ANGPTL3

Summary

ANGPTL3 (angiopoietin like 3, HGNC:491) is a protein-coding gene on chromosome 1p31.3, encoding Angiopoietin-related protein 3 (Q9Y5C1). Acts in part as a hepatokine that is involved in regulation of lipid and glucose metabolism.

This gene encodes a member of a family of secreted proteins that function in angiogenesis. The encoded protein, which is expressed predominantly in the liver, is further processed into an N-terminal coiled-coil domain-containing chain and a C-terminal fibrinogen chain. The N-terminal chain is important for lipid metabolism, while the C-terminal chain may be involved in angiogenesis. Mutations in this gene cause familial hypobetalipoproteinemia type 2.

Source: NCBI Gene 27329 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial hypobetalipoproteinemia 2 (Definitive, ClinGen)
• GWAS associations: 37
• Clinical variants (ClinVar): 161 total — 14 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 3
• Druggable target: yes
• MANE Select transcript: NM_014495

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:491
Approved symbol	ANGPTL3
Name	angiopoietin like 3
Location	1p31.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000132855
Ensembl biotype	protein_coding
OMIM	604774
Entrez	27329

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000371129, ENST00000482591, ENST00000493994, ENST00000895485, ENST00000895486, ENST00000895487, ENST00000895488, ENST00000895489, ENST00000895490, ENST00000895491, ENST00000895492, ENST00000895493, ENST00000895494, ENST00000895495

RefSeq mRNA: 1 — MANE Select: NM_014495 NM_014495

CCDS: CCDS622

Canonical transcript exons

ENST00000371129 — 7 exons

Exon	Start	End
ENSE00000773251	62598696	62598806
ENSE00000773252	62601082	62601196
ENSE00000773255	62603969	62604235
ENSE00001454405	62604633	62606313
ENSE00001454409	62597520	62598061
ENSE00003523493	62602285	62602380
ENSE00003627854	62601769	62601882

Expression profiles

Bgee: expression breadth ubiquitous, 153 present calls, max score 98.54.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.3722 / max 1474.4337, expressed in 34 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
3156	3.2293	30
3155	0.1428	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.54	gold quality
liver	UBERON:0002107	98.14	gold quality
nephron tubule	UBERON:0001231	88.32	gold quality
kidney epithelium	UBERON:0004819	82.63	gold quality
adult mammalian kidney	UBERON:0000082	80.63	gold quality
metanephric glomerulus	UBERON:0004736	79.51	gold quality
renal glomerulus	UBERON:0000074	78.46	gold quality
kidney	UBERON:0002113	77.80	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.64	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	73.23	gold quality
buccal mucosa cell	CL:0002336	72.85	gold quality
cortex of kidney	UBERON:0001225	72.66	gold quality
calcaneal tendon	UBERON:0003701	71.41	gold quality
adrenal tissue	UBERON:0018303	70.60	gold quality
metanephros	UBERON:0000081	68.40	gold quality
colonic epithelium	UBERON:0000397	68.40	gold quality
metanephros cortex	UBERON:0010533	65.69	gold quality
stomach	UBERON:0000945	63.61	gold quality
body of stomach	UBERON:0001161	62.95	gold quality
corpus callosum	UBERON:0002336	60.56	gold quality
tendon	UBERON:0000043	60.06	gold quality
islet of Langerhans	UBERON:0000006	58.82	gold quality
fundus of stomach	UBERON:0001160	58.13	gold quality
cerebellar vermis	UBERON:0004720	56.77	gold quality
left ovary	UBERON:0002119	55.35	gold quality
pancreatic ductal cell	CL:0002079	55.32	silver quality
pancreas	UBERON:0001264	54.91	gold quality
oocyte	CL:0000023	54.07	gold quality
lower esophagus mucosa	UBERON:0035834	54.03	gold quality
right ovary	UBERON:0002118	53.78	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10553	yes	39.45
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1H3, PPARD, THRA, THRB

miRNA regulators (miRDB)

82 targeting ANGPTL3, 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-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-33A-3P	99.70	70.27	3362

Literature-anchored findings (GeneRIF, showing 40)

