GPIHBP1

Summary

GPIHBP1 (glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1, HGNC:24945) is a protein-coding gene on chromosome 8q24.3, encoding Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (Q8IV16). Mediates the transport of lipoprotein lipase LPL from the basolateral to the apical surface of endothelial cells in capillaries.

This gene encodes a capillary endothelial cell protein that facilitates the lipolytic processing of triglyceride-rich lipoproteins. The encoded protein is a glycosylphosphatidylinositol-anchored protein that is a member of the lymphocyte antigen 6 (Ly6) family. This protein plays a major role in transporting lipoprotein lipase (LPL) from the subendothelial spaces to the capillary lumen. Mutations in this gene are the cause of hyperlipoproteinemia, type 1D. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 338328 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyperlipoproteinemia, type 1D (Strong, GenCC)
• GWAS associations: 12
• Clinical variants (ClinVar): 200 total — 15 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 17
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_178172

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24945
Approved symbol	GPIHBP1
Name	glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	LOC338328, GPI-HBP1
Ensembl gene	ENSG00000277494
Ensembl biotype	protein_coding
OMIM	612757
Entrez	338328

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000622500, ENST00000852007, ENST00000852008

RefSeq mRNA: 2 — MANE Select: NM_178172 NM_001301772, NM_178172

CCDS: CCDS34954

Canonical transcript exons

ENST00000622500 — 4 exons

Exon	Start	End
ENSE00003730000	143213822	143213950
ENSE00003740185	143215013	143215126
ENSE00003743548	143215259	143217170
ENSE00003746165	143213218	143213319

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 94.04.

FANTOM5 (CAGE): breadth broad, TPM avg 3.0110 / max 574.3008, expressed in 244 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
91393	2.9588	243
91392	0.0522	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	94.04	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.98	gold quality
spinal cord	UBERON:0002240	92.50	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.34	gold quality
omental fat pad	UBERON:0010414	92.27	gold quality
peritoneum	UBERON:0002358	92.19	gold quality
adipose tissue	UBERON:0001013	91.06	gold quality
subcutaneous adipose tissue	UBERON:0002190	90.84	gold quality
substantia nigra	UBERON:0002038	87.95	gold quality
heart left ventricle	UBERON:0002084	87.49	gold quality
midbrain	UBERON:0001891	87.05	gold quality
cardiac ventricle	UBERON:0002082	87.05	gold quality
sural nerve	UBERON:0015488	86.84	gold quality
upper lobe of left lung	UBERON:0008952	84.68	gold quality
right lung	UBERON:0002167	84.46	gold quality
upper lobe of lung	UBERON:0008948	84.46	gold quality
muscle of leg	UBERON:0001383	84.13	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.91	gold quality
gastrocnemius	UBERON:0001388	83.90	gold quality
tibialis anterior	UBERON:0001385	83.37	silver quality
kidney epithelium	UBERON:0004819	83.36	gold quality
inferior vagus X ganglion	UBERON:0005363	83.21	gold quality
subthalamic nucleus	UBERON:0001906	82.80	gold quality
pons	UBERON:0000988	82.62	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.48	gold quality
vastus lateralis	UBERON:0001379	82.02	silver quality
lower lobe of lung	UBERON:0008949	82.02	silver quality
quadriceps femoris	UBERON:0001377	81.93	silver quality
mucosa of stomach	UBERON:0001199	81.62	gold quality
lung	UBERON:0002048	81.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	41.12
E-ANND-3	yes	11.36

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARG

miRNA regulators (miRDB)

41 targeting GPIHBP1, 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-12118	100.00	65.88	1270
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-4721	99.26	66.05	818
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-5197-3P	98.71	67.05	1905
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-6882-3P	98.23	67.01	1119

