ANGPTL4

Summary

ANGPTL4 (angiopoietin like 4, HGNC:16039) is a protein-coding gene on chromosome 19p13.2, encoding Angiopoietin-related protein 4 (Q9BY76). Mediates inactivation of the lipoprotein lipase LPL, and thereby plays a role in the regulation of triglyceride clearance from the blood serum and in lipid metabolism.

This gene encodes a glycosylated, secreted protein containing a C-terminal fibrinogen domain. The encoded protein is induced by peroxisome proliferation activators and functions as a serum hormone that regulates glucose homeostasis, lipid metabolism, and insulin sensitivity. This protein can also act as an apoptosis survival factor for vascular endothelial cells and can prevent metastasis by inhibiting vascular growth and tumor cell invasion. The C-terminal domain may be proteolytically-cleaved from the full-length secreted protein. Decreased expression of this gene has been associated with type 2 diabetes. Alternative splicing results in multiple transcript variants. This gene was previously referred to as ANGPTL2 but has been renamed ANGPTL4.

Source: NCBI Gene 51129 — RefSeq curated summary.

At a glance

• GWAS associations: 56
• Clinical variants (ClinVar): 75 total
• MANE Select transcript: NM_139314

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16039
Approved symbol	ANGPTL4
Name	angiopoietin like 4
Location	19p13.2
Locus type	gene with protein product
Status	Approved
Aliases	pp1158, PGAR, ARP4, HFARP, FIAF, NL2
Ensembl gene	ENSG00000167772
Ensembl biotype	protein_coding
OMIM	605910
Entrez	51129

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000301455, ENST00000393962, ENST00000593998, ENST00000594348, ENST00000594875, ENST00000595079, ENST00000597137, ENST00000598255, ENST00000599192, ENST00000601770, ENST00000601886, ENST00000955922, ENST00000955923

RefSeq mRNA: 2 — MANE Select: NM_139314 NM_001039667, NM_139314

CCDS: CCDS12200, CCDS42493

Canonical transcript exons

ENST00000301455 — 7 exons

Exon	Start	End
ENSE00001250851	8373705	8374370
ENSE00001300958	8364155	8364639
ENSE00003486893	8369219	8369332
ENSE00003527075	8371241	8371522
ENSE00003552173	8366202	8366319
ENSE00003568477	8371056	8371151
ENSE00003586590	8365954	8366064

Expression profiles

Bgee: expression breadth ubiquitous, 239 present calls, max score 97.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.9651 / max 1807.5395, expressed in 1312 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173651	26.9651	1312

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pericardium	UBERON:0002407	97.93	gold quality
omental fat pad	UBERON:0010414	96.94	gold quality
peritoneum	UBERON:0002358	96.87	gold quality
type B pancreatic cell	CL:0000169	96.77	silver quality
adipose tissue of abdominal region	UBERON:0007808	96.71	gold quality
sural nerve	UBERON:0015488	95.76	gold quality
subcutaneous adipose tissue	UBERON:0002190	95.66	gold quality
adipose tissue	UBERON:0001013	95.32	gold quality
right lobe of liver	UBERON:0001114	95.01	gold quality
connective tissue	UBERON:0002384	94.26	gold quality
lower esophagus mucosa	UBERON:0035834	93.29	gold quality
vena cava	UBERON:0004087	92.43	gold quality
saphenous vein	UBERON:0007318	91.15	gold quality
body of pancreas	UBERON:0001150	90.97	gold quality
liver	UBERON:0002107	90.46	gold quality
pancreatic ductal cell	CL:0002079	90.40	silver quality
mucosa of stomach	UBERON:0001199	89.05	gold quality
cartilage tissue	UBERON:0002418	89.02	gold quality
stromal cell of endometrium	CL:0002255	88.74	gold quality
right lobe of thyroid gland	UBERON:0001119	88.68	gold quality
olfactory bulb	UBERON:0002264	88.60	gold quality
esophagus mucosa	UBERON:0002469	88.57	gold quality
left coronary artery	UBERON:0001626	88.33	gold quality
left lobe of thyroid gland	UBERON:0001120	88.06	gold quality
coronary artery	UBERON:0001621	87.94	gold quality
pancreas	UBERON:0001264	87.53	gold quality
amygdala	UBERON:0001876	87.49	gold quality
skin of abdomen	UBERON:0001416	86.88	gold quality
tibial nerve	UBERON:0001323	86.76	gold quality
caudate nucleus	UBERON:0001873	86.69	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	24.83
E-HCAD-4	yes	16.10
E-CURD-112	yes	8.31
E-HCAD-25	yes	4.88
E-CURD-10	no	472.94
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, EGR1, ESR1, HIF1A, MYC, NR3C1, PPARA, PPARD, PPARG, SMAD3