• ANGPTL3 is the first member of the angiopoietin-like family of secreted factors binding to integrin alpha(v)beta(3), which suggests a possible role in the regulation of angiogenesis. (PMID:11877390)
• ANGPTL3 stimulates endothelial cell adhesion and migration via integrin alpha vbeta 3 and induces blood vessel formation in vivo (PMID:11877390)
• Angptl3 gene is a direct target of the liver X receptor (LXR). (PMID:12518032)
• Data show that angiopoietin-like protein 3 (ANGPTL3) targets adipose cells and induces lipolysis. (PMID:12565906)
• the cleavage of ANGPTL3 at two sites is important for the activation of ANGPTL3 in vivo (PMID:12909640)
• liver-derived Angptl3 inhibits lipoprotein lipase activity primarily in the fed state (PMID:16531751)
• Angptl3 acts as an inhibitor of EL and may be involved in the regulation of plasma HDL cholesterol and HDL-PL levels in humans and rodents. (PMID:17110602)
• The pilot study supports the hypothesis about the role of Angptl3 as a new class of lipid metabolism modulator. (PMID:18063851)
• probucol decreases plasma ANGPTL3 and HDL phospholipids while increasing prebeta1-HDL and cholesteryl ester transfer protein (PMID:18279878)
• Our results also indicated that the integrin alphaVbeta3 antibody (LM609) could block the Angptl3-induced protein kinase B phosphorylation. (PMID:18535744)
• ANGPTL3, the inhibitor of endothelial lipase, may be strongly associated with increased HDL-cholesterol (PMID:18804459)
• The finding that ANGPTL3 and ANGPTL4 inhibit LPL activity through distinct mechanisms indicates that the two proteins play unique roles in modulation of lipid metabolism in vivo. (PMID:19028676)
• Dysmorphic findings in two cases involving FBHL2 are reported. (PMID:19282754)
• ANGPTL3 may be a novel factor contributing to uremic dyslipidemia. (PMID:19540497)
• Like ANGPTL4, ANGPTL3 inhibited nonstabilized LPL but not GPIHBP1-stabilized LPL (PMID:19542565)
• Data show that SNPs associated with TG in normolipidemic samples, including APOA5, TRIB1, TBL2, GCKR, GALNT2 and ANGPTL3 were significantly associated with HLP types 2B, 3, 4 and 5. (PMID:19656773)
• Data suggest roles for ANGPTL3 and ANGPTL4 in modulation of serum TG and HDL levels in obesity in a Finnish population sample. (PMID:19826106)
• The present study underlines the role of ANGPTL3 in HDL-cholesterol metabolism as early as in adolescence (PMID:19890028)
• Serum Angptl3 was positively correlated with adiponectin in metabolic syndrome patients. (PMID:20360639)
• relationship between plasma angiopoietin-like protein 3 (ANGPTL3), and lipoprotein lipase (LPL) activity and hepatic triglyceride lipase (PMID:20595410)
• ANGPTL3 activation is modulated by O-glycosylation and the proprotein undergoes convertase processing for activation. (PMID:20837471)
• Found two distinct nonsense mutations in ANGPTL3 in 2 family members out of 38 with combined hypolipidemia. (PMID:20942659)
• Data show no differences in triglyceride or total cholesterol levels in relation to any allelic variants of ANGPTL3, CILP2, or TRIB1 SNPs. (PMID:21691831)
• ANGPTL-2 and -3 have enhancing effect on human hematopoietic progenitor cell survival, effects requiring the CC domain of the ANGPTL molecules. (PMID:21983347)