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• a very rare GPIHBP1 missense mutation appears to be associated with severe hypertriglyceridemia and chylomicronemia. (PMID:17883852)
• Data show that the G56R substitution did not affect the ability of GPIHBP1 to reach the cell surface, nor did the amino acid substitution have any discernible effect on the binding of lipoprotein lipase, chylomicrons, or apo-AV. (PMID:17997385)
• the acidic domain of GPIHBP1 is important and electrostatic interactions play a key role in ligand binding (PMID:18713736)
• Case Report: Chylomicronemia with a mutant GPIHBP1 (Q115P) that cannot bind lipoprotein lipase. (PMID:19304573)
• GPIHBP1 functions as an LPL stabilizer (PMID:19542565)
• The conserved cysteines in the Ly6 domain are crucial for GPIHBP1 function. (PMID:20026666)
• GPIHBP1 binds lipoprotein lipase but does not bind other lipase family members. GPIHBP1 binds apoAV but does not bind apoAI or high-density lipoprotein. GPIHBP1 binding to chylomicrons is mediated by lipoprotein lipase. (PMID:20966398)
• Findings provide further evidence that GPIHBP1 is involved in the catabolism of triglyceride-rich lipoproteins and plays a role in childhood-onset chylomicronaemia. (PMID:21314738)
• the Ly6 domain of GPIHBP1 is important for the ability of GPIHBP1 to bind and transport LPL. (PMID:21478160)
• report that two LPL missense mutations initially identified in patients with chylomicronemia, C418Y and E421K, abolish LPL’s ability to bind to GPIHBP1 without interfering with LPL catalytic activity or binding to heparin (PMID:21518912)
• we first report a mutation of the hydrophobic C-terminal domain that impairs GPIHBP1 membrane targeting (PMID:21816778)
• function and genetics of GPIHBP1 in lipoprotein lipase transport (PMID:21844202)
• A polymorphism in the GPIHBP1 gene promoter was associated with an increased risk of hypertriglyceridemia and had an additive effect on the risk conferred by LPL defective alleles. (PMID:21978733)
• analysis of a neonate with complete GPIHBP1 deficiency due to homozygosity for a deletion of GPIHBP1 [case report] (PMID:22008945)
• Expression of glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 tended to be higher in young healthy subjects than in subjects with type 2 diabetes mellitus or Colder control subjects (PMID:22078753)
• Mutations in GPIHBP1 are rare but the associated clinical phenotype of hypertriglyceridaemia is severe. (PMID:22239554)
• Homozygosity for a deletion of exons 3 and 4 of GPIHBP1 results in Type 1 hyperlipoproteinemia. (PMID:24589565)
• Wild-type lipoprotein lipase (LPL) and a mutated (S447X-LPL) protein bind to the endothelial cell LPL transporter GPIHBP1 with equal efficiency. (PMID:24704550)
• patient with type I hyperlipoproteinemia harbored homozygous mutation in case series (PMID:24793350)
• an extra cysteine in the GPIHBP1 Ly6 motif results in multimerization of GPIHBP1, defective LPL binding, and severe hypertriglyceridemia. (PMID:24847059)
• No GPIHBP1 mutations were identified in a cohort of patients with diabetic lipemia. (PMID:25131724)
• GPIHBP1 missense mutations leading to protein multimerization prevent lipoprotein lipase binding. (PMID:25387803)
• the two domains of GPIHBP1 interact independently with LPL and the functionality of LPL depends on its localization on GPIHBP1 (PMID:25873395)
• GPIHBP1 mutations should be considered in neonates with chylomicronemia negative for mutations in LPL gene (PMID:25911085)
• The acidic domain of GPIHBP1 stabilizes LPL catalytic activity by mitigating the global unfolding of LPL’s catalytic domain. (PMID:26725083)
• 2 novel GPIHBP1 missense mutations in 2 unrelated patients as the cause of their severe hypertriglyceridemia (PMID:26892125)
• The binding of both antibody 88B8 and GPIHBP1 to LPL depends on large segments of LPL’s carboxyl-terminal domain. (PMID:27494936)
• familial chylomicronemia due to mutations in GPIHBP1 gene (PMID:27578123)
• mAbs RE3 and RG3 bound with reduced affinity to a mutant GPIHBP1 containing an Ly6 domain mutation (W109S) that abolishes LPL binding. Immunohistochemistry studies with the GPIHBP1 mAbs revealed that human GPIHBP1 is expressed only in capillary endothelial cells. Finally, we created an ELISA that detects GPIHBP1 in human plasma. (PMID:27875259)
• The authors now show: (1) that ANGPTL4 inactivates LPL by catalyzing the unfolding of its hydrolase domain; (2) that binding to GPIHBP1 renders LPL largely refractory to this inhibition; and (3) that both the LU domain and the intrinsically disordered acidic domain of GPIHBP1 are required for this protective effect. (PMID:27929370)
• An LPL structural model suggests that the LPL S447X truncation exposes residues implicated in LPL binding to lipoprotein binding uptake receptors, such as GPIHBP1. (PMID:27984852)
• mutation of a conserved cysteine in GPIHBP1 abolishes the ability of GPIHBP1 to bind LPL (PMID:28476858)
• Triglyceride-raising variant alleles of the GPIHBP1, encoding glycosylphosphatidylinositol-anchored HDL-binding protein 1,associated with clinical Cardiovascular endpoints. (PMID:28534127)
• One of 33 patients with unexplained chylomicronemia had the GPIHBP1 autoantibody syndrome (PMID:28666713)
• apoC-III potently inhibits triglyceride hydrolysis when LPL is bound to GPIHBP1 (PMID:28694296)
• The increased GPIHBP1 was significantly associated with decreased body weight. (PMID:29056530)
• the negatively charged IDR of GPIHBP1 traverses a vast space, facilitating capture of LPL by capillary endothelial cells and simultaneously contributing to GPIHBP1’s ability to preserve LPL structure and activity. (PMID:29899144)
• The GPIHBP1 gene, protein, its expression and function focus on its regulation and provides critical evidence supporting its role in triglyceride-rich lipoprotein (TRL) metabolism. (PMID:30218660)
• we assessed visceral adipose tissue GPIHBP1 protein expression in type 2 diabetes Lepr db/db mouse model as well as in subjects with ranging levels of insulin resistance. We report that insulin reduces the expression of GPIHBP1 protein in HMVECs. Furthermore, GPIHBP1 protein expression in visceral adipose tissue in Lepr db/db mice is significantly reduced as is the active monomeric form of GPIHBP1 as compared to Leprdb/m (PMID:30408040)
• The LPL-GPIHBP1 structure provides insights into mutations causing chylomicronemia. (PMID:30559189)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gpihbp1	ENSMUSG00000022579
rattus_norvegicus	Gpihbp1	ENSRNOG00000064680

