LRPAP1

Summary

LRPAP1 (LDL receptor related protein associated protein 1, HGNC:6701) is a protein-coding gene on chromosome 4p16.3, encoding Alpha-2-macroglobulin receptor-associated protein (P30533). Molecular chaperone for LDL receptor-related proteins that may regulate their ligand binding activity along the secretory pathway.

This gene encodes a protein that interacts with the low density lipoprotein (LDL) receptor-related protein and facilitates its proper folding and localization by preventing the binding of ligands. Mutations in this gene have been identified in individuals with myopia 23. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 4043 — RefSeq curated summary.

At a glance

• Gene–disease (curated): myopia 23, autosomal recessive (Definitive, GenCC)
• GWAS associations: 10
• Clinical variants (ClinVar): 83 total — 2 pathogenic
• Phenotypes (HPO): 5
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_002337

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6701
Approved symbol	LRPAP1
Name	LDL receptor related protein associated protein 1
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Aliases	HBP44, Alpha-2-MRAP
Ensembl gene	ENSG00000163956
Ensembl biotype	protein_coding
OMIM	104225
Entrez	4043

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000296325, ENST00000509198, ENST00000515119, ENST00000648517, ENST00000650182, ENST00000650633, ENST00000897672, ENST00000897673, ENST00000897674, ENST00000897675, ENST00000931149, ENST00000931150, ENST00000941405

RefSeq mRNA: 1 — MANE Select: NM_002337 NM_002337

CCDS: CCDS3371

Canonical transcript exons

ENST00000650182 — 8 exons

Exon	Start	End
ENSE00003463272	3524907	3525051
ENSE00003467254	3518034	3518192
ENSE00003536128	3520072	3520193
ENSE00003567654	3514752	3514928
ENSE00003617689	3516116	3516198
ENSE00003670309	3518871	3518991
ENSE00003831456	3503612	3513036
ENSE00003835885	3532209	3532422

Expression profiles

Bgee: expression breadth ubiquitous, 302 present calls, max score 99.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 60.4440 / max 529.1233, expressed in 1825 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51171	60.4440	1825

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.04	gold quality
right atrium auricular region	UBERON:0006631	98.58	gold quality
right coronary artery	UBERON:0001625	98.40	gold quality
apex of heart	UBERON:0002098	98.33	gold quality
middle frontal gyrus	UBERON:0002702	98.31	gold quality
descending thoracic aorta	UBERON:0002345	98.26	gold quality
putamen	UBERON:0001874	98.25	gold quality
thoracic aorta	UBERON:0001515	98.24	gold quality
caudate nucleus	UBERON:0001873	98.24	gold quality
ascending aorta	UBERON:0001496	98.23	gold quality
corpus striatum	UBERON:0000369	98.21	gold quality
nucleus accumbens	UBERON:0001882	98.12	gold quality
monocyte	CL:0000576	98.09	gold quality
adenohypophysis	UBERON:0002196	98.08	gold quality
endocervix	UBERON:0000458	97.96	gold quality
pituitary gland	UBERON:0000007	97.82	gold quality
aorta	UBERON:0000947	97.79	gold quality
prefrontal cortex	UBERON:0000451	97.78	gold quality
left ovary	UBERON:0002119	97.78	gold quality
left coronary artery	UBERON:0001626	97.77	gold quality
right ovary	UBERON:0002118	97.73	gold quality
right lung	UBERON:0002167	97.72	gold quality
granulocyte	CL:0000094	97.71	gold quality
body of pancreas	UBERON:0001150	97.70	gold quality
heart left ventricle	UBERON:0002084	97.68	gold quality
mononuclear cell	CL:0000842	97.66	gold quality
coronary artery	UBERON:0001621	97.65	gold quality
parotid gland	UBERON:0001831	97.63	gold quality
leukocyte	CL:0000738	97.61	gold quality
body of stomach	UBERON:0001161	97.59	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	111.43
E-MTAB-5061	yes	26.39
E-HCAD-31	yes	25.93
E-MTAB-9067	yes	14.29
E-HCAD-13	yes	11.97
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, CEBPB, CEBPG

miRNA regulators (miRDB)