• the homozygous or compound heterozygous for ANGPTL3 loss-of-function mutations (p.G400VfsX5, p.I19LfsX22/p.N147X) had low plasma ANGPTL3 and moderately reduced low-density lipoprotein cholesterol but normal plasma high-density lipoprotein cholesterol. (PMID:22062970)
• The prevalence and effect of mutations in ANGPTL3, in carriers of pathogenic autosomal dominant hypercholesterolemia mutations with unexpected low LDL-C levels. (PMID:22095935)
• It denominated familial combined hypolipidemia, which consist of a biochemical phenotype of low LDLc, low apoB, low TG and, unlike APOB mutations, low HDL cholesterol, due to a loss-of-function mutation in ANGPTL3. (PMID:22155345)
• In a cohort of subjects with severe primary hypobetalipoproteinemia the prevalence of ANGPTL3 gene mutations responsible for a combined hypolipidemia phenotype is about 10%. (PMID:22247256)
• Familial combined hypolipidemia segregates as a recessive trait so that apolipoprotein B- and apolipoprotein A-I-containing lipoproteins are comprehensively affected only by the total deficiency of Angptl3. (PMID:22659251)
• No gene-gene interaction was identified other than an interaction between SNPs in the ANGPTL3 and RXRA regions, which results in the inhibition of ApoB reduction in response to statin-FNA therapy. (PMID:22896670)
• Although partial Angptl3 deficiency did not affect the activities of lipolytic enzymes, the complete absence of Angptl3 results in an increased lipoprotein lipase activity and mass and low circulating free fatty acid levels. (PMID:23661675)
• Identification of loss-of-function ANGPTL3 mutation is shedding light on a possible role of ANGPTL3 at the crossroads of lipoproteins, fatty acids, and glucose metabolism. [Review] (PMID:23839332)
• HCV core represses ANGPTL-3 expression through loss of HNF-1alpha binding activity and blockage of LXR/RXR transactivation (PMID:23978712)
• ANGPTL3 is positively associated with low-density lipoprotein cholesterol and high-density lipoprotein cholesterol and not with metabolic syndrome traits including triglycerides. (PMID:24626437)
• Data suggest that genetic polymorphisms in ANGPTL3 (angiopoietin-like 3 protein), TIMD4 (T cell immunoglobulin mucin-4), and apolipoproteins A5 and B are among the genetic determinants of hypertriglyceridemia in Amerindian populations. [REVIEW] (PMID:24768220)
• Data suggest that silencing of ANGPTL 3 (angiopoietin-like protein 3) improves insulin sensitivity. (PMID:25495645)
• Novel mutation Y344S found in ANGPTL3 gene in two diabetic patients with familial hypobetalipoproteinemia. (PMID:25733326)
• Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion (PMID:25954050)
• The present data leads to new insights into the role of ANGPTL3 in glioblastomas and provides an independent predictive factor (PMID:26639238)
• ANGPTL3 levels were associated with fasting insulin and the homeostasis model assessment of insulin resistance in Korean children. (PMID:26739706)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	angptl3	ENSDARG00000044365
mus_musculus	Angptl3	ENSMUSG00000028553
rattus_norvegicus	Angptl3	ENSRNOG00000008638