miRNA regulators (miRDB)

15 targeting ANGPTL4, 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-3925-3P	100.00	69.95	1237
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-377-5P	99.70	65.28	712
HSA-MIR-6086	99.70	65.38	699
HSA-MIR-7112-5P	99.59	65.76	104
HSA-MIR-6801-3P	98.04	64.64	805
HSA-MIR-4303	98.01	68.13	2304
HSA-MIR-6810-3P	97.96	64.57	1023
HSA-MIR-874-5P	96.93	63.92	1014
HSA-MIR-2276-5P	96.27	65.85	937
HSA-MIR-4281	92.91	63.60	271

Literature-anchored findings (GeneRIF, showing 40)

• This protein is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma. (PMID:12707035)
• a link between metabolic disorders and hypoxia-induced angiogenesis. (PMID:12707035)
• FIAF (angiopoietin-like 4 protein) may partially exert its function via a truncated form. (PMID:15190076)
• Angptl4 transgenic mice displayed elevated plasma triglycerides and reduced postheparin plasma lipoprotein lipase(LPL). Recombinant Angptl4 inhibited mouse LPL and recombinant human LPL activity in vitro. (PMID:16081640)
• Angptl4 plays important roles in lipoprotein lipase activity in both fed and fasted states (PMID:16531751)
• Our hypothesis that variations of pO2 could exist between adipose tissue from anatomical origins was supported by staining of the hypoxic-induced angiopoietin ANGPTL4 depended on the location of fat. (PMID:17049073)
• Resequencing of ANGPTL4 in a multiethnic population allowed analysis of the phenotypic effects. (PMID:17322881)
• TGFbeta induction of Angptl4 in cancer cells that are about to enter the circulation enhances their subsequent retention in the lungs, but not in the bone. (PMID:18394990)
• Microarray expression profile reveals the change of molecules involved in the synoikis-like hepatoma cells and our data indicated that ANGPTL4 contributed to anoikis resistance of hepatoma cells. (PMID:18433990)
• common genetic variation within the ANGPTL4 gene may not play a major role in the development of prediabetic phenotypes in our white population. (PMID:18442626)
• ANGPTL4 has a role in HDL-cholesterol and triglyceride concentrations in white men (PMID:18599063)
• Hypoxia upregulates the expression of angiopoietin-like-4 in human articular chondrocytes: role of angiopoietin-like-4 in the expression of matrix metalloproteinases MMP1 and MMP3 and cartilage degradation (PMID:18634015)
• triglyceride concentration differences among adipokine angiopoietin-like 4 (ANGPTL4[E40K]) A allele carriers and G allele homozygotes are maintained over time; degree of triglyceride increase was similar between groups and not modified by weight changes (PMID:18809343)
• the 40K variant of ANGPTL4 appeared to confer reduced genetic risk for CHD. (PMID:18940399)
• Although associated with an atheroprotective lipid profile, E40K was associated with increased CHD risk, suggesting Angptl4 influences parameters beyond lipid levels. T266M showed effects only under conditions of postprandial stress. (PMID:18974381)
• The coiled-coil domain of ANGPTL4 is required for the protein to fulfill its antiangiogeneic activity function. (PMID:19019854)
• 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)
• ANGPTL4 is produced by human myotubes in response to long chain fatty acids via PPAR-delta. (PMID:19074989)
• the 12-amino acid consensus motif within the CCD of Angptl4, especially the three polar residues within this motif, is responsible for its interaction with and inhibition of LPL by blocking the enzyme dimerization. (PMID:19246456)
• Genetic variation in ANGPTL4 provides insights into protein processing and function. (PMID:19270337)