234 targeting LRPAP1, 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-4673	100.00	66.64	1490
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-4267	99.96	66.53	2368

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 29)

• Adenoviral-mediated expression of human receptor-asociated protein RAP in a murine model of von Willebrand disease results in a continuous rise in FVIII over 6 days. (PMID:11992244)
• Allosteric modulation of ligand binding to low density lipoprotein receptor-related protein by the receptor-associated protein requires critical lysine residues within its carboxyl-terminal domain (PMID:12637503)
• RAP is organized into three domains located in the first third (1D), middle third (2D), and last third (3D) of the protein; all three domains adopt stable tertiary structure as isolated domains and are monomers. (PMID:14674767)
• NMR structure of domain 1 of receptor-associated protein (PMID:15213425)
• RAP binds to LPL with high affinity both in purified systems and cell extracts and RAP-deficient adipocytes secrete poorly assembled LPL (PMID:16517593)
• An insertion allele is found to be associated with gallstone disease. (PMID:16704534)
• RAP is expressed by thyrocytes in a TSH-dependent manner, both in cultured thyroid cells and in vivo (PMID:17123336)
• analysis of the relationship between ACE and LRPAP1 gene polymorphisms and age in an Italian population (PMID:17536759)
• Low-density lipoprotein receptor-related protein-associated protein (LRPAP1) gene IVS5 insertion/deletion polymorphism is not a risk factor for gallstone disease in a Polish population. (PMID:17913606)
• Low-density lipoprotein receptor-related protein associated protein (LRPAP1) insertion/deletion polymorphism is associated with gallstone disease and gallbladder carcinoma (PMID:17987404)
• LRP-1/LDLR-mediated uptake of A beta results in degeneration of perivascular cells. (PMID:18055545)
• alterations of the RAP gene are not a common cause of hypothyroidism (PMID:18075286)
• Our study suggests that LRPAP1-D and APOE E4 alleles significantly increase the susceptibility to degenerative dementias. (PMID:18721259)
• Findings reveal that RAP is a novel Abeta-binding protein that promotes cellular internalization of Abeta. (PMID:19826010)
• LRP1-C/T, A2M-Ile/Val and APOE-epsilon 2/epsilon 3/epsilon 4 polymorphisms are associated with AD. (PMID:20637261)
• Data indicate that the region of complement-type repeats 2-5 in LDLR was identified as the binding site for FVIII and for alpha-2-macroglobulin receptor-associated protein (RAP). (PMID:23754288)
• Mutations in LRPAP1 are associated with severe myopia in humans. (PMID:23830514)
• RAP inhibited light chain (LC)endocytosis by approximately 88% and ameliorated LC-induced cytokine responses and epithelial-to-mesenchymal transformation in human proximal tubular cells. (PMID:23894629)
• The LRPAP1 I allelic variant may be considered a candidate gene for PD, predominantly in patients having the APOE epsilon4 allelic variant. (PMID:24504617)
• The inhibition caused by reagents that prevented the activation of Rap was reversed by mobilizing intracellular calcium pharmacologically, whereas that caused by acrosome reaction inhibitors that impeded Rab3’s binding to GTP was not. (PMID:25159528)
• The clinical and biometric features we describe in this report characterize LRPAP1-related high myopia and should raise suspicion for mutations in the gene. (PMID:26271838)
• data also reveal that D1D2 is able to bind to a second distinct site on LRP1 to form a monovalent complex. The studies confirm the canonical model for ligand recognition by this class of receptors, which is initiated by pairs of lysine residues that dock into acidic pockets on the receptor (PMID:27402839)
• LRPAP1 can be used for a novel therapeutic approach that targets mantle cell lymphomas with LRPAP1-reactive BCRs with high specificity (PMID:29955130)
• Rhegmatogenous Retinal Detachment in Nonsyndromic High Myopia Associated with Recessive Mutations in LRPAP1. (PMID:31607522)
• Molecular chaperone RAP interacts with LRP1 in a dynamic bivalent mode and enhances folding of ligand-binding regions of other LDLR family receptors. (PMID:34058195)
• Identification of intracellular glycosaminoglycan-interacting proteins by affinity purification mass spectrometry. (PMID:34472763)
• The relationship of ADAMTSL2 and LRPAP1 gene methylation level with rheumatoid arthritis activity. (PMID:34936547)
• Lrpap1 (RAP) Inhibits Proximal Tubule Clathrin Mediated and Clathrin Independent Endocytosis, Ameliorating Renal Aminoglycoside Nephrotoxicity. (PMID:36848531)
• LRPAP1 is released from activated microglia and inhibits microglial phagocytosis and amyloid beta aggregation. (PMID:38035103)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrpap1	ENSDARG00000033604
mus_musculus	Lrpap1	ENSMUSG00000029103
rattus_norvegicus	Lrpap1	ENSRNOG00000009313
drosophila_melanogaster	CG8507	FBGN0037756
caenorhabditis_elegans		WBGENE00007606