Paralogs (2): LY6E (ENSG00000160932), PSCA (ENSG00000167653)

Protein

Protein identifiers

Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 — Q8IV16 (reviewed: Q8IV16)

Alternative names: High density lipoprotein-binding protein 1

All UniProt accessions (1): Q8IV16

UniProt curated annotations — full annotation on UniProt →

Function. Mediates the transport of lipoprotein lipase LPL from the basolateral to the apical surface of endothelial cells in capillaries. Anchors LPL on the surface of endothelial cells in the lumen of blood capillaries. Protects LPL against loss of activity, and against ANGPTL4-mediated unfolding. Thereby, plays an important role in lipolytic processing of chylomicrons by LPL, triglyceride metabolism and lipid homeostasis. Binds chylomicrons and phospholipid particles that contain APOA5. Binds high-density lipoprotein (HDL) and plays a role in the uptake of lipids from HDL.

Subunit / interactions. Mostly monomer, but also homodimer and homooligomer. Interacts with lipoprotein lipase (LPL) with 1:1 stoichiometry. Interacts with high affinity with high-density lipoprotein (HDL). Interacts with chylomicrons. Interacts with APOA5.

Subcellular location. Apical cell membrane. Basolateral cell membrane. Cell membrane.

Post-translational modifications. Glycosylation of Asn-78 is critical for cell surface localization. Sulfation of a Tyr in the N-terminal acidic region increases the affinity for LPL.

Disease relevance. Hyperlipoproteinemia 1D (HLPP1D) [MIM:615947] An autosomal recessive disorder characterized by hyperlipoproteinemia, decreased plasma LPL levels in some patients, high plasma triglyceride levels, and refractory fasting chylomicronemia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminal acidic region is intrinsically disordered. This region contributes to LPL binding, stabilizes LPL and protects LPL against loss of activity.

