LDLRAP1

Summary

LDLRAP1 (low density lipoprotein receptor adaptor protein 1, HGNC:18640) is a protein-coding gene on chromosome 1p36.11, encoding Low density lipoprotein receptor adapter protein 1 (Q5SW96). Adapter protein (clathrin-associated sorting protein (CLASP)) required for efficient endocytosis of the LDL receptor (LDLR) in polarized cells such as hepatocytes and lymphocytes, but not in non-polarized cells (fibroblasts).

The protein encoded by this gene is a cytosolic protein which contains a phosphotyrosine binding (PTD) domain. The PTD domain has been found to interact with the cytoplasmic tail of the LDL receptor. Mutations in this gene lead to LDL receptor malfunction and cause the disorder autosomal recessive hypercholesterolaemia.

Source: NCBI Gene 26119 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypercholesterolemia, familial, 4 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 15
• Clinical variants (ClinVar): 652 total — 39 pathogenic, 22 likely-pathogenic
• Phenotypes (HPO): 37
• MANE Select transcript: NM_015627

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18640
Approved symbol	LDLRAP1
Name	low density lipoprotein receptor adaptor protein 1
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	ARH, ARH2, FHCB1, FHCB2, MGC34705, DKFZp586D0624
Ensembl gene	ENSG00000157978
Ensembl biotype	protein_coding
OMIM	605747
Entrez	26119

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 9 protein_coding, 6 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000374338, ENST00000412797, ENST00000462394, ENST00000470950, ENST00000474283, ENST00000484476, ENST00000485476, ENST00000488127, ENST00000718277, ENST00000718287, ENST00000718288, ENST00000894922, ENST00000894923, ENST00000894924, ENST00000894925, ENST00000915364, ENST00000960394

RefSeq mRNA: 1 — MANE Select: NM_015627 NM_015627

CCDS: CCDS30639

Canonical transcript exons

ENST00000374338 — 9 exons

Exon	Start	End
ENSE00001463197	25566848	25568886
ENSE00001463203	25543606	25543786
ENSE00003476951	25562644	25562716
ENSE00003496253	25553922	25554064
ENSE00003504313	25563070	25563153
ENSE00003522576	25565173	25565207
ENSE00003577902	25563661	25563791
ENSE00003608050	25557153	25557267
ENSE00003613873	25554860	25554972

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 97.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.2572 / max 481.8678, expressed in 1777 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1511	12.9127	1775
1517	2.0874	93
1518	0.6334	69
1510	0.4419	226
1514	0.0639	23
1513	0.0507	24
1519	0.0364	12
1515	0.0308	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	97.00	gold quality
cerebellar cortex	UBERON:0002129	96.94	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.82	gold quality
cerebellum	UBERON:0002037	96.42	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.99	gold quality
granulocyte	CL:0000094	94.47	gold quality
spinal cord	UBERON:0002240	94.19	gold quality
spleen	UBERON:0002106	94.16	gold quality
endothelial cell	CL:0000115	93.13	gold quality
lymph node	UBERON:0000029	93.13	gold quality
body of pancreas	UBERON:0001150	92.88	gold quality
hair follicle	UBERON:0002073	92.59	gold quality
pancreas	UBERON:0001264	92.45	gold quality
islet of Langerhans	UBERON:0000006	92.41	gold quality
cervix squamous epithelium	UBERON:0006922	92.36	gold quality
inferior vagus X ganglion	UBERON:0005363	92.31	gold quality
blood	UBERON:0000178	92.06	gold quality
mucosa of transverse colon	UBERON:0004991	91.89	gold quality
secondary oocyte	CL:0000655	91.09	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.77	gold quality
parotid gland	UBERON:0001831	90.43	gold quality
ascending aorta	UBERON:0001496	90.37	gold quality
thoracic aorta	UBERON:0001515	90.29	gold quality
leukocyte	CL:0000738	90.18	gold quality
epithelium of nasopharynx	UBERON:0001951	90.14	gold quality
vermiform appendix	UBERON:0001154	90.00	gold quality
monocyte	CL:0000576	89.77	gold quality
mononuclear cell	CL:0000842	89.74	gold quality
saliva-secreting gland	UBERON:0001044	89.65	gold quality
cerebellar vermis	UBERON:0004720	89.49	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.86
E-MTAB-4850	no	647.52

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

119 targeting LDLRAP1, 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-9-5P	100.00	72.28	2361
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621

Literature-anchored findings (GeneRIF, showing 33)

