0003233	Decreased HDL cholesterol concentration
HP:0003362	Increased VLDL cholesterol concentration
HP:0003563	Decreased LDL cholesterol concentration
HP:0004416	Precocious atherosclerosis
HP:0012238	Increased circulating chylomicron concentration
HP:0040075	Hypopituitarism
HP:0010980	Hyperlipoproteinemia
HP:0000726	Dementia

GWAS associations

227 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
GCST000324_1	Carotenoid and tocopherol levels	8.000000e-10
GCST000583_1	Hematological and biochemical traits	9.000000e-10
GCST000584_2	Triglycerides	1.000000e-49
GCST000737_1	Hypertriglyceridemia	5.000000e-24
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
GCST000789_1	Cardiovascular risk factors (age interaction)	8.000000e-06
GCST000805_4	HDL cholesterol	2.000000e-11
GCST000807_7	LDL cholesterol	2.000000e-06
GCST000809_11	Triglycerides	4.000000e-21
GCST000974_10	HDL cholesterol	2.000000e-07
GCST000998_20	Coronary heart disease	1.000000e-17
GCST001003_5	Metabolic syndrome	2.000000e-09
GCST001004_6	Triglycerides-Blood Pressure (TG-BP)	4.000000e-08
GCST001005_3	HDL Cholesterol - Triglycerides (HDLC-TG)	5.000000e-13
GCST001006_3	Waist Circumference - Triglycerides (WC-TG)	2.000000e-16
GCST001142_1	Vitamin E levels	8.000000e-12
GCST001230_3	Triglycerides	2.000000e-86
GCST001367_2	Triglycerides	9.000000e-26

EFO canonical traits (18, 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:0004738	tocopherol measurement
EFO:0008007	age at assessment
EFO:0000195	metabolic syndrome
EFO:0004529	lipid measurement
EFO:0004723	coronary artery calcification
EFO:0007931	non-HDL cholesterol:HDL cholesterol ratio
EFO:0007929	triglyceride:HDL cholesterol ratio
EFO:0004309	platelet count
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004348	hematocrit
EFO:0010346	cholesteryl ester 18:3 measurement
EFO:0004340	body mass index
EFO:0007805	HDL cholesterol change measurement
EFO:0004614	apolipoprotein A 1 measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003704	Dementia	C10.228.140.380; F03.615.400
D008072	Hyperlipoproteinemia Type I	C16.320.565.398.465; C18.452.584.500.500.644.237; C18.452.584.563.465; C18.452.648.398.465
D006954	Hyperlipoproteinemia Type V	C16.320.565.398.493; C18.452.584.500.500.644.495; C18.452.584.500.500.851.750; C18.452.584.563.493; C18.452.648.398.493
D006951	Hyperlipoproteinemias	C18.452.584.500.500.644
D015228	Hypertriglyceridemia	C18.452.584.500.500.851

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs3135506	Efficacy	3	fenofibrate	Hypertriglyceridemia
rs662799	Efficacy	3	atorvastatin;lovastatin;simvastatin	Hyperlipidemias