RefSeq proteins (2): NP_001288701, NP_835466* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR035076	Toxin/TOLIP	Domain
IPR045860	Snake_toxin-like_sf	Homologous_superfamily
IPR051110	Ly-6/neurotoxin-like_GPI-ap	Family

Pfam: PF00087

UniProt features (53 total): mutagenesis site 16, sequence variant 13, strand 7, disulfide bond 5, region of interest 3, signal peptide 1, chain 1, glycosylation site 1, propeptide 1, domain 1, turn 1, compositionally biased region 1, modified residue 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6OAU	X-RAY DIFFRACTION	2.48
6E7K	X-RAY DIFFRACTION	2.8
6OB0	X-RAY DIFFRACTION	2.81
6OAZ	X-RAY DIFFRACTION	3.04

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IV16-F1	73.70	0.44

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): 38, 151

Disulfide bonds (5): 65–89, 68–77, 83–110, 114–130, 131–136

Glycosylation sites (1): 78

Mutagenesis-validated functional residues (16):

Position	Phenotype
38	loss of sulfotyrosine formation.
66	promotes formation of dimers and oligomers reducing number of monomers.
71	promotes formation of dimers and oligomers reducing number of monomers.
91	promotes formation of dimers and oligomers reducing number of monomers.
92	only slightly increased formation of dimers and oligomers. no effect on number of monomers. loss of lpl interaction.
93	promotes formation of dimers and oligomers reducing number of monomers.
101	promotes formation of dimers and oligomers reducing number of monomers. retained some interaction with lpl.
104	promotes formation of dimers and oligomers reducing number of monomers. retained some interaction with lpl.
105	promotes formation of dimers and oligomers reducing number of monomers.
106	promotes formation of dimers and oligomers severely reducing number of monomers.
107	promotes formation of dimers and oligomers reducing number of monomers.
108	retained some interaction with lpl. no effect on number of monomers.
109	promotes formation of dimers and oligomers reducing number of monomers. loss of lpl interaction.
109	loss of interaction with lpl. only slightly increased formation of dimers and oligomers. no effect on number of monomers
115	no effect on number of monomers.
126	promotes formation of dimers and oligomers reducing number of monomers.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-163125	Post-translational modification: synthesis of GPI-anchored proteins
R-HSA-8963889	Assembly of active LPL and LIPC lipase complexes
R-HSA-8963901	Chylomicron remodeling
R-HSA-975634	Retinoid metabolism and transport

MSigDB gene sets: 187 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_ACYLGLYCEROL_HOMEOSTASIS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_STEROL_HOMEOSTASIS, GOCC_CELL_SURFACE, GOBP_PROTEIN_IMPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_KETONE_METABOLIC_PROCESS, HUMMERICH_SKIN_CANCER_PROGRESSION_UP, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_FATTY_ACID_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_FATTY_ACID_BIOSYNTHETIC_PROCESS, GOBP_LIPID_HOMEOSTASIS

GO Biological Process (12): intracellular protein transport (GO:0006886), protein import (GO:0017038), triglyceride catabolic process (GO:0019433), protein localization to cell surface (GO:0034394), cholesterol homeostasis (GO:0042632), transcytosis (GO:0045056), positive regulation of fatty acid biosynthetic process (GO:0045723), protein stabilization (GO:0050821), triglyceride homeostasis (GO:0070328), response to heparin (GO:0071503), positive regulation of chylomicron remodeling (GO:0090319), positive regulation of chylomicron remnant clearance (GO:0090321)

GO Molecular Function (7): lipid binding (GO:0008289), lipase binding (GO:0035473), chylomicron binding (GO:0035478), lipoprotein lipase activator activity (GO:0060230), lipoprotein particle binding (GO:0071813), protein transporter activity (GO:0140318), protein binding (GO:0005515)