• ARH functions as an adaptor protein that couples LDLR to the endocytic machinery (PMID:12221107)
• The autosomal recessive hypercholesterolemia (ARH) protein interfaces directly with the clathrin-coat machinery. In ARH patients, defective sorting adaptor function in hepatocytes leads to faulty LDL receptor traffic and hypercholesterolemia. (PMID:12451172)
• restoration of LDL receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression (PMID:12464675)
• Single nucleotide polymorphism discovered among normal subjects at position 604 (cytosine to thymine: ARH-604C to ARH-604T), which changes proline residue at 202 to serine. ARH caused by mutation of cytosine to adenine at this same position. (PMID:12788851)
• ARH facilitates endocytosis of megalin, escorts megalin along its endocytic route (PMID:14528014)
• findings indicate that low density lipoprotein (LDL) receptor adaptor protein(ARH) is required not only for internalization of the LDL.LDL Receptor complex but also for efficient binding of LDL to the receptor (PMID:15166224)
• Splice site mutant lacks 26 amino acids, resulting in the loss of beta-strands beta6 and beta7 from the PTB domain. (PMID:15599766)
• ARH protein has an AP-2 beta2 appendage-binding sequence (PMID:15728179)
• ARH is an endocytic sorting adaptor that actively participates in the internalization of the LDL-LDLR complex, possibly enhancing the efficiency of its packaging into the endocytic vesicles (PMID:16129683)
• Dab2 expression is exceptionally low in hepatocytes, likely accounting for the pathological hypercholesterolemia that accompanies ARH loss. (PMID:16870701)
• ARH might accelerate later steps in LDLR endocytosis in cooperation with AP-2. (PMID:16984970)
• Large deletion in the ARH gene is associated with autosomal recessive hypercholesterolemia (PMID:17686643)
• the endocytic adaptor protein ARH associates with motor and centrosomal proteins and is involved in centrosome assembly and cytokinesis (PMID:18417616)
• PCSK9-mediated LDLR degradation is not entirely dependent on ARH function (PMID:19081568)
• Report prevalence and clinical features of heterozygous carriers of autosomal recessive hypercholesterolemia in Sardinia. (PMID:19477448)
• The report provides evidence that endocytosis of the ROMK potassium channel is controlled by LDLRAP1 (ARH). ROMK binds directly to the LDLRAP1, and this interaction is mediated by a novel variant of the canonical “NPXY” endocytotic signal, YxNPxFV. LDLRAP1-knockout mice are unable to physiologically regulate ROMK. (PMID:19841541)
• newly identified a rare Thr56Met missense mutation located in the phosphotyrosine-binding domain of ARH; among 1,800 Japanese individuals, only 4 were heterozygous for Thr56Met and all had hypercholesterolemia resembling familiar hypercholesterolemia (PMID:20124734)
• Knockdown of ARH in polarized epithelial cells leads to specific apical missorting of truncated LDLR, which encodes only the FxNPxY motif (LDLR-CT27). (PMID:21444685)
• ARH protein is involved in cell cycle progression, possibly by affecting nuclear membrane formation through interaction with lamin B1 or other mitotic proteins, and its absence affects cell proliferation and induces premature senescence. (PMID:21778424)
• LDL receptor/LDLRAP1 double heterozygous mutations may account for severer phenotype in terms of xanthoma and atherosclerotic cardiovascular disease in familial hypercholesterolemia patients. (PMID:21872251)
• report the crystal structure at 1.37-A resolution of the phosphotyrosine-binding (PTB) domain of ARH in complex with an LDLR tail peptide containing the FxNPxY(0) internalization signal (PMID:22509010)
• This work identified a combined LDL receptor and LDLRAP1 mutation as the cause for severe familial hypercholesterolemia in a family of Turkish descent. (PMID:23510778)
• cells that depend upon ARH for LDL uptake can control which lipoproteins are internalized by their LDLRs through changes in nitric oxide. (PMID:23564733)
• Identification of ARH gene and characterization of its mutations in Autosomal Recessive Hypercholesterolemia patients [Review] (PMID:25225128)
• Numb specifically regulates NPC1L1-mediated cholesterol absorption both in human intestine and liver, distinct from ARH and Dab2, which selectively participate in LDLR-mediated LDL uptake. (PMID:25331956)
• LDLRAP1 associated with Familial Hypercholesterolemia and Polygenic Hypercholesterolemia in patients with Acute Coronary Syndrome , age </=65 years, and LDL-C levels >/=160 mg/dl. (PMID:28958330)
• The results show that phosphorylated ARH1 has more ordered structure than the non-phosphorylated type. (PMID:28963484)
• Case Report: combined variants in LDLR/LDLRAP1 genes trigger a severe familial hypercholesterolemia phenotype. (PMID:30270081)
• new variant in the LDLRAP1 gene associated with autosomal recessive hypercholesterolemia (PMID:30876877)
• Pathogenic mutations in LDLR, APOB, PCSK9 and LDLRAP1 genes were found in 17 of 225 patients with familial hypercholesterolemia leading to premature myocardial infarction. (PMID:30971288)
• Molecular insights into the coding region mutations of low-density lipoprotein receptor adaptor protein 1 (LDLRAP1) linked to familial hypercholesterolemia. (PMID:32073192)
• A Novel Splice Site Variant in the LDLRAP1 Gene Causes Familial Hypercholesterolemia (PMID:34425670)
• Methylation status of LDLR, PCSK9 and LDLRAP1 is associated with cardiovascular events in familial hypercholesterolemia. (PMID:38884343)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
danio_rerio	ldlrap1b	ENSDARG00000039750
mus_musculus	Ldlrap1	ENSMUSG00000037295
rattus_norvegicus	Ldlrap1	ENSRNOG00000000151
drosophila_melanogaster	Dab	FBGN0000414
drosophila_melanogaster	numb	FBGN0002973
drosophila_melanogaster	CG8312	FBGN0037720
drosophila_melanogaster	Aplip1	FBGN0040281
drosophila_melanogaster	CG42673	FBGN0261555
caenorhabditis_elegans		WBGENE00000894
caenorhabditis_elegans		WBGENE00001116
caenorhabditis_elegans		WBGENE00002176
caenorhabditis_elegans		WBGENE00003830
caenorhabditis_elegans		WBGENE00009930