• Caloric restriction and exercise increase plasma ANGPTL4 levels in humans via elevated free fatty acids. (PMID:19342599)
• Like ANGPTL4, ANGPTL3 inhibited nonstabilized LPL but not GPIHBP1-stabilized LPL (PMID:19542565)
• ANGPTL4 is a direct GR target that participates in glucocorticoid-regulated triglyceride metabolism. (PMID:19628874)
• Data suggest roles for ANGPTL4 and ANGPTL3 in modulation of serum TG and HDL levels in obesity in a Finnish population sample. (PMID:19826106)
• Our data also suggest possible associations between ANGPTL4 polymorphisms and body fat (PMID:19890028)
• Angptl4 mRNA expression was highly associated with ccRCC; moreover, angptl4 mRNA allows to discriminate the renal origin of metastases of clear-cell carcinomas arising from various organs (PMID:20454689)
• Data show that PPARbeta/delta and transforming growth factor-beta (TGFbeta) pathways functionally interact with each other and synergistically induce ANGPTL4 transcription. (PMID:20595396)
• vGPCR up-regulation of ANGPTL4 plays a prominent role in promoting the angiogenesis and vessel permeability observed in Kaposi’s sarcoma (PMID:20660728)
• Suggest that the ANGPTL4 is one of the factors involved in the venous invasion and metastasis of human gastric cancer. (PMID:20664963)
• Results demonstrate that HIF is sufficient to enhance osteoclast-mediated bone resorption and that ANGPTL4 can compensate for HIF-1alpha deficiency with respect to stimulation of osteoclast activity and augments osteoblast proliferation and differentiation. (PMID:20667978)
• ANGPTL4 interacts with vitronectin and fibronectin in the wound bed, delaying their proteolytic degradation by metalloproteinases. (PMID:20729546)
• Angptl4 plays a role in in triglyceride metabolism and coronary heart disease risk. (PMID:20829508)
• Decreased fat storage by Lactobacillus paracasei is associated with increased levels of ANGPTL4. (PMID:20927337)
• Serum Angptl4 levels are significantly increased in end-stage renal disease. (PMID:20972945)
• A synonymous SNP in ANGPTL4 and haplotypes carrying it are associated with risk of brain arteriovenous malformations (BAVM) but not with intracranial hemorrhage presentation in BAVM cases. (PMID:21212665)
• Podocyte injury in minimal change disease causes increased expression and secretion of ANGPTL4 in humans. (PMID:21217681)
• High ANGPTL4 is associated with olorectal cancer venous invasion and distant metastasis. (PMID:21308352)
• Data show that that elevated ANGPTL4 expression is widespread in tumors, and its suppression impairs tumor growth associated with enhanced apoptosis. (PMID:21397862)
• the cleavage of ANGPTL4 by these PCs modulates its inhibitory effect on LPL activity. (PMID:21398697)
• Angptl4 is a novel methylation-silenced gene both in rat and human mammary carcinomas. (PMID:21489049)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	angptl4	ENSDARG00000035859
mus_musculus	Angptl4	ENSMUSG00000002289
rattus_norvegicus	Angptl4	ENSRNOG00000007545

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), ANGPTL3 (ENSG00000132855), ANGPTL2 (ENSG00000136859), FCN3 (ENSG00000142748), FNDC7 (ENSG00000143107), ANGPT1 (ENSG00000154188), FCN2 (ENSG00000160339), MFAP4 (ENSG00000166482), TNXB (ENSG00000168477), FGG (ENSG00000171557), FGA (ENSG00000171560), FGB (ENSG00000171564), ANGPTL7 (ENSG00000171819), ANGPTL5 (ENSG00000187151)

Protein

Protein identifiers

Angiopoietin-related protein 4 — Q9BY76 (reviewed: Q9BY76)

Alternative names: Angiopoietin-like protein 4, Hepatic fibrinogen/angiopoietin-related protein