PharmGKB variants

5 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs662799	APOA5	3	4.50	1	atorvastatin;lovastatin;simvastatin
rs3135506	APOA5	3	8.00	1	fenofibrate
rs2072560	APOA5, ZPR1		0.00	0
rs651821	APOA5		0.00	0
rs2266788	APOA5, ZPR1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, affects cotreatment, decreases expression, increases methylation	6
Aflatoxin B1	affects expression, decreases expression, decreases methylation	4
bisphenol A	affects expression, decreases methylation	2
Cyclosporine	decreases expression	2
dicrotophos	decreases expression	1
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
pirinixic acid	increases expression, affects binding, increases activity	1
benzo(b)fluoranthene	affects cotreatment, decreases expression	1
chlortoluron	decreases expression	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	decreases expression, increases abundance	1
benz(a)anthracene	affects cotreatment, decreases expression	1
chrysene	decreases expression, affects cotreatment	1
benazol P	affects expression	1
CGP 52608	affects binding, increases reaction	1
cyproconazole	decreases expression	1
perfluoro-n-heptanoic acid	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
GW 4064	affects cotreatment, increases expression	1
GW 7647	affects cotreatment, increases expression	1
perfluorohexanesulfonic acid	increases expression	1
6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime	affects cotreatment, increases expression	1
perfluorohexanoic acid	increases expression	1
Estradiol	decreases expression	1
Farnesol	affects cotreatment, increases expression	1
Hydrogen Peroxide	affects expression	1
Manganese	decreases expression, increases abundance	1
N-Nitrosopyrrolidine	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00473655	PHASE4	COMPLETED	Effect of Rosuvastatin on Triglyceride Levels in Mexican Hypertriglyceridemic Patients
NCT00246636	PHASE4	COMPLETED	Evaluation of Efficacy and Safety of Omacor (Omega-3-acid Ethyl Esters) as Add-on Therapy in Hypertriglyceridemic Subjects Treated With Antara (Fenofibrate) Followed by an 8-week Extension
NCT00286234	PHASE4	COMPLETED	Niacin, N-3 Fatty Acids and Insulin Resistance
NCT00346697	PHASE4	COMPLETED	Omega-3 Fatty Acids for High Triglycerides in HIV-infected Patients
NCT00397358	PHASE4	WITHDRAWN	Effect of Extraneal (Icodextrin)on Triglyceride Levels in PD Patients
NCT00632840	PHASE4	COMPLETED	Pharmacological Regulation of Fat Transport in Metabolic Syndrome
NCT00745407	PHASE4	COMPLETED	Effects of Fenofibrate on Adipocytokine Levels In Hypertriglyceridemic Patients
NCT00758927	PHASE4	UNKNOWN	The Effects of Omega-3 Fatty Acid (OMACOR) on the Low-density Lipoprotein (LDL) Sub-fraction in Type 2 Diabetic Patients
NCT00891293	PHASE4	COMPLETED	A Second Open-Label Extension of a Double-Blind, Parallel, Phase IV Study to Assess the Efficacy and Safety of Adjunctive Lovaza® (Formerly Known as Omacor®) Therapy in Hypertriglyceridemic Subjects Treated With Antara™
NCT00931879	PHASE4	COMPLETED	Lovaza® and Microvascular Function in Type 2 Diabetes
NCT00934219	PHASE4	UNKNOWN	Triglyceride Lowering Study
NCT01003847	PHASE4	COMPLETED	Differential Metabolic Effects of Fenofibrate and Fatty Acid
NCT01010399	PHASE4	COMPLETED	Boosted Lexiva With Lovaza Adjunctive Therapy in Hypertriglyceridemic, HIV-Infected Subjects
NCT01180764	PHASE4	WITHDRAWN	Effects of Lovaza on High Density Lipoprotein (HDL) Composition and Function in Hypertriglyceridemia
NCT01462877	PHASE4	COMPLETED	A Study to Evaluate Fenofibrate Combination With Statin in Chinese Patients With Dyslipidemic
NCT01480687	PHASE4	UNKNOWN	Fish Oil Supplementation and Vascular Function in Hypertensive Patients With Hypertriglyceridemia
NCT01527747	PHASE4	SUSPENDED	Effects of DPP-4 Inhibition on Triglycerides
NCT01569724	PHASE4	COMPLETED	Carbohydrate Metabolism Disorder Frequency in Hypertriglyceridemia Induced by Bexarotene of Cutaneous T Cell Lymphoma
NCT01625442	PHASE4	COMPLETED	Crocus Sativus (Saffron) and Berberis Vulgaris (Barberry Fruit) in Metabolic Syndrome
NCT01660932	PHASE4	COMPLETED	Vascular and Metabolic Effects of Omega-3 Fatty Acids
NCT01666041	PHASE4	COMPLETED	Vascular and Metabolic Effects of Fenofibrate/Omega vs Fenofibrate
NCT02015988	PHASE4	UNKNOWN	Simvastatin and Fenofibrate vs Simvastatin Alone in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome
NCT02926027	PHASE4	COMPLETED	Effect of Vascepa on Improving Coronary Atherosclerosis in People With High Triglycerides Taking Statin Therapy
NCT03120299	PHASE4	COMPLETED	The Effect of Omega-3 FA on Hypertriglyceridemia in Patients With T2DM(OCEAN)
NCT03342807	PHASE4	UNKNOWN	Intravenous Administration of Insulin and Plasma Exchange on Triglyceride Levels in Early Stage of Hypertriglyceridemia-induced Pancreatitis
NCT03501680	PHASE4	UNKNOWN	Intensive Insulin for Severe/Moderate Hypertriglyceridemia Pancreatitis.
NCT05487833	PHASE4	UNKNOWN	Insulin and Standard Management in Hypertriglyceridemic Acute Pancreatitis
NCT06129526	PHASE4	UNKNOWN	Study of the Efficacy and Safety of EPA in Patients With Type-2 Diabetes
NCT01239992	PHASE4	TERMINATED	Effect of Niacin/Laropiprant on Postprandial Lipoprotein Metabolism in Patients With Dyslipoproteinemia
NCT00043849	PHASE4	COMPLETED	Treatment of Agitation/Psychosis in Dementia/Parkinsonism (TAP/DAP)
NCT00127114	PHASE4	WITHDRAWN	Amantadine for the Treatment of Behavioral Disturbance in Frontotemporal Dementia (FTD)
NCT00164970	PHASE4	COMPLETED	Can Oral Vitamin B12 and Folate Supplementation Preserve Cognitive Function of Patients With Early Dementia?
NCT00177671	PHASE4	COMPLETED	Antidepressant Medication Plus Donepezil for Treating Late-life Depression
NCT00208819	PHASE4	COMPLETED	A Comparison of Two Standard Therapies in the Management of Dementia With Agitation
NCT00245206	PHASE4	COMPLETED	Side Effects of Newer Antipsychotics in Older Adults
NCT00254033	PHASE4	COMPLETED	Apathy Associated With Alzheimer’s Disease
NCT00371059	PHASE4	COMPLETED	Memantine for Agitation in Dementia
NCT00375557	PHASE4	WITHDRAWN	Safety and Efficacy of Divalproex and Quetiapine in Elderly Alzheimer’s Dementia Patients
NCT00385684	PHASE4	COMPLETED	Low-Dose Opiate Therapy for Discomfort in Dementia (L-DOT)
NCT00433121	PHASE4	COMPLETED	Discontinuation of Antipsychotics and Antidepressants Among Patients With BPSD