Paralogs (11): MAPK8IP2 (ENSG00000008735), NUMBL (ENSG00000105245), MAPK8IP1 (ENSG00000121653), NUMB (ENSG00000133961), GULP1 (ENSG00000144366), DAB2 (ENSG00000153071), DAB1 (ENSG00000173406), FAM43B (ENSG00000183114), FAM43A (ENSG00000185112), NOS1AP (ENSG00000198929), C1orf226 (ENSG00000239887)

Protein

Protein identifiers

Low density lipoprotein receptor adapter protein 1 — Q5SW96 (reviewed: Q5SW96)

Alternative names: Autosomal recessive hypercholesterolemia protein

All UniProt accessions (1): Q5SW96

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein (clathrin-associated sorting protein (CLASP)) required for efficient endocytosis of the LDL receptor (LDLR) in polarized cells such as hepatocytes and lymphocytes, but not in non-polarized cells (fibroblasts). May be required for LDL binding and internalization but not for receptor clustering in coated pits. May facilitate the endocytosis of LDLR and LDLR-LDL complexes from coated pits by stabilizing the interaction between the receptor and the structural components of the pits. May also be involved in the internalization of other LDLR family members. Binds to phosphoinositides, which regulate clathrin bud assembly at the cell surface. Required for trafficking of LRP2 to the endocytic recycling compartment which is necessary for LRP2 proteolysis, releasing a tail fragment which translocates to the nucleus and mediates transcriptional repression.

Subunit / interactions. Interacts (via PID domain) with LDLR (via NPXY motif). Binds to soluble clathrin trimers. Interacts with AP2B1; the interaction mediates the association with the AP-2 complex. Interacts with VLDLR. Interacts with LRP2.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed at high levels in the kidney, liver, and placenta, with lower levels detectable in brain, heart, muscle, colon, spleen, intestine, lung, and leukocytes.

Disease relevance. Hypercholesterolemia, familial, 4 (FHCL4) [MIM:603813] A form of hypercholesterolemia, a disorder of lipoprotein metabolism characterized by elevated serum low-density lipoprotein (LDL) cholesterol levels, which result in excess deposition of cholesterol in tissues and leads to xanthelasma, xanthomas, accelerated atherosclerosis and increased risk of premature coronary heart disease. FHCL4 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction the AP-2 complex subunit AP2B1. The PID domain mediates interaction with the NPXY internalization motif of LDLR.

RefSeq proteins (1): NP_056442* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006020	PTB/PI_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR051133	Adapter_Engulfment-Domain	Family

Pfam: PF00640

UniProt features (20 total): mutagenesis site 7, modified residue 4, sequence variant 3, short sequence motif 2, chain 1, domain 1, helix 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2G30	X-RAY DIFFRACTION	1.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5SW96-F1	69.90	0.39

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 (4): 1, 14, 186, 202

Mutagenesis-validated functional residues (7):

Position	Phenotype
165	abolishes ldlr cytoplasmic tail binding.
212–213	abolishes clathrin binding.
214	abolishes clathrin binding.
216	abolishes clathrin binding.
256	abolishes interaction with ap2b1.
266	abolishes ap-2 complex binding.

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-196791	Vitamin D (calciferol) metabolism
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-8964026	Chylomicron clearance
R-HSA-8964038	LDL clearance
R-HSA-9758890	Transport of RCbl within the body
R-HSA-1430728	Metabolism
R-HSA-174824	Plasma lipoprotein assembly, remodeling, and clearance
R-HSA-196741	Cobalamin (Cbl, vitamin B12) transport and metabolism
R-HSA-196849	Metabolism of water-soluble vitamins and cofactors
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-199991	Membrane Trafficking
R-HSA-382551	Transport of small molecules
R-HSA-556833	Metabolism of lipids
R-HSA-5653656	Vesicle-mediated transport
R-HSA-8957322	Metabolism of steroids
R-HSA-8964043	Plasma lipoprotein clearance

MSigDB gene sets: 450 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_REGULATION_OF_PROTEIN_BINDING, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_RESPONSE_TO_PEPTIDE, GOBP_STEROL_HOMEOSTASIS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_STEROL_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_POSITIVE_REGULATION_OF_RECEPTOR_MEDIATED_ENDOCYTOSIS, GOBP_MUSCLE_CELL_PROLIFERATION, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_POSITIVE_REGULATION_OF_LIPID_TRANSPORT, GOBP_LOW_DENSITY_LIPOPROTEIN_PARTICLE_CLEARANCE