All UniProt accessions (6): Q9BY76, M0QZ51, M0R0N8, M0R2X8, M0R369, M0R3A2

UniProt curated annotations — full annotation on UniProt →

Function. Mediates inactivation of the lipoprotein lipase LPL, and thereby plays a role in the regulation of triglyceride clearance from the blood serum and in lipid metabolism. May also play a role in regulating glucose homeostasis and insulin sensitivity. Inhibits proliferation, migration, and tubule formation of endothelial cells and reduces vascular leakage. Upon heterologous expression, inhibits the adhesion of endothelial cell to the extracellular matrix (ECM), and inhibits the reorganization of the actin cytoskeleton, formation of actin stress fibers and focal adhesions in endothelial cells that have adhered to ANGPTL4-containing ECM (in vitro). Depending on context, may modulate tumor-related angiogenesis. Mediates inactivation of the lipoprotein lipase LPL, and thereby plays an important role in the regulation of triglyceride clearance from the blood serum and in lipid metabolism. Has higher activity in LPL inactivation than the uncleaved protein.

Subunit / interactions. Homooligomer; disulfide-linked via Cys residues in the N-terminal part of the protein. The homooligomer undergoes proteolytic processing to release the ANGPTL4 C-terminal chain, which circulates as a monomer. The homooligomer unprocessed form is able to interact with the extracellular matrix.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Detected in blood plasma (at protein level). Detected in liver. Detected in white fat tissue and placenta. Expressed at high levels in the placenta, heart, liver, muscle, pancreas and lung but expressed poorly in the brain and kidney.

Post-translational modifications. N-glycosylated. Forms disulfide-linked dimers and tetramers. Cleaved into a smaller N-terminal chain and a larger chain that contains the fibrinogen C-terminal domain; both cleaved and uncleaved forms are detected in the extracellular space. The cleaved form is not present within the cell.

Induction. Up-regulated when cells are exposed to severe hypoxia (in vitro).

Polymorphism. Genetic variations in ANGPTL4 are associated with low plasma triglyceride levels and define the plasma triglyceride level quantitative trait locus (TGQTL) [MIM:615881].

Isoforms (3)

UniProt ID	Names	Canonical?
Q9BY76-1	1	yes
Q9BY76-2	2
Q9BY76-3	3

RefSeq proteins (2): NP_001034756, NP_647475* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002181	Fibrinogen_a/b/g_C_dom	Domain
IPR014716	Fibrinogen_a/b/g_C_1	Homologous_superfamily
IPR020837	Fibrinogen_CS	Conserved_site
IPR036056	Fibrinogen-like_C	Homologous_superfamily
IPR037579	FIB_ANG-like	Family

Pfam: PF00147

UniProt features (76 total): sequence variant 28, sequence conflict 10, strand 10, mutagenesis site 8, helix 8, chain 3, splice variant 2, disulfide bond 2, signal peptide 1, domain 1, coiled-coil region 1, site 1, glycosylation site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6U1U	X-RAY DIFFRACTION	1.75
6U0A	X-RAY DIFFRACTION	2.11
6EUB	X-RAY DIFFRACTION	2.3
6U73	X-RAY DIFFRACTION	2.38

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BY76-F1	78.92	0.46

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 (1): 164–165 (cleavage)

Disulfide bonds (2): 188–216, 341–354

Glycosylation sites (1): 177

Mutagenesis-validated functional residues (8):

Position	Phenotype
40	loss of inactivation of lipoprotein lipase lpl.
40	decreased inactivation of lipoprotein lipase lpl.
76	no effect on secretion and proteolytic cleavage. loss of oligomerization; when associated with a-80.
80	no effect on secretion and proteolytic cleavage. loss of oligomerization; when associated with a-76.
161–164	loss of proteolytic cleavage. no effect on the ability to inactivate lipoprotein lipase lpl.
161	loss of proteolytic cleavage. decreased ability to inactivate lipoprotein lipase lpl.
164	loss of proteolytic cleavage.
223	impaired protein folding.