Paralogs (25): TNC (ENSG00000041982), FCN1 (ENSG00000085265), ANGPT2 (ENSG00000091879), ANGPT4 (ENSG00000101280), FGL1 (ENSG00000104760), FN1 (ENSG00000115414), TNR (ENSG00000116147), ANGPTL1 (ENSG00000116194), TNN (ENSG00000120332), FGL2 (ENSG00000127951), FIBCD1 (ENSG00000130720), ANGPTL6 (ENSG00000130812), ANGPTL2 (ENSG00000136859), FCN3 (ENSG00000142748), FNDC7 (ENSG00000143107), ANGPT1 (ENSG00000154188), FCN2 (ENSG00000160339), MFAP4 (ENSG00000166482), ANGPTL4 (ENSG00000167772), TNXB (ENSG00000168477), FGG (ENSG00000171557), FGA (ENSG00000171560), FGB (ENSG00000171564), ANGPTL7 (ENSG00000171819), ANGPTL5 (ENSG00000187151)

Protein

Protein identifiers

Angiopoietin-related protein 3 — Q9Y5C1 (reviewed: Q9Y5C1)

Alternative names: Angiopoietin-5, Angiopoietin-like protein 3

All UniProt accessions (1): Q9Y5C1

UniProt curated annotations — full annotation on UniProt →

Function. Acts in part as a hepatokine that is involved in regulation of lipid and glucose metabolism. Proposed to play a role in the trafficking of energy substrates to either storage or oxidative tissues in response to food intake. Has a stimulatory effect on plasma triglycerides (TG), which is achieved by suppressing plasma TG clearance via inhibition of LPL activity. The inhibition of LPL activity appears to be an indirect mechanism involving recruitment of proprotein convertases PCSK6 and FURIN to LPL leading to cleavage and dissociation of LPL from the cell surface; the function does not require ANGPTL3 proteolytic cleavage but seems to be mediated by the N-terminal domain, and is not inhibited by GPIHBP1. Can inhibit endothelial lipase, causing increased plasma levels of high density lipoprotein (HDL) cholesterol and phospholipids. Can bind to adipocytes to activate lipolysis, releasing free fatty acids and glycerol. Suppresses LPL specifically in oxidative tissues which is required to route very low density lipoprotein (VLDL)-TG to white adipose tissue (WAT) for storage in response to food; the function may involve cooperation with circulating, liver-derived ANGPTL8 and ANGPTL4 expression in WAT. Contributes to lower plasma levels of low density lipoprotein (LDL)-cholesterol by a mechanism that is independent of the canonical pathway implicating APOE and LDLR. May stimulate hypothalamic LPL activity. In vitro inhibits LPL activity; not effective on GPIHBP1-stabilized LPL. Involved in angiogenesis. Binds to endothelial cells via integrin alpha-V/beta-3 (ITGAV:ITGB3), activates FAK, MAPK and Akt signaling pathways and induces cell adhesion and cell migration. Secreted from podocytes, may modulate properties of glomerular endothelial cells involving integrin alpha-V/beta-3 and Akt signaling. May increase the motility of podocytes. May induce actin filament rearrangements in podocytes implicating integrin alpha-V/beta-3 and Rac1 activation. Binds to hematopoietic stem cells (HSC) and is involved in the regulation of HSC activity probably implicating down-regulation of IKZF1/IKAROS.

Subunit / interactions. Interacts with ANGPTL8. Interacts with ITGB3.

Subcellular location. Secreted. Cell projection. Lamellipodium.

Tissue specificity. Expressed principally in liver. Weakly expressed in kidney. Binds to adipocytes. Increased expression and colocalization with activated ITGB3 in glomeruli of patients with nephrotic syndrome showing effaced podocyte foot processes (at protein level).

Post-translational modifications. O-glycosylated at Thr-226 by GALNT2; blocks processing and activation by proprotein convertases. In part proteolytically cleaved by proprotein convertases; proposed to be involved in activation.

Disease relevance. Hypobetalipoproteinemia, familial, 2 (FHBL2) [MIM:605019] A disorder of lipid metabolism characterized by less than 5th percentile age- and sex-specific levels of low density lipoproteins, and dietary fat malabsorption. Affected individuals present with combined hypolipidemia, consisting of extremely low plasma levels of LDL cholesterol, HDL cholesterol, and triglycerides. The disease is caused by variants affecting the gene represented in this entry. May be involved in atherosclerosis. Plasma levels are closely associated with arterial wall thickness. May be involved in nephrotic syndrome.

Domain organisation. The fibrinogen C-terminal domain is sufficient to mediate endothelial cell adhesion.

Induction. Down-regulated by insulin.

Miscellaneous. Was suggested to inhibit LPL through a direct mechanism; however, the necessary concentration to achieve in vitro inhibition is at least 30-fold higher than ANGPTL3 plasma concentration.

RefSeq proteins (1): NP_055310* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002181	Fibrinogen_a/b/g_C_dom	Domain
IPR014716	Fibrinogen_a/b/g_C_1	Homologous_superfamily
IPR036056	Fibrinogen-like_C	Homologous_superfamily
IPR050373	Fibrinogen_C-term_domain	Family

Pfam: PF00147

UniProt features (57 total): strand 15, sequence variant 13, mutagenesis site 8, helix 5, glycosylation site 4, chain 3, region of interest 3, disulfide bond 2, signal peptide 1, sequence conflict 1, domain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6EUA	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5C1-F1	79.94	0.48

Functional residue map

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

Disulfide bonds (2): 246–274, 394–408

Glycosylation sites (4): 226, 296, 357, 115

Mutagenesis-validated functional residues (8):

Position	Phenotype
62–63	abolishes effect on plasma triglyceride level; when associated with n-65.
63	abolishes inhibitory effect on lipg/el phospholipase activity; when associated with n-65.
65	abolishes effect on plasma triglyceride level; when associated with 62-i-n-63.
65	abolishes inhibitory effect on lipg/el phospholipase activity; when associated with n-63.
204–205	abolishes proteolytical cleavage and effect on plasma triglyceride levels, keeps in vitro inactivation of lpl activity;
221	abolishes proteolytical cleavage and effect on plasma triglyceride levels, keeps in vitro inactivation of lpl activity;
224	abolishes proteolytical cleavage and effect on plasma triglyceride levels, keeps in vitro inactivation of lpl activity;
235	abolishes proteolytical cleavage and effect on plasma triglyceride levels, keeps in vitro inactivation of lpl activity;