GO Cellular Component (8): extracellular region (GO:0005576), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), catalytic complex (GO:1902494), membrane (GO:0016020), side of membrane (GO:0098552)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Plasma lipoprotein remodeling	2
Post-translational protein modification	1
Visual phototransduction	1
Metabolism of fat-soluble vitamins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular protein localization	2
protein transport	2
binding	2
membrane	2
plasma membrane region	2
intracellular transport	1
triglyceride metabolic process	1
acylglycerol catabolic process	1
sterol homeostasis	1
vesicle-mediated transport	1
multicellular organismal process	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
regulation of protein stability	1
acylglycerol homeostasis	1
response to nitrogen compound	1
response to oxygen-containing compound	1
chylomicron remodeling	1
positive regulation of cellular component organization	1
positive regulation of multicellular organismal process	1
regulation of chylomicron remodeling	1
positive regulation of lipoprotein particle clearance	1
chylomicron remnant clearance	1
regulation of chylomicron remnant clearance	1
enzyme binding	1
lipoprotein particle binding	1
lipoprotein lipase activity	1
lipase activator activity	1
protein-lipid complex binding	1
transporter activity	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
basal plasma membrane	1
apical part of cell	1
protein-containing complex	1

Protein interactions and networks

STRING

854 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPIHBP1	LPL	P06858	998
GPIHBP1	LMF1	Q96S06	894
GPIHBP1	APOA5	Q6Q788	873
GPIHBP1	APOC2	P02655	871
GPIHBP1	ANGPTL3	Q9Y5C1	821
GPIHBP1	ANGPTL8	Q6UXH0	802
GPIHBP1	LIPC	P11150	771
GPIHBP1	ANGPTL4	Q9BY76	707
GPIHBP1	APOC3	P02656	697
GPIHBP1	HDLBP	Q00341	681
GPIHBP1	PLCG1	P19174	646
GPIHBP1	SLURP1	P55000	628
GPIHBP1	LY6H	O94772	627
GPIHBP1	LYNX1	P0DP58	609
GPIHBP1	LIPG	Q9Y5X9	586

IntAct

20 interactions, top by confidence:

A	B	Type	Score
GPIHBP1	LPL	psi-mi:“MI:0407”(direct interaction)	0.740
GPIHBP1	LPL	psi-mi:“MI:0403”(colocalization)	0.740
GPIHBP1	LPL	psi-mi:“MI:0915”(physical association)	0.740
LPL	GPIHBP1	psi-mi:“MI:0915”(physical association)	0.740
GPIHBP1	HTT	psi-mi:“MI:0915”(physical association)	0.560
NDUFA12	NDUFS4	psi-mi:“MI:0914”(association)	0.530
GPIHBP1	ADAM10	psi-mi:“MI:0914”(association)	0.530
IL1RN	GPIHBP1	psi-mi:“MI:0915”(physical association)	0.400
UBE2L6	UBA6	psi-mi:“MI:0914”(association)	0.350
GPIHBP1	SAC3D1	psi-mi:“MI:0914”(association)	0.350
TYROBP	MTHFR	psi-mi:“MI:0914”(association)	0.350
RFESD	PRKAG1	psi-mi:“MI:0914”(association)	0.350
PPY	DPY19L3	psi-mi:“MI:0914”(association)	0.350

BioGRID (132): MYO19 (Affinity Capture-MS), SULF1 (Affinity Capture-MS), EDEM2 (Affinity Capture-MS), CNTNAP3 (Affinity Capture-MS), ITGA7 (Affinity Capture-MS), GCNT1 (Affinity Capture-MS), MBTPS1 (Affinity Capture-MS), ADAM11 (Affinity Capture-MS), COL6A2 (Affinity Capture-MS), WDR5B (Affinity Capture-MS), PCSK5 (Affinity Capture-MS), TUBB8 (Affinity Capture-MS), VWDE (Affinity Capture-MS), FAM69A (Affinity Capture-MS), GTPBP2 (Affinity Capture-MS)

ESM2 similar proteins: B3MFC2, B3NSF6, B4QBL6, B5A5T4, B5E022, D3ZTT2, D4A6L0, H3BQJ8, O43653, P12645, P19438, P22444, P23352, P46657, P49002, P50555, P57096, P58658, P58659, Q16553, Q1RMB5, Q28216, Q32LD3, Q505J3, Q568T5, Q5R510, Q5T848, Q66IA6, Q68US5, Q6UWL2, Q6UWN0, Q6UX15, Q6WN34, Q80XH4, Q86Y78, Q8BHE5, Q8BPP5, Q8BVP6, Q8C351, Q8C419

Diamond homologs: Q8IV16, Q9D1N2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	7
Uncertain significance	68
Likely benign	77
Benign	21