Function

Pathways and Gene Ontology

Reactome pathways

25 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation
R-HSA-8963889	Assembly of active LPL and LIPC lipase complexes
R-HSA-9762292	Regulation of CDH11 function
R-HSA-9841922	MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis
R-HSA-1266738	Developmental Biology
R-HSA-1430728	Metabolism
R-HSA-1500931	Cell-Cell communication
R-HSA-174824	Plasma lipoprotein assembly, remodeling, and clearance
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-382551	Transport of small molecules
R-HSA-400206	Regulation of lipid metabolism by PPARalpha
R-HSA-418990	Adherens junctions interactions
R-HSA-421270	Cell-cell junction organization
R-HSA-446728	Cell junction organization
R-HSA-556833	Metabolism of lipids
R-HSA-74160	Gene expression (Transcription)
R-HSA-8963899	Plasma lipoprotein remodeling
R-HSA-9759475	Regulation of CDH11 Expression and Function
R-HSA-9759476	Regulation of Homotypic Cell-Cell Adhesion
R-HSA-9764260	Regulation of Expression and Function of Type II Classical Cadherins
R-HSA-9818564	Epigenetic regulation of gene expression by MLL3 and MLL4 complexes
R-HSA-9843745	Adipogenesis
R-HSA-9851695	Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes
R-HSA-9917777	Epigenetic regulation by WDR5-containing histone modifying complexes

MSigDB gene sets: 337 (showing top): REACTOME_TRANSCRIPTIONAL_REGULATION_OF_WHITE_ADIPOCYTE_DIFFERENTIATION, GGGACCA_MIR133A_MIR133B, GOBP_ACYLGLYCEROL_HOMEOSTASIS, XU_HGF_TARGETS_REPRESSED_BY_AKT1_UP, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOLDRATH_IMMUNE_MEMORY, MENSE_HYPOXIA_UP, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_KETONE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, WOTTON_RUNX_TARGETS_UP, GOBP_REGULATION_OF_FATTY_ACID_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION

GO Biological Process (15): angiogenesis (GO:0001525), response to hypoxia (GO:0001666), lipid metabolic process (GO:0006629), blood coagulation (GO:0007596), negative regulation of very-low-density lipoprotein particle remodeling (GO:0010903), negative regulation of apoptotic process (GO:0043066), protein unfolding (GO:0043335), negative regulation of fatty acid biosynthetic process (GO:0045717), positive regulation of angiogenesis (GO:0045766), triglyceride homeostasis (GO:0070328), endothelial cell apoptotic process (GO:0072577), regulation of chylomicron remodeling (GO:0090318), negative regulation of endothelial cell apoptotic process (GO:2000352), regulation of lipid metabolic process (GO:0019216), positive regulation of multicellular organismal process (GO:0051240)

GO Molecular Function (5): enzyme inhibitor activity (GO:0004857), lipase binding (GO:0035473), identical protein binding (GO:0042802), lipase inhibitor activity (GO:0055102), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), blood microparticle (GO:0072562)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Regulation of lipid metabolism by PPARalpha	1
Adipogenesis	1
Plasma lipoprotein remodeling	1
Regulation of CDH11 Expression and Function	1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1
Transport of small molecules	1
Gene expression (Transcription)	1
Metabolism of lipids	1
Cell-cell junction organization	1
Cell junction organization	1
Cell-Cell communication	1
Metabolism	1
Plasma lipoprotein assembly, remodeling, and clearance	1
Regulation of Expression and Function of Type II Classical Cadherins	1
Adherens junctions interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
apoptotic process	2
regulation of multicellular organismal process	2
cellular anatomical structure	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
response to stress	1
response to decreased oxygen levels	1
primary metabolic process	1
hemostasis	1
wound healing	1
coagulation	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 apoptotic process	1
negative regulation of programmed cell death	1
cellular process	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
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
acylglycerol homeostasis	1
chylomicron remodeling	1
regulation of cellular component organization	1
negative regulation of apoptotic process	1
endothelial cell apoptotic process	1
regulation of endothelial cell apoptotic process	1
lipid metabolic process	1
regulation of primary metabolic process	1
multicellular organismal process	1
positive regulation of biological process	1
catalytic activity	1
enzyme regulator activity	1
molecular function inhibitor activity	1
enzyme binding	1
protein binding	1