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-8963889	Assembly of active LPL and LIPC lipase complexes
R-HSA-9029558	NR1H2 & NR1H3 regulate gene expression linked to lipogenesis
R-HSA-162582	Signal Transduction
R-HSA-174824	Plasma lipoprotein assembly, remodeling, and clearance
R-HSA-382551	Transport of small molecules
R-HSA-8963899	Plasma lipoprotein remodeling
R-HSA-9006931	Signaling by Nuclear Receptors
R-HSA-9024446	NR1H2 and NR1H3-mediated signaling

MSigDB gene sets: 190 (showing top): GOBP_ACYLGLYCEROL_HOMEOSTASIS, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_STEROL_HOMEOSTASIS, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_POLYOL_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOCC_CELL_SURFACE, GOBP_ARTERY_DEVELOPMENT, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOMF_GROWTH_FACTOR_ACTIVITY, CERVERA_SDHB_TARGETS_1_DN, HNF1_Q6, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION

GO Biological Process (26): angiogenesis (GO:0001525), glycerol metabolic process (GO:0006071), fatty acid metabolic process (GO:0006631), phospholipid metabolic process (GO:0006644), cell-matrix adhesion (GO:0007160), signal transduction (GO:0007165), integrin-mediated signaling pathway (GO:0007229), cholesterol metabolic process (GO:0008203), phospholipid catabolic process (GO:0009395), response to hormone (GO:0009725), negative regulation of very-low-density lipoprotein particle remodeling (GO:0010903), lipid storage (GO:0019915), positive regulation of cell migration (GO:0030335), cholesterol homeostasis (GO:0042632), positive regulation of angiogenesis (GO:0045766), artery morphogenesis (GO:0048844), positive regulation of lipid catabolic process (GO:0050996), lipid homeostasis (GO:0055088), acylglycerol homeostasis (GO:0055090), phospholipid homeostasis (GO:0055091), triglyceride homeostasis (GO:0070328), regulation of chylomicron remodeling (GO:0090318), lipid metabolic process (GO:0006629), cell adhesion (GO:0007155), blood coagulation (GO:0007596), regulation of lipid metabolic process (GO:0019216)

GO Molecular Function (7): enzyme inhibitor activity (GO:0004857), phospholipase inhibitor activity (GO:0004859), integrin binding (GO:0005178), growth factor activity (GO:0008083), heparin binding (GO:0008201), lipase binding (GO:0035473), lipase inhibitor activity (GO:0055102)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), early endosome (GO:0005769), Golgi apparatus (GO:0005794), cell surface (GO:0009986), lamellipodium (GO:0030027), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Plasma lipoprotein remodeling	1
NR1H2 and NR1H3-mediated signaling	1
Transport of small molecules	1
Plasma lipoprotein assembly, remodeling, and clearance	1
Signal Transduction	1
Signaling by Nuclear Receptors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
blood vessel morphogenesis	2
lipid metabolic process	2
lipid catabolic process	2
lipid homeostasis	2
anatomical structure formation involved in morphogenesis	1
carbohydrate metabolic process	1
polyol metabolic process	1
monocarboxylic acid metabolic process	1
organophosphate metabolic process	1
cell-substrate adhesion	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell surface receptor signaling pathway	1
sterol metabolic process	1
secondary alcohol metabolic process	1
phospholipid metabolic process	1
organophosphate catabolic process	1
response to endogenous stimulus	1
response to chemical	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
nutrient storage	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
sterol homeostasis	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
artery development	1
positive regulation of catabolic process	1
positive regulation of lipid metabolic process	1
regulation of lipid catabolic process	1
chemical homeostasis	1