GO Biological Process (19): receptor-mediated endocytosis (GO:0006898), cholesterol metabolic process (GO:0008203), cholesterol transport (GO:0030301), receptor internalization (GO:0031623), low-density lipoprotein particle clearance (GO:0034383), cholesterol homeostasis (GO:0042632), amyloid precursor protein metabolic process (GO:0042982), regulation of protein binding (GO:0043393), positive regulation of receptor-mediated endocytosis (GO:0048260), cellular response to cytokine stimulus (GO:0071345), receptor-mediated endocytosis involved in cholesterol transport (GO:0090118), positive regulation of cholesterol metabolic process (GO:0090205), regulation of protein localization to plasma membrane (GO:1903076), positive regulation of vascular associated smooth muscle cell proliferation (GO:1904707), positive regulation of low-density lipoprotein particle clearance (GO:1905581), positive regulation of receptor-mediated endocytosis involved in cholesterol transport (GO:1905602), lipid metabolic process (GO:0006629), endocytosis (GO:0006897), steroid metabolic process (GO:0008202)

GO Molecular Function (11): amyloid-beta binding (GO:0001540), phosphotyrosine residue binding (GO:0001784), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), signaling receptor complex adaptor activity (GO:0030159), clathrin binding (GO:0030276), signaling adaptor activity (GO:0035591), AP-2 adaptor complex binding (GO:0035612), clathrin-cargo adaptor activity (GO:0035615), AP-1 adaptor complex binding (GO:0035650), low-density lipoprotein particle receptor binding (GO:0050750), protein binding (GO:0005515)

GO Cellular Component (10): early endosome (GO:0005769), cytosol (GO:0005829), neurofilament (GO:0005883), plasma membrane (GO:0005886), cytoplasmic side of plasma membrane (GO:0009898), basal plasma membrane (GO:0009925), axon (GO:0030424), clathrin-coated endocytic vesicle membrane (GO:0030669), recycling endosome (GO:0055037), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Plasma lipoprotein clearance	2
Metabolism	2
Metabolism of steroids	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
Cobalamin (Cbl, vitamin B12) transport and metabolism	1
Transport of small molecules	1
Metabolism of water-soluble vitamins and cofactors	1
Metabolism of vitamins and cofactors	1
Vesicle-mediated transport	1
Metabolism of lipids	1
Plasma lipoprotein assembly, remodeling, and clearance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
receptor-mediated endocytosis	3
protein binding	2
protein-containing complex binding	2
endosome	2
cytoplasm	2
cellular anatomical structure	2
endocytosis	1
sterol metabolic process	1
secondary alcohol metabolic process	1
sterol transport	1
plasma lipoprotein particle clearance	1
low-density lipoprotein particle disassembly	1
sterol homeostasis	1
protein metabolic process	1
regulation of binding	1
positive regulation of endocytosis	1
regulation of receptor-mediated endocytosis	1
response to cytokine	1
intracellular cholesterol transport	1
intracellular transport	1
cholesterol metabolic process	1
positive regulation of steroid metabolic process	1
positive regulation of small molecule metabolic process	1
regulation of cholesterol metabolic process	1
protein localization to plasma membrane	1
regulation of protein localization to cell periphery	1
regulation of protein localization to membrane	1
positive regulation of smooth muscle cell proliferation	1
regulation of vascular associated smooth muscle cell proliferation	1
vascular associated smooth muscle cell proliferation	1
positive regulation of lipoprotein particle clearance	1
regulation of low-density lipoprotein particle clearance	1
low-density lipoprotein particle clearance	1
positive regulation of intracellular cholesterol transport	1
positive regulation of receptor-mediated endocytosis	1
receptor-mediated endocytosis involved in cholesterol transport	1
primary metabolic process	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1

Protein interactions and networks

STRING

891 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LDLRAP1	PCSK9	Q8NBP7	808
LDLRAP1	APOB	P04114	764
LDLRAP1	ABCG5	Q9H222	679
LDLRAP1	ABCG8	Q9H221	674
LDLRAP1	LTF	P02788	666
LDLRAP1	LDLR	P01130	664
LDLRAP1	LRP2	P98164	641
LDLRAP1	CBLIF	P27352	639
LDLRAP1	PNPLA5	Q7Z6Z6	603
LDLRAP1	CLTC	Q00610	596
LDLRAP1	GC	P02774	584
LDLRAP1	STAP1	Q9ULZ2	580
LDLRAP1	APOE	P02649	571
LDLRAP1	CUBN	O60494	564
LDLRAP1	LPL	P06858	548

IntAct

93 interactions, top by confidence:

A	B	Type	Score
LDLRAP1	STN1	psi-mi:“MI:0915”(physical association)	0.890
STN1	LDLRAP1	psi-mi:“MI:0915”(physical association)	0.890
AP2B1	LDLRAP1	psi-mi:“MI:0915”(physical association)	0.760
LDLRAP1	AP2B1	psi-mi:“MI:0915”(physical association)	0.760
LDLRAP1	MAPK8IP3	psi-mi:“MI:0915”(physical association)	0.720
MAPK8IP3	LDLRAP1	psi-mi:“MI:0915”(physical association)	0.720
LDLRAP1	PSD4	psi-mi:“MI:0915”(physical association)	0.720
LDLRAP1	AP2B1	psi-mi:“MI:0915”(physical association)	0.700
AP2B1	LDLRAP1	psi-mi:“MI:0915”(physical association)	0.700
LDLRAP1	VID24	psi-mi:“MI:0915”(physical association)	0.610
VID24	LDLRAP1	psi-mi:“MI:0915”(physical association)	0.610
LDLRAP1	CSA1	psi-mi:“MI:0915”(physical association)	0.560
CSA1	LDLRAP1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (71): OBFC1 (Two-hybrid), NLN (Affinity Capture-MS), CHEK1 (Affinity Capture-MS), CCDC85C (Affinity Capture-MS), DCAF16 (Affinity Capture-MS), LDLRAP1 (Affinity Capture-MS), LDLRAP1 (Two-hybrid), LDLRAP1 (Affinity Capture-MS), OBFC1 (Two-hybrid), PSD4 (Two-hybrid), NLN (Affinity Capture-MS), LDLRAP1 (Affinity Capture-MS), CCDC85C (Affinity Capture-MS), CHEK1 (Affinity Capture-MS), LDLRAP1 (Two-hybrid)