Protein interactions and networks

STRING

2212 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANGPTL4	LPL	P06858	930
ANGPTL4	CLDN5	O00501	907
ANGPTL4	CDH5	P33151	867
ANGPTL4	FSCN1	Q16658	841
ANGPTL4	ANGPTL8	Q6UXH0	805
ANGPTL4	EREG	O14944	761
ANGPTL4	PPARG	P37231	756
ANGPTL4	ITGB1	P05556	756
ANGPTL4	PPARA	Q07869	749
ANGPTL4	AREG	P15514	725
ANGPTL4	HIF1A	Q16665	724
ANGPTL4	PDK4	Q16654	708
ANGPTL4	GPIHBP1	Q8IV16	707
ANGPTL4	PLIN2	Q99541	704
ANGPTL4	CD36	P16671	686

IntAct

34 interactions, top by confidence:

A	B	Type	Score
	LPL	psi-mi:“MI:1355”(lipid cleavage)	0.620
ITGB5	ANGPTL4	psi-mi:“MI:0407”(direct interaction)	0.560
ANGPTL4	ITGB5	psi-mi:“MI:0914”(association)	0.560
ITGB5	ANGPTL4	psi-mi:“MI:2364”(proximity)	0.560
CASP8	ANGPTL4	psi-mi:“MI:0915”(physical association)	0.550
	ANGPTL4	psi-mi:“MI:0407”(direct interaction)	0.540
	ANGPTL4	psi-mi:“MI:0915”(physical association)	0.540
ANGPTL4	NMT2	psi-mi:“MI:0914”(association)	0.530
ITGB1	ANGPTL4	psi-mi:“MI:0407”(direct interaction)	0.510
ANGPTL4	ITGB1	psi-mi:“MI:2364”(proximity)	0.510
ANGPTL4	ANGPTL4	psi-mi:“MI:0407”(direct interaction)	0.440
ANGPTL4	LPL	psi-mi:“MI:0407”(direct interaction)	0.440
ANGPTL4	Hspg2	psi-mi:“MI:0407”(direct interaction)	0.440
APP	ANGPTL4	psi-mi:“MI:0407”(direct interaction)	0.440
	Hspg2	psi-mi:“MI:0915”(physical association)	0.400
AURKA	ANGPTL4	psi-mi:“MI:0915”(physical association)	0.370
ANGPTL4	BRMS1	psi-mi:“MI:0915”(physical association)	0.370
ANGPTL4	CDKN2A	psi-mi:“MI:0915”(physical association)	0.370
CDKN2C	ANGPTL4	psi-mi:“MI:0915”(physical association)	0.370
ESR1	ANGPTL4	psi-mi:“MI:0915”(physical association)	0.370
FBXW7	ANGPTL4	psi-mi:“MI:0915”(physical association)	0.370
ANGPTL4	FGFR4	psi-mi:“MI:0915”(physical association)	0.370
TGFB1	ANGPTL4	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (36): ANGPTL4 (Two-hybrid), ANGPTL4 (Two-hybrid), ANGPTL4 (Two-hybrid), ANGPTL4 (Two-hybrid), ANGPTL4 (Two-hybrid), ANGPTL4 (Two-hybrid), ANGPTL4 (Two-hybrid), ANGPTL4 (Two-hybrid), ANGPTL4 (Two-hybrid), WDR47 (Affinity Capture-MS), NMT2 (Affinity Capture-MS), PM20D2 (Affinity Capture-MS), AASDHPPT (Affinity Capture-MS), NMT1 (Affinity Capture-MS), ITIH2 (Affinity Capture-MS)

ESM2 similar proteins: A2AV25, A5PJQ2, O35764, O43278, O43827, O70165, O95841, O95897, P02675, P02678, P04115, P12804, P14480, P30203, P33573, Q0P4P2, Q14314, Q1RMR1, Q24K15, Q29041, Q29042, Q29RY7, Q2KJ51, Q2TNK5, Q568Y7, Q5EA66, Q5FB95, Q5I2E5, Q5XK91, Q640P2, Q6AX44, Q6TMA8, Q8BM13, Q8IUK5, Q8K0E8, Q8N539, Q8NI99, Q8R0Z6, Q8R1Q3, Q91ZV7

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.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 20 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of gene expression	5	19.2×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	7
Benign	9

Top pathogenic / likely-pathogenic (0)

SpliceAI

1117 predictions. Top by Δscore:

Variant	Effect	Δscore
19:8364636:GCAG:G	donor_gain	1.0000
19:8364637:CAGG:C	donor_loss	1.0000
19:8364638:AGGT:A	donor_loss	1.0000
19:8364639:GGT:G	donor_loss	1.0000
19:8364640:GTAC:G	donor_loss	1.0000
19:8364641:T:A	donor_loss	1.0000
19:8365949:CCCA:C	acceptor_loss	1.0000
19:8365950:CCAG:C	acceptor_loss	1.0000
19:8365951:CAG:C	acceptor_loss	1.0000
19:8365952:A:AG	acceptor_gain	1.0000
19:8365952:A:C	acceptor_loss	1.0000
19:8365953:G:GA	acceptor_gain	1.0000
19:8365953:GA:G	acceptor_gain	1.0000
19:8365953:GAC:G	acceptor_gain	1.0000
19:8365953:GACA:G	acceptor_gain	1.0000
19:8365953:GACAC:G	acceptor_gain	1.0000
19:8366060:GCCAG:G	donor_gain	1.0000
19:8366061:CCAG:C	donor_loss	1.0000
19:8366065:G:GA	donor_loss	1.0000
19:8366066:T:G	donor_loss	1.0000
19:8366197:CCTA:C	acceptor_loss	1.0000
19:8366198:CTAGT:C	acceptor_loss	1.0000
19:8366199:TAGTT:T	acceptor_loss	1.0000
19:8366200:A:AG	acceptor_gain	1.0000
19:8366200:AGTTT:A	acceptor_gain	1.0000
19:8366201:G:GA	acceptor_gain	1.0000
19:8366201:GT:G	acceptor_gain	1.0000
19:8366201:GTT:G	acceptor_gain	1.0000
19:8366201:GTTT:G	acceptor_gain	1.0000
19:8366201:GTTTG:G	acceptor_gain	1.0000

AlphaMissense

2652 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:8371459:T:C	F326L	0.993
19:8371461:C:A	F326L	0.993
19:8371461:C:G	F326L	0.993
19:8371103:T:C	F237L	0.992
19:8371105:C:A	F237L	0.992
19:8371105:C:G	F237L	0.992
19:8369317:T:A	C216S	0.989
19:8369318:G:C	C216S	0.989
19:8371136:T:C	F248L	0.989
19:8371138:T:A	F248L	0.989
19:8371138:T:G	F248L	0.989
19:8371460:T:G	F326C	0.987
19:8373715:G:C	W350C	0.986
19:8373715:G:T	W350C	0.986
19:8373713:T:A	W350R	0.985
19:8373713:T:C	W350R	0.985
19:8373716:T:C	F351L	0.985
19:8373718:T:A	F351L	0.985
19:8373718:T:G	F351L	0.985
19:8371083:G:C	R230P	0.984
19:8371117:G:C	W241C	0.983
19:8371117:G:T	W241C	0.983
19:8371082:C:A	R230S	0.982
19:8373745:C:A	N360K	0.982
19:8373745:C:G	N360K	0.982
19:8371249:T:A	W256R	0.981
19:8371249:T:C	W256R	0.981
19:8371137:T:G	F248C	0.980
19:8371104:T:G	F237C	0.979
19:8371460:T:C	F326S	0.979

dbSNP variants (sampled 300 via entrez): RS1000182337 (19:8372823 G>A), RS1000235949 (19:8372621 T>G), RS1000584534 (19:8362163 C>T), RS1000714703 (19:8366900 C>T), RS1000863946 (19:8367571 G>A), RS1000933150 (19:8372156 A>C), RS1001230410 (19:8367121 G>A,C), RS1001351097 (19:8363457 C>T), RS1001460392 (19:8368778 C>T), RS1001911960 (19:8366812 A>C), RS1002044605 (19:8371611 T>C,G), RS1002180609 (19:8369773 C>G), RS10024 (19:8374061 C>A), RS1002715623 (19:8369127 A>G), RS1003241110 (19:8369244 G>A)

Disease associations

OMIM: gene MIM:605910 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

56 associations (top):