Protein interactions and networks

STRING

1261 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANGPTL3	ANGPTL8	Q6UXH0	987
ANGPTL3	LPL	P06858	922
ANGPTL3	TEK	Q02763	871
ANGPTL3	APOA5	Q6Q788	865
ANGPTL3	APOB	P04114	845
ANGPTL3	GPIHBP1	Q8IV16	821
ANGPTL3	APOC3	P02656	802
ANGPTL3	LIPG	Q9Y5X9	777
ANGPTL3	PCSK9	Q8NBP7	771
ANGPTL3	TIE1	P35590	763
ANGPTL3	APOA1	P02647	727
ANGPTL3	TRIB1	Q96RU8	703
ANGPTL3	DOCK7	Q96N67	679
ANGPTL3	APOC2	P02655	665
ANGPTL3	LMF1	Q96S06	646

IntAct

7 interactions, top by confidence:

A	B	Type	Score
	LPL	psi-mi:“MI:1355”(lipid cleavage)	0.620
	LPL	psi-mi:“MI:0407”(direct interaction)	0.620
LPL	ANGPTL3	psi-mi:“MI:0407”(direct interaction)	0.440
ANGPTL3	ANGPTL8	psi-mi:“MI:0915”(physical association)	0.400
ANGPTL3	CCDC91	psi-mi:“MI:0914”(association)	0.350
ITGAV	ANGPTL3	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (11): CCDC91 (Affinity Capture-MS), GULP1 (Affinity Capture-MS), FBXO28 (Affinity Capture-MS), BIRC6 (Affinity Capture-MS), ANGPTL3 (Synthetic Lethality), ANGPTL3 (Affinity Capture-RNA), CCDC91 (Affinity Capture-MS), FBXO28 (Affinity Capture-MS), GULP1 (Affinity Capture-MS), BIRC6 (Affinity Capture-MS), ANGPTL3 (Reconstituted Complex)

ESM2 similar proteins: A0A8J8, O08538, O15123, O18920, O35460, O35462, O35608, O43827, O77802, O95841, P02675, P02676, P02678, P02679, P02680, P04115, P12799, P12804, P14480, P17634, P21758, P30204, P86239, Q02020, Q08830, Q0P4P2, Q14314, Q15389, Q1RMR1, Q29RY7, Q3SZZ7, Q5EA66, Q5M8C6, Q5XK91, Q60FC1, Q640P2, Q6AX44, Q71KU9, Q86XS5, Q8K0E8

Diamond homologs: A0A8J8, A2AV25, D8VNS7, D8VNS8, D8VNS9, D8VNT0, E2IYB3, E9PV24, O00602, O08538, O15123, O18920, O35460, O35462, O35608, O43827, O70165, O70497, O75636, O77802, O93526, O95841, P02671, P02675, P02676, P02678, P02679, P02680, P04115, P06399, P10039, P12799, P12804, P14448, P14480, P17634, P19477, P21520, P22105, P24821

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	3
Uncertain significance	71
Likely benign	56
Benign	9

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1031836	NM_014495.4(ANGPTL3):c.575del (p.Gln192fs)	Pathogenic
1455430	NC_000001.10:g.(?62921085)(63153935_?)del	Pathogenic
18439	NM_014495.4(ANGPTL3):c.50_51delinsGA (p.Ser17Ter)	Pathogenic
18440	NM_014495.4(ANGPTL3):c.385G>T (p.Glu129Ter)	Pathogenic
2525900	NM_014495.4(ANGPTL3):c.950dup (p.Glu318fs)	Pathogenic
2579168	GRCh38/hg38 1p31.3(chr1:61077177-62865614)x1	Pathogenic
3247842	NC_000001.10:g.(?62976228)(63153935_?)del	Pathogenic
3706742	NM_014495.4(ANGPTL3):c.177del (p.Phe60fs)	Pathogenic
4694450	NM_014495.4(ANGPTL3):c.994C>T (p.Arg332Ter)	Pathogenic
4752496	NM_014495.4(ANGPTL3):c.906C>A (p.Tyr302Ter)	Pathogenic
91863	NM_014495.4(ANGPTL3):c.1198+1G>T	Pathogenic
91864	NM_014495.4(ANGPTL3):c.55del (p.Ile19fs)	Pathogenic
91866	NM_014495.4(ANGPTL3):c.363_367del (p.Asn121fs)	Pathogenic
91867	NM_014495.4(ANGPTL3):c.883T>C (p.Phe295Leu)	Pathogenic
2893114	NM_014495.4(ANGPTL3):c.835+1G>C	Likely pathogenic
3712309	NM_014495.4(ANGPTL3):c.932-2A>G	Likely pathogenic
4845847	NM_014495.4(ANGPTL3):c.372del (p.Glu125fs)	Likely pathogenic