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
144013	NM_178172.6(GPIHBP1):c.344A>C (p.Gln115Pro)	Pathogenic
144014	NM_178172.6(GPIHBP1):c.194G>C (p.Cys65Ser)	Pathogenic
144015	NM_178172.6(GPIHBP1):c.202T>G (p.Cys68Gly)	Pathogenic
144017	NM_178172.6(GPIHBP1):c.266G>T (p.Cys89Phe)	Pathogenic
144018	NM_178172.6(GPIHBP1):c.331A>C (p.Thr111Pro)	Pathogenic
144019	NM_178172.6(GPIHBP1):c.417_433del (p.Pro140fs)	Pathogenic
144020	NM_178172.6(GPIHBP1):c.194G>A (p.Cys65Tyr)	Pathogenic
144022	NC_000008.11:g.(?143213218)(143217170_?)del	Pathogenic
1677951	NM_178172.6(GPIHBP1):c.267C>A (p.Cys89Ter)	Pathogenic
1685860	NM_178172.6(GPIHBP1):c.182-1G>T	Pathogenic
2427568	NC_000008.10:g.(?144295143)(144297393_?)del	Pathogenic
2735230	NM_178172.6(GPIHBP1):c.203G>A (p.Cys68Tyr)	Pathogenic
3653843	NM_178172.6(GPIHBP1):c.158_161del (p.Arg53fs)	Pathogenic
3677071	NM_178172.6(GPIHBP1):c.70C>T (p.Gln24Ter)	Pathogenic
684997	GRCh37/hg19 8q24.13-24.3(chr8:125496223-146295771)x3	Pathogenic
144021	NM_178172.6(GPIHBP1):c.320C>G (p.Ser107Cys)	Likely pathogenic
1803904	NM_178172.6(GPIHBP1):c.397del (p.Ser133fs)	Likely pathogenic
3391055	NM_178172.6(GPIHBP1):c.299C>G (p.Ser100Ter)	Likely pathogenic
3681349	NM_178172.6(GPIHBP1):c.182-2A>C	Likely pathogenic
4292487	NM_178172.6(GPIHBP1):c.381del (p.Thr127_Met128insTer)	Likely pathogenic
917845	NM_178172.6(GPIHBP1):c.230G>A (p.Cys77Tyr)	Likely pathogenic
975917	NM_178172.6(GPIHBP1):c.422G>A (p.Trp141Ter)	Likely pathogenic

SpliceAI

751 predictions. Top by Δscore:

Variant	Effect	Δscore
8:143213948:GAG:G	donor_gain	1.0000
8:143213949:AGGT:A	donor_loss	1.0000
8:143213950:GGTA:G	donor_loss	1.0000
8:143215008:CCCA:C	acceptor_loss	1.0000
8:143215009:CCA:C	acceptor_loss	1.0000
8:143215010:CA:C	acceptor_loss	1.0000
8:143215011:A:AG	acceptor_gain	1.0000
8:143215011:AGT:A	acceptor_gain	1.0000
8:143215012:G:GT	acceptor_gain	1.0000
8:143215012:GT:G	acceptor_gain	1.0000
8:143215012:GTG:G	acceptor_gain	1.0000
8:143215012:GTGC:G	acceptor_gain	1.0000
8:143215012:GTGCT:G	acceptor_gain	1.0000
8:143215127:G:GC	donor_loss	1.0000
8:143215127:G:GG	donor_gain	1.0000
8:143215128:T:A	donor_loss	1.0000
8:143215258:GA:G	acceptor_gain	1.0000
8:143214913:GC:G	donor_gain	0.9900
8:143215013:T:TA	acceptor_gain	0.9900
8:143215016:T:A	acceptor_gain	0.9900
8:143215124:CCG:C	donor_gain	0.9900
8:143215257:A:AG	acceptor_gain	0.9900
8:143215258:G:GG	acceptor_gain	0.9900
8:143213460:G:GT	donor_gain	0.9800
8:143213816:G:A	acceptor_gain	0.9800
8:143213906:TGG:T	donor_gain	0.9800
8:143213951:G:GG	donor_gain	0.9800
8:143215258:GAGT:G	acceptor_gain	0.9800
8:143215258:GAGTC:G	acceptor_gain	0.9800
8:143213410:G:GT	donor_gain	0.9700