ESM2 similar proteins: A6QQV9, D3ZAR1, D4AB98, F1LYQ8, F7EL49, F8VPU2, O54960, O60343, O70143, O75052, O97790, P29353, P42331, P98083, Q0IIE2, Q15678, Q2I6J1, Q32PV0, Q4V8Y7, Q5M824, Q5PQS4, Q5R7W7, Q5RAB8, Q5SW96, Q60949, Q61120, Q62130, Q62136, Q67FQ3, Q69Z98, Q801G1, Q80T23, Q812E4, Q86TI0, Q8AY68, Q8BN58, Q8BYJ6, Q8BYW1, Q8BZI0, Q8C0V9

Diamond homologs: A1L1I3, O08919, O88797, P16554, P49757, P98078, P98081, P98082, Q2LC84, Q5PQS4, Q5SW96, Q801G1, Q8C142, Q8K2A1, Q9QZS3, Q9UBP9, Q9XTY6, Q9Y6R0, A0A8I3NFE2, A5PMU4, D3ZAR1, O09127, O15357, O70143, P0C6S7, P29321, P29353, P54753, P54754, P54755, P54756, P54758, P59672, P98083, Q03145, Q07498, Q09YL6, Q0IIE2, Q2I6J1, Q32PV0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	39
Likely pathogenic	22
Uncertain significance	231
Likely benign	291
Benign	17

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074905	NM_015627.3(LDLRAP1):c.400C>T (p.Gln134Ter)	Pathogenic
1365639	NC_000001.10:g.(?25870190)(26142209_?)del	Pathogenic
1399626	NM_015627.3(LDLRAP1):c.604del (p.Ser202fs)	Pathogenic
1455119	NM_015627.3(LDLRAP1):c.89-2A>G	Pathogenic
1456558	NM_015627.3(LDLRAP1):c.547del (p.Asp183fs)	Pathogenic
1751270	NM_015627.3(LDLRAP1):c.604delinsCC (p.Ser202fs)	Pathogenic
1792217	NM_015627.3(LDLRAP1):c.24dup (p.Arg9fs)	Pathogenic
2154296	NM_015627.3(LDLRAP1):c.301_304del (p.Asp101fs)	Pathogenic
2697613	NM_015627.3(LDLRAP1):c.17C>A (p.Ser6Ter)	Pathogenic
2698048	NM_015627.3(LDLRAP1):c.567_570del (p.Gly190fs)	Pathogenic
2789329	NM_015627.3(LDLRAP1):c.466del (p.Ala156fs)	Pathogenic
2804597	NM_015627.3(LDLRAP1):c.178C>T (p.Gln60Ter)	Pathogenic
2831407	NM_015627.3(LDLRAP1):c.442_443del (p.Cys148fs)	Pathogenic
2832489	NM_015627.3(LDLRAP1):c.105G>A (p.Trp35Ter)	Pathogenic
2835248	NM_015627.3(LDLRAP1):c.516G>A (p.Trp172Ter)	Pathogenic
2850621	NM_015627.3(LDLRAP1):c.58C>T (p.Gln20Ter)	Pathogenic
2855236	NM_015627.3(LDLRAP1):c.148del (p.Leu50fs)	Pathogenic
296981	NM_015627.3(LDLRAP1):c.487C>T (p.Gln163Ter)	Pathogenic
3247771	NC_000001.10:g.(?25870190)(25870297_?)del	Pathogenic
3247772	NC_000001.10:g.(?25883624)(25883778_?)del	Pathogenic
3247773	NC_000001.10:g.(?25889115)(25889664_?)del	Pathogenic
3633064	NM_015627.3(LDLRAP1):c.55_79del (p.Lys19fs)	Pathogenic
3720184	NM_015627.3(LDLRAP1):c.207del (p.Ala70fs)	Pathogenic
468290	NM_015627.3(LDLRAP1):c.71del (p.Gly24fs)	Pathogenic
4687614	NM_015627.3(LDLRAP1):c.71_87del (p.Gly24fs)	Pathogenic
4766926	NM_015627.3(LDLRAP1):c.559C>T (p.Gln187Ter)	Pathogenic
4773	NM_015627.3(LDLRAP1):c.65G>A (p.Trp22Ter)	Pathogenic
4774	NM_015627.3(LDLRAP1):c.432_433insA (p.Ala145fs)	Pathogenic
4775	NM_015627.3(LDLRAP1):c.406C>T (p.Gln136Ter)	Pathogenic
4777	NM_015627.3(LDLRAP1):c.74dup (p.Gly26fs)	Pathogenic