SpliceAI

629 predictions. Top by Δscore:

Variant	Effect	Δscore
1:62598058:TAAA:T	donor_gain	1.0000
1:62598058:TAAAG:T	donor_loss	1.0000
1:62598060:AA:A	donor_gain	1.0000
1:62598060:AAG:A	donor_loss	1.0000
1:62598061:AGTA:A	donor_loss	1.0000
1:62598062:G:GG	donor_gain	1.0000
1:62598062:GT:G	donor_loss	1.0000
1:62598063:TAA:T	donor_loss	1.0000
1:62603967:A:AG	acceptor_gain	1.0000
1:62603968:G:GG	acceptor_gain	1.0000
1:62603968:GGA:G	acceptor_gain	1.0000
1:62603968:GGAGA:G	acceptor_gain	1.0000
1:62597549:T:TC	acceptor_gain	0.9900
1:62598044:G:GT	donor_gain	0.9900
1:62598057:TTAAA:T	donor_gain	0.9900
1:62598059:AAA:A	donor_gain	0.9900
1:62598691:TCCA:T	acceptor_gain	0.9900
1:62598692:CCA:C	acceptor_gain	0.9900
1:62598693:CA:C	acceptor_gain	0.9900
1:62598694:AG:A	acceptor_gain	0.9900
1:62598695:G:C	acceptor_gain	0.9900
1:62598695:GA:G	acceptor_gain	0.9900
1:62598808:T:TC	donor_loss	0.9900
1:62601767:A:AG	acceptor_gain	0.9900
1:62601768:G:GG	acceptor_gain	0.9900
1:62601878:ATCAG:A	donor_loss	0.9900
1:62601879:TCAG:T	donor_loss	0.9900
1:62601880:CAG:C	donor_loss	0.9900
1:62601881:AGGT:A	donor_loss	0.9900
1:62601882:GGTAA:G	donor_loss	0.9900

AlphaMissense

3053 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:62597736:T:C	L57P	0.995
1:62597705:G:C	A47P	0.993
1:62597715:T:C	L50P	0.993
1:62602312:G:C	R288P	0.993
1:62597790:T:C	L75P	0.992
1:62597718:T:C	L51P	0.991
1:62597736:T:A	L57H	0.991
1:62597724:T:C	L53S	0.990
1:62597715:T:A	L50H	0.987
1:62597706:C:A	A47D	0.985
1:62597727:G:A	G54E	0.985
1:62604178:T:C	F381L	0.985
1:62604180:T:A	F381L	0.985
1:62604180:T:G	F381L	0.985
1:62597726:G:A	G54R	0.984
1:62597726:G:C	G54R	0.984
1:62602365:T:C	F306L	0.984
1:62602367:T:A	F306L	0.984
1:62602367:T:G	F306L	0.984
1:62597703:T:C	L46S	0.983
1:62602332:T:C	F295L	0.981
1:62602334:C:A	F295L	0.981
1:62602334:C:G	F295L	0.981
1:62603977:T:A	W314R	0.981
1:62603977:T:C	W314R	0.981
1:62597820:T:C	L85P	0.978
1:62597748:T:A	V61D	0.977
1:62604179:T:C	F381S	0.976
1:62604641:T:A	W403R	0.975
1:62604641:T:C	W403R	0.975

dbSNP variants (sampled 300 via entrez): RS1000171942 (1:62603356 A>G), RS1000233924 (1:62602950 A>T), RS1000406813 (1:62596063 T>A,C), RS1000520294 (1:62602805 G>T), RS1000693667 (1:62598035 G>C), RS1000718769 (1:62600934 T>C), RS1001756591 (1:62595585 C>A), RS1002393603 (1:62602512 T>C,G), RS1002693012 (1:62600798 T>C), RS1003289828 (1:62598757 A>G), RS1003323749 (1:62599167 T>C), RS1003615157 (1:62595924 G>A), RS1004531542 (1:62598381 A>C), RS1004895380 (1:62604345 C>A,T), RS1005073144 (1:62597054 G>A,C)