Study	Trait	p-value
GCST000290_12	HDL cholesterol	1.000000e-08
GCST000755_19	HDL cholesterol	3.000000e-08
GCST002223_42	HDL cholesterol	2.000000e-08
GCST002897_21	Triglycerides	4.000000e-15
GCST002899_4	HDL cholesterol	2.000000e-14
GCST003661_21	Triglycerides	4.000000e-13
GCST004207_22	HDL cholesterol	6.000000e-10
GCST004232_47	HDL cholesterol levels	1.000000e-16
GCST004787_68	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	3.000000e-07
GCST005194_130	Coronary artery disease	1.000000e-11
GCST005195_26	Coronary artery disease	4.000000e-10
GCST005196_232	Coronary artery disease	1.000000e-11
GCST005446_5	Total cholesterol levels in HDL	9.000000e-06
GCST005449_52	Total triglycerides levels	1.000000e-07
GCST005499_9	Phospholipid levels in large HDL	8.000000e-10
GCST006611_108	HDL cholesterol	3.000000e-137
GCST006613_87	Triglycerides	6.000000e-134
GCST007500_7	Waist-to-hip ratio adjusted for BMI (additive genetic model)	1.000000e-09
GCST007502_6	Waist-to-hip ratio adjusted for BMI (additive genetic model)	7.000000e-10
GCST007849_6	Triglycerides	3.000000e-37
GCST007850_1	HDL cholesterol	2.000000e-29
GCST008070_29	HDL cholesterol levels	5.000000e-10
GCST008070_76	HDL cholesterol levels	1.000000e-11
GCST008074_104	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	2.000000e-19
GCST008074_46	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	4.000000e-21
GCST008075_159	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	8.000000e-30
GCST008075_20	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	7.000000e-30
GCST008076_50	Triglyceride levels	2.000000e-06
GCST008076_76	Triglyceride levels	8.000000e-06
GCST008083_147	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	4.000000e-22

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004329	alcohol drinking
EFO:0000195	metabolic syndrome
EFO:0004614	apolipoprotein A 1 measurement
EFO:0007986	reticulocyte count
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1152003	ANGPTL4		0.00	0
rs2920500	ANGPTL4		0.00	0
rs2960421	ANGPTL4		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
perfluorooctanoic acid	decreases expression, increases expression	7
Oxygen	decreases reaction, increases expression	7
bisphenol A	affects expression, affects cotreatment, decreases methylation, decreases expression, increases expression	5
sodium arsenite	decreases expression, increases expression	5
perfluorooctane sulfonic acid	affects expression, decreases expression, increases expression	5
(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid	affects binding, increases activity, increases expression, affects cotreatment, decreases reaction (+1 more)	5
Valproic Acid	increases methylation, affects expression, decreases expression, increases expression	5
cobaltous chloride	increases expression, decreases reaction	4
Rosiglitazone	increases expression, increases reaction, affects binding, increases activity	4
Decitabine	affects expression, affects cotreatment, increases expression	4
Cisplatin	affects expression, affects cotreatment, increases expression	4
mono-(2-ethylhexyl)phthalate	increases expression, increases methylation	3
nickel chloride	increases abundance, increases expression, affects reaction, decreases methylation	3
Benzo(a)pyrene	increases expression, affects methylation	3
Tobacco Smoke Pollution	affects expression, increases expression	3
Tretinoin	increases expression	3
Particulate Matter	decreases expression, decreases reaction, increases abundance, increases expression, affects cotreatment	3
tungsten carbide	affects cotreatment, affects binding, increases expression	2
pirinixic acid	increases expression	2
nickel sulfate	affects cotreatment, increases expression	2
diallyl trisulfide	decreases reaction, increases expression	2
chloropicrin	decreases expression, increases expression	2
perfluoro-n-nonanoic acid	increases expression	2
GW 501516	affects binding, increases expression	2
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction, increases expression	2
bisphenol S	decreases expression, increases expression	2
(+)-JQ1 compound	increases expression	2
Troglitazone	increases expression	2
Acetaminophen	affects expression, increases expression	2
Air Pollutants	increases expression, affects cotreatment, increases abundance, increases oxidation	2

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SC51	HAP1 ANGPTL4 (-) 1	Cancer cell line	Male
CVCL_XL33	HAP1 ANGPTL4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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