SpliceAI

1697 predictions. Top by Δscore:

Variant	Effect	Δscore
1:25543787:G:GG	donor_gain	1.0000
1:25554065:G:GG	donor_gain	1.0000
1:25554082:G:GT	donor_gain	1.0000
1:25554857:AAG:A	acceptor_gain	1.0000
1:25554858:A:G	acceptor_gain	1.0000
1:25554859:G:A	acceptor_gain	1.0000
1:25554969:ACAGG:A	donor_loss	1.0000
1:25554970:CAGG:C	donor_loss	1.0000
1:25554971:AGGTA:A	donor_loss	1.0000
1:25554972:GGTAC:G	donor_loss	1.0000
1:25554973:G:GA	donor_loss	1.0000
1:25554974:T:A	donor_loss	1.0000
1:25557261:G:GT	donor_gain	1.0000
1:25557264:GATG:G	donor_gain	1.0000
1:25561682:G:GT	donor_gain	1.0000
1:25561683:A:T	donor_gain	1.0000
1:25562714:A:T	donor_gain	1.0000
1:25563151:GCT:G	donor_gain	1.0000
1:25563656:CACA:C	acceptor_loss	1.0000
1:25563657:ACAGT:A	acceptor_gain	1.0000
1:25563658:CAGT:C	acceptor_loss	1.0000
1:25563659:A:AG	acceptor_gain	1.0000
1:25563659:AGT:A	acceptor_gain	1.0000
1:25563660:G:GG	acceptor_gain	1.0000
1:25563660:GT:G	acceptor_gain	1.0000
1:25563660:GTG:G	acceptor_gain	1.0000
1:25553916:CCCCA:C	acceptor_loss	0.9900
1:25553917:CCCA:C	acceptor_loss	0.9900
1:25553918:CCA:C	acceptor_loss	0.9900
1:25553919:CA:C	acceptor_loss	0.9900

AlphaMissense

2026 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:25562654:T:A	V157D	1.000
1:25562660:T:C	L159P	1.000
1:25562674:G:C	A164P	1.000
1:25562677:T:C	F165L	1.000
1:25562679:C:A	F165L	1.000
1:25562679:C:G	F165L	1.000
1:25553976:T:C	F48S	0.999
1:25553993:G:C	G54R	0.999
1:25553994:G:T	G54V	0.999
1:25554042:C:A	A70D	0.999
1:25554897:T:C	L90P	0.999
1:25554966:T:A	I113K	0.999
1:25554966:T:G	I113R	0.999
1:25557164:G:A	C119Y	0.999
1:25557165:C:G	C119W	0.999
1:25557194:T:C	F129S	0.999
1:25557197:C:A	A130E	0.999
1:25557199:T:G	Y131D	0.999
1:25557235:T:C	C143R	0.999
1:25557237:C:G	C143W	0.999
1:25557242:C:A	A145D	0.999
1:25557245:T:C	F146S	0.999
1:25557250:T:C	C148R	0.999
1:25557252:C:G	C148W	0.999
1:25562675:C:A	A164D	0.999
1:25562687:C:A	A168D	0.999
1:25553936:T:A	W35R	0.998
1:25553936:T:C	W35R	0.998
1:25553938:G:C	W35C	0.998
1:25553938:G:T	W35C	0.998

dbSNP variants (sampled 300 via entrez): RS1000014845 (1:25554521 T>G), RS1000348809 (1:25567702 A>G), RS1000402428 (1:25567457 C>T), RS1000557870 (1:25574269 C>T), RS1000589240 (1:25575154 G>A), RS1000664553 (1:25564437 A>C), RS1000872804 (1:25548334 T>C), RS1000958582 (1:25563229 C>A,T), RS1001033839 (1:25552041 A>G), RS1001064297 (1:25575595 A>G), RS1001067492 (1:25541648 T>C), RS1001077790 (1:25580842 TC>T), RS1001119358 (1:25564749 G>A), RS1001123061 (1:25542910 G>A), RS1001204662 (1:25546932 C>A)

Disease associations

OMIM: gene MIM:605747 | disease phenotypes: MIM:603813, MIM:143890, MIM:602771

GenCC curated gene-disease

Disease	Classification	Inheritance
hypercholesterolemia, familial, 4	Strong	Autosomal recessive
homozygous familial hypercholesterolemia	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hypercholesterolemia, familial, 4	Definitive	AR

Mondo (5): hypercholesterolemia, familial, 4 (MONDO:0011374), familial hypercholesterolemia (MONDO:0005439), rigid spine muscular dystrophy 1 (MONDO:0011271), hypercholesterolemia, familial, 1 (MONDO:0007750), homozygous familial hypercholesterolemia (MONDO:0018328)