Disease associations

OMIM: gene MIM:604774 | disease phenotypes: MIM:615859, MIM:605019, MIM:613735

GenCC curated gene-disease

Disease	Classification	Inheritance
familial hypobetalipoproteinemia 2	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
familial hypobetalipoproteinemia 2	Definitive	AR

Mondo (3): developmental and epileptic encephalopathy, 23 (MONDO:0014371), familial hypobetalipoproteinemia 2 (MONDO:0011505), brain malformations with or without urinary tract defects (MONDO:0100478)

Orphanet (1): Early-onset epileptic encephalopathy-cortical blindness-intellectual disability-facial dysmorphism syndrome (Orphanet:411986)

HPO phenotypes

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

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0003563	Decreased LDL cholesterol concentration
HP:0012153	Hypotriglyceridemia

GWAS associations

37 associations (top):

Study	Trait	p-value
GCST000138_4	Triglycerides	2.000000e-08
GCST000139_6	Triglycerides	2.000000e-10
GCST000286_9	Triglycerides	3.000000e-07
GCST000533_54	Lipid metabolism phenotypes	1.000000e-13
GCST000533_55	Lipid metabolism phenotypes	2.000000e-11
GCST000533_56	Lipid metabolism phenotypes	3.000000e-10
GCST000533_57	Lipid metabolism phenotypes	4.000000e-09
GCST000533_58	Lipid metabolism phenotypes	7.000000e-10
GCST000533_59	Lipid metabolism phenotypes	1.000000e-12
GCST000533_60	Lipid metabolism phenotypes	1.000000e-14
GCST000584_3	Triglycerides	2.000000e-09
GCST000758_15	Triglycerides	9.000000e-43
GCST000759_19	LDL cholesterol	3.000000e-18
GCST000760_7	Cholesterol, total	5.000000e-41
GCST000809_6	Triglycerides	6.000000e-08
GCST001392_3	Lipid metabolism phenotypes	3.000000e-13
GCST001639_12	Metabolite levels	8.000000e-15
GCST002216_20	Triglycerides	3.000000e-74
GCST002221_6	Cholesterol, total	4.000000e-80
GCST002222_15	LDL cholesterol	3.000000e-32
GCST002896_5	Cholesterol, total	2.000000e-34
GCST002897_11	Triglycerides	6.000000e-34
GCST002898_2	LDL cholesterol	2.000000e-11
GCST003214_2	Cholesterol, total	5.000000e-08
GCST003217_2	Triglycerides	8.000000e-12
GCST004132_95	Crohn’s disease	4.000000e-06
GCST004233_41	LDL cholesterol levels	1.000000e-31
GCST004235_11	Total cholesterol levels	3.000000e-82
GCST004235_2	Total cholesterol levels	2.000000e-06
GCST004237_25	Triglyceride levels	3.000000e-92

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004529	lipid measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004723	coronary artery calcification
EFO:0009592	social interaction measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C565732	Hypobetalipoproteinemia, Familial, 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3710485 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	3
Chenodeoxycholic Acid	decreases expression, affects cotreatment	2
Valproic Acid	decreases expression, decreases methylation	2
Aflatoxin B1	affects expression, decreases methylation	2
aminomethylphosphonic acid (AMPA)	decreases expression	1
dicrotophos	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	decreases expression	1
sodium arsenite	decreases expression	1
tianeptine	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
Troglitazone	decreases expression	1
Acetaminophen	decreases expression	1
Glyphosate	decreases expression	1
Allopurinol	decreases expression	1
Amiodarone	decreases expression	1
Aspirin	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Deoxycholic Acid	decreases expression, affects cotreatment	1
Estradiol	decreases expression	1
Fluorouracil	decreases expression	1
Glycochenodeoxycholic Acid	affects cotreatment, decreases expression	1
Glycocholic Acid	affects cotreatment, decreases expression	1
Glycodeoxycholic Acid	affects cotreatment, decreases expression	1
Indomethacin	decreases expression	1
N-Nitrosopyrrolidine	decreases expression	1
Phenobarbital	affects expression	1
Rifampin	decreases expression	1
Sulindac	decreases expression	1
Tamoxifen	decreases expression	1

Clinical trials (associated diseases)

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