AlphaMissense

1187 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:143215290:G:C	W109C	0.994
8:143215290:G:T	W109C	0.994
8:143215386:G:C	W141C	0.994
8:143215386:G:T	W141C	0.994
8:143215291:T:A	C110S	0.988
8:143215292:G:C	C110S	0.988
8:143215096:T:A	C89S	0.985
8:143215097:G:C	C89S	0.985
8:143215369:T:A	C136S	0.984
8:143215370:G:C	C136S	0.984
8:143215024:T:A	C65S	0.982
8:143215025:G:C	C65S	0.982
8:143215096:T:C	C89R	0.981
8:143215060:T:A	C77S	0.980
8:143215061:G:C	C77S	0.980
8:143215098:C:G	C89W	0.980
8:143215024:T:C	C65R	0.976
8:143215097:G:A	C89Y	0.976
8:143215291:T:C	C110R	0.976
8:143215370:G:A	C136Y	0.975
8:143215369:T:C	C136R	0.973
8:143215303:T:A	C114S	0.972
8:143215304:G:C	C114S	0.972
8:143215078:T:A	C83S	0.971
8:143215079:G:C	C83S	0.971
8:143215282:T:C	S107P	0.971
8:143215293:C:G	C110W	0.971
8:143215354:T:A	C131S	0.970
8:143215355:G:C	C131S	0.970
8:143215292:G:A	C110Y	0.967

dbSNP variants (sampled 300 via entrez): RS1000212149 (8:143213863 G>A,C,T), RS1000548619 (8:143212721 G>A,T), RS1000816787 (8:143214432 G>A,C), RS1001108367 (8:143212578 G>A,T), RS1001426055 (8:143216150 G>A,T), RS1001790409 (8:143216329 C>G), RS1001815140 (8:143211745 T>A,C,G), RS1001906144 (8:143212308 A>T), RS1002297671 (8:143217405 T>C), RS1003285790 (8:143212618 C>G,T), RS1003562155 (8:143216101 G>A), RS1003650998 (8:143212431 C>A,G), RS1004171531 (8:143217351 T>C), RS1004656070 (8:143213508 T>A), RS1005291212 (8:143217205 C>G,T)

Disease associations

OMIM: gene MIM:612757 | disease phenotypes: MIM:615947, MIM:238600

GenCC curated gene-disease

Disease	Classification	Inheritance
hyperlipoproteinemia, type 1D	Strong	Autosomal recessive

Mondo (2): hyperlipoproteinemia, type 1D (MONDO:0014412), familial lipoprotein lipase deficiency (MONDO:0009387)

Orphanet (3): Familial chylomicronemia syndrome (Orphanet:444490), Familial GPIHBP1 deficiency (Orphanet:535458), Familial lipoprotein lipase deficiency (Orphanet:309015)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000660	Lipemia retinalis
HP:0001013	Eruptive xanthomas
HP:0001508	Failure to thrive
HP:0001733	Pancreatitis
HP:0001744	Splenomegaly
HP:0002155	Hypertriglyceridemia
HP:0002240	Hepatomegaly
HP:0002583	Colitis
HP:0003233	Decreased HDL cholesterol concentration
HP:0003563	Decreased LDL cholesterol concentration
HP:0005181	Premature coronary artery atherosclerosis
HP:0010980	Hyperlipoproteinemia
HP:0011463	Childhood onset
HP:0012238	Increased circulating chylomicron concentration
HP:0025708	Early young adult onset
HP:0100027	Recurrent pancreatitis