Orphanet (1): Homozygous familial hypercholesterolemia (Orphanet:391665)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000799	Renal steatosis
HP:0000822	Hypertension
HP:0000991	Xanthomatosis
HP:0001138	Optic neuropathy
HP:0001397	Hepatic steatosis
HP:0001645	Sudden cardiac death
HP:0001653	Mitral regurgitation
HP:0001658	Myocardial infarction
HP:0001677	Coronary artery atherosclerosis
HP:0001681	Angina pectoris
HP:0001920	Renal artery stenosis
HP:0002094	Dyspnea
HP:0002155	Hypertriglyceridemia
HP:0002621	Atherosclerosis
HP:0002829	Arthralgia
HP:0003077	Hyperlipidemia
HP:0003124	Hypercholesterolemia
HP:0003141	Increased LDL cholesterol concentration
HP:0003563	Decreased LDL cholesterol concentration
HP:0004381	Supravalvular aortic stenosis
HP:0004416	Precocious atherosclerosis
HP:0004950	Peripheral arterial stenosis
HP:0004963	Calcification of the aorta
HP:0005162	Abnormal left ventricular function
HP:0005177	Premature arteriosclerosis
HP:0005181	Premature coronary artery atherosclerosis
HP:0006693	Myocardial steatosis
HP:0007201	Cerebral artery atherosclerosis
HP:0010874	Tendon xanthomatosis

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000759_33	LDL cholesterol	1.000000e-10
GCST000760_48	Cholesterol, total	4.000000e-11
GCST002221_63	Cholesterol, total	5.000000e-12
GCST002222_33	LDL cholesterol	2.000000e-14
GCST002896_34	Cholesterol, total	3.000000e-09
GCST002898_32	LDL cholesterol	4.000000e-09
GCST004233_50	LDL cholesterol levels	2.000000e-18
GCST004235_64	Total cholesterol levels	3.000000e-16
GCST004599_242	Mean platelet volume	4.000000e-16
GCST004599_243	Mean platelet volume	5.000000e-25
GCST004603_161	Platelet count	7.000000e-10
GCST90002395_298	Mean platelet volume	5.000000e-37
GCST90002395_299	Mean platelet volume	8.000000e-49
GCST90002401_8	Platelet distribution width	6.000000e-14
GCST90002402_534	Platelet count	2.000000e-24

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004309	platelet count
EFO:0007984	platelet component distribution width

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000090542	Homozygous Familial Hypercholesterolemia	C16.320.565.398.481.500; C18.452.584.500.500.644.475.500; C18.452.584.563.481.500; C18.452.648.398.481.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects cotreatment, increases expression, affects expression, affects methylation	4
trichostatin A	affects cotreatment, increases expression	3
Tobacco Smoke Pollution	decreases expression, affects expression	3
sodium arsenite	increases abundance, decreases expression, affects cotreatment	2
entinostat	affects cotreatment, increases expression	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Cisplatin	affects cotreatment, increases expression	2
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
ginger extract	decreases reaction, increases abundance, decreases expression	1
daidzein	affects cotreatment, affects expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases reaction, increases abundance, decreases expression	1
daidzin	affects cotreatment, affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression, affects response to substance, increases expression	1
genistin	affects cotreatment, affects expression	1
di-n-butylphosphoric acid	affects expression	1
glycitein	affects expression, affects cotreatment	1
glycitin	affects cotreatment, affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Calcitriol	increases expression	1
Demecolcine	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1

Cellosaurus cell lines

5 cell lines: 5 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_CX57	GM00695	Finite cell line	Male
CVCL_DN44	GM00667	Finite cell line	Male
CVCL_DN45	GM00694	Finite cell line	Female
CVCL_DN46	GM00696	Finite cell line	Female
CVCL_DN47	GM00697	Finite cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00655265	PHASE4	COMPLETED	A Study of the Safety and Efficacy of Patients With Familial Hypercholesterolaemia Taking Colesevelam as add-on Therapy to Their Existing Medication
NCT00916643	PHASE4	COMPLETED	Low-Density Lipoprotein (LDL) Apheresis Using H.E.L.P. Therapy
NCT03331666	PHASE4	TERMINATED	Impact of LDL-cholesterol Lowering on Platelet Activation
NCT05465278	PHASE4	COMPLETED	Alirocumab and Plaque Burden In Familial Hypercholesterolaemia
NCT00730236	PHASE3	COMPLETED	A Safety and Efficacy Study of AEGR-733 to Treat Homozygous Familial Hypercholesterolemia (FH)
NCT01841684	PHASE3	TERMINATED	Efficacy and Tolerability of Anacetrapib Added to Ongoing Lipid-Lowering Therapy in Adult Participants With Homozygous Familial Hypercholesterolemia (HoFH) (MK-0859-042)
NCT02226198	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Rosuvastatin in Children and Adolescents With Homozygous Familial Hypercholesterolemia
NCT02434497	PHASE3	COMPLETED	A Study to Evaluate the Safety of Rosuvastatin in Children and Adolescents With Homozygous Familial Hypercholesterolemia
NCT02765841	PHASE3	WITHDRAWN	Evaluate the Efficacy and Safety of Lomitapide in Pediatric Patients With Homozygous Familial Hypercholesterolemia on Stable Lipid-lowering Therapy
NCT03156621	PHASE3	COMPLETED	Study in Participants With Homozygous Familial Hypercholesterolemia (HoFH)
NCT03399786	PHASE3	COMPLETED	Efficacy and Safety of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia
NCT03409744	PHASE3	COMPLETED	Evaluate the Long-Term Safety and Efficacy of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia
NCT03814187	PHASE3	COMPLETED	Trial to Assess the Effect of Long Term Dosing of Inclisiran in Subjects With High CV Risk and Elevated LDL-C
NCT03851705	PHASE3	COMPLETED	A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia (HoFH)
NCT04034485	PHASE3	COMPLETED	Phase 3 Study to Evaluate the Efficacy and Safety of LIB003 With Evolocumab in HoFH
NCT04233918	PHASE3	COMPLETED	Evaluate the Efficacy and Safety of Evinacumab in Pediatric Patients With Homozygous Familial Hypercholesterolemia
NCT05611528	PHASE3	COMPLETED	Safety and Effectiveness of Evinacumab for the Treatment of Homozygous Familial Hypercholesterolemia
NCT05682378	PHASE3	RECRUITING	Long-term Safety and Tolerability of Inclisiran in Participants With HeFH or HoFH Who Have Completed the Pediatric ORION-16, ORION-13, ORION-20, or ORION-19 Studies
NCT06712771	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Clinical Trial to Evaluate the Efficacy and Safety of VSA003 in Chinese HoFH Patients
NCT06723652	PHASE3	COMPLETED	A Multicenter, Randomized, Double-blind, Placebo-controlled Phase III Clinical Study Evaluating the Efficacy and Safety of SHR-1918 in Patients With Homozygous Familial Hypercholesterolemia
NCT07037771	PHASE3	RECRUITING	A Phase 3 Study of Zodasiran in Adolescent and Adult Subjects With Homozygous Familial Hypercholesterolemia (YOSEMITE)
NCT07473843	PHASE3	NOT_YET_RECRUITING	Study of Zodasiran in Adolescent Participants With Homozygous Familial Hypercholesterolemia
NCT00355615	PHASE3	COMPLETED	PLUTO: Pediatric Lipid-redUction Trial of rOsuvastatin
NCT00552097	PHASE3	COMPLETED	Effect of Ezetimibe Plus Simvastatin Versus Simvastatin Alone on Atherosclerosis in the Carotid Artery (ENHANCE)(P02578)
NCT00607373	PHASE3	COMPLETED	Study to Assess the Safety and Efficacy of ISIS 301012 (Mipomersen) in Homozygous Familial Hypercholesterolemia
NCT00694109	PHASE3	COMPLETED	An Open-label Extension Study to Assess the Long-term Safety and Efficacy of ISIS 301012 (Mipomersen) in Patients With Familial Hypercholesterolemia or Severe-Hypercholesterolemia
NCT00827606	PHASE3	COMPLETED	Atorvastatin Three Year Pediatric Study
NCT00943306	PHASE3	COMPLETED	Long Term, Follow-on Study of Lomitapide in Patients With Homozygous Familial Hypercholesterolemia
NCT01524289	PHASE3	COMPLETED	Study to Assess the Tolerability and Efficacy of Anacetrapib (MK-0859) Co-Administered With Statin in Participants With Heterozygous Familial Hypercholesterolemia (MK-0859-020)
NCT01813006	PHASE3	COMPLETED	Effect of Omega-3 Fatty Acid on Endothelial Function
NCT02624869	PHASE3	COMPLETED	Safety, Tolerability and Efficacy of Evolocumab (AMG 145) in Children With Inherited Elevated Low-density Lipoprotein Cholesterol (Familial Hypercholesterolemia)
NCT02748057	PHASE3	COMPLETED	A Clinical Trial to Assess the Long Term Safety and Tolerability of MK-0653H in Japanese Participants With Hypercholesterolemia (MK-0653H-833)
NCT03884452	PHASE3	COMPLETED	Ezetimibe (SCH 58235) Taken With Either Atorvastatin or Simvastatin in Participants With Familial Hypercholesterolemia (MK-0653-018)
NCT04798430	PHASE3	ENROLLING_BY_INVITATION	Long-term Efficacy and Safety of OLE LIB003 in HoFH, HeFH, and High-risk CVD Patients Requiring Further LDL-C Reduction
NCT05142722	PHASE3	COMPLETED	Randomized Study to Evaluate the Effect of Obicetrapib on Top of Maximum Tolerated Lipid-Modifying Therapies
NCT05238519	PHASE3	ACTIVE_NOT_RECRUITING	Improved Diagnosis of Familial Hypercholesterolemia Across the Northland (ID-FH)
NCT05425745	PHASE3	COMPLETED	Evaluate the Effect of Obicetrapib in Patients With HeFH on Top of Maximum Tolerated Lipid-Modifying Therapies.
NCT05952856	PHASE3	COMPLETED	A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Hypercholesterolemia (MK-0616-013) CORALreef Lipids
NCT05952869	PHASE3	COMPLETED	A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Heterozygous Familial Hypercholesterolemia (MK-0616-017/CORALreef HeFH)
NCT06005597	PHASE3	COMPLETED	Study of Obicetrapib & Ezetimibe Fixed Dose Combination on Top of Maximum Tolerated Lipid-Modifying Therapies