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST006611_83	HDL cholesterol	3.000000e-09
GCST008070_105	HDL cholesterol levels	2.000000e-06
GCST008070_26	HDL cholesterol levels	2.000000e-10
GCST008075_115	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	7.000000e-16
GCST008075_61	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	9.000000e-12
GCST008084_21	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	8.000000e-13
GCST008084_231	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	8.000000e-18
GCST008085_156	HDL cholesterol levels in current drinkers	2.000000e-09
GCST008085_24	HDL cholesterol levels in current drinkers	1.000000e-12
GCST010241_103	Apolipoprotein A1 levels	1.000000e-46
GCST010242_463	HDL cholesterol levels	4.000000e-42
GCST010244_92	Triglyceride levels	3.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004530	triglyceride measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Nickel	decreases expression	2
clothianidin	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	increases methylation	1
Cyclosporine	decreases methylation	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	increases expression	1
Copper Sulfate	increases expression	1
Particulate Matter	increases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01514461	PHASE3	COMPLETED	A Randomized, Double-blind, Placebo Controlled Study to Assess Efficacy, Safety and Tolerability of LCQ908 in Subjects With Familial Chylomicronemia Syndrome
NCT01589237	PHASE3	TERMINATED	Extension to a Randomized, Double-blind, Placebo Controlled Study of LCQ908 in Subjects With Familial Chylomicronemia Syndrome.
NCT02211209	PHASE3	COMPLETED	The APPROACH Study: A Study of Volanesorsen (Formerly IONIS-APOCIIIRx) in Patients With Familial Chylomicronemia Syndrome
NCT02658175	PHASE3	COMPLETED	The Approach Open Label Study: A Study of Volanesorsen (Formerly IONIS-APOCIIIRx) in Participants With Familial Chylomicronemia Syndrome
NCT04568434	PHASE3	COMPLETED	A Study of Olezarsen (Formerly Known as AKCEA-APOCIII-LRx) Administered to Patients With Familial Chylomicronemia Syndrome (FCS)
NCT05130450	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Olezarsen (Formerly Known as AKCEA-APOCIII-LRx) in Participants With Familial Chylomicronemia Syndrome (FCS)
NCT05185843	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Olezarsen (Formerly Known as AKCEA-APOCIII-LRX) Administered to Adults With Familial Chylomicronemia Syndrome (FCS) Previously Treated With Volanesorsen
NCT05902598	PHASE3	COMPLETED	A Phase 3 Study of ARO-APOC3 / VSA001 / SAR449124 (Plozasiran) in Chinese Adults With Familial Chylomicronemia Syndrome
NCT02098278	PHASE2	COMPLETED	Pilot Study To Assess CAT-2003 in Patients With Chylomicronemia
NCT02767531	PHASE2	COMPLETED	Orlistat for the Treatment of Type I Hyperlipoproteinemia
NCT02904772	PHASE2	WITHDRAWN	Alipogene Tiparvovec for the Treatment of LPLD Patients
NCT03360747	PHASE2	COMPLETED	Phase 2 Study of AKCEA-ANGPTL3-LRx (ISIS 703802) in Participants With Familial Chylomicronemia Syndrome (FCS)
NCT00891306	PHASE2/PHASE3	COMPLETED	Efficacy and Safety of Human Lipoprotein Lipase (LPL)[S447X] Expressed by an Adeno-Associated Viral Vector in LPL-deficient Subjects
NCT01109498	PHASE2/PHASE3	UNKNOWN	Safety and Efficacy in LPL-Deficient Subjects of AMT-011, an Adeno-Associated Viral Vector Expressing Human Lipoprotein Lipase [S447X]
NCT06471543	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study of RN0361in Adult Healthy Subjects and Adult Hypertriglyceridemic Subjects
NCT07176923	EARLY_PHASE1	RECRUITING	CS-121 APOC3 Base Editing in FCS
NCT07371767	EARLY_PHASE1	RECRUITING	CS-121 APOC3 Base Editing in Children and Adolescents With Hyperchylomicronemia
NCT01447901	Not specified	TERMINATED	Duration of Effect of Alipogene Tiparvovec Treatment, Which Was Administered in Other Studies
NCT03293810	Not specified	COMPLETED	Glybera Registry, Lipoprotein Lipase Deficient (LPLD) Patients
NCT03912181	Not specified	COMPLETED	Medical Complications in Familial and Multifactorial Chylomicronaemia Syndromes
NCT04223908	Not specified	COMPLETED	InFocus France Epidemiological Study of Health Burden in Major Hypertriglyceridemia
NCT06360237	Not specified	APPROVED_FOR_MARKETING	Olezarsen Early Access Program for Patients With Familial Chylomicronemia Syndrome (FCS)