Protein

Protein identifiers

Alpha-2-macroglobulin receptor-associated protein — P30533 (reviewed: P30533)

Alternative names: Low density lipoprotein receptor-related protein-associated protein 1

All UniProt accessions (3): A0A3B3IRQ7, D6REW6, P30533

UniProt curated annotations — full annotation on UniProt →

Function. Molecular chaperone for LDL receptor-related proteins that may regulate their ligand binding activity along the secretory pathway.

Subunit / interactions. Interacts with the LRP1/alpha-2-macroglobulin receptor heavy and light chains; the interaction is transient and coincides with a reduction of ligand binding by the receptor. Interacts with LRP2/glycoprotein 330. Interacts with LRP1B; binding is followed by internalization and degradation. Interacts with LDLR. Interacts with SORL1. Interacts with LRP1; this interaction is followed by rapid internalization.

Subcellular location. Rough endoplasmic reticulum lumen. Endoplasmic reticulum-Golgi intermediate compartment lumen. Golgi apparatus. cis-Golgi network. Golgi apparatus lumen. Endosome lumen. Cell surface.

Post-translational modifications. N-glycosylated.

Disease relevance. Myopia 23, autosomal recessive (MYP23) [MIM:615431] A refractive error of the eye, in which parallel rays from a distant object come to focus in front of the retina, vision being better for near objects than for far. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the alpha-2-MRAP family.

RefSeq proteins (1): NP_002328* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009066	MG_RAP_rcpt_1	Domain
IPR010483	Alpha_2_MRAP_C	Domain
IPR036744	RAP_sf	Homologous_superfamily
IPR037999	RAP_D3	Domain
IPR038001	RAP_D2	Domain
IPR038003	A2-macroglobuin_RAP	Family

Pfam: PF06400, PF06401

UniProt features (40 total): helix 9, mutagenesis site 8, strand 6, sequence conflict 3, modified residue 3, sequence variant 2, region of interest 2, signal peptide 1, chain 1, glycosylation site 1, turn 1, coiled-coil region 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
2FCW	X-RAY DIFFRACTION	1.26
9QAW	ELECTRON MICROSCOPY	3.34
1LRE	SOLUTION NMR
1NRE	SOLUTION NMR
1OP1	SOLUTION NMR
1OV2	SOLUTION NMR
2FTU	SOLUTION NMR
2FYL	SOLUTION NMR
2P01	SOLUTION NMR
2P03	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30533-F1	75.80	0.14

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 (3): 50, 135, 248

Glycosylation sites (1): 268

Mutagenesis-validated functional residues (8):

Position	Phenotype
283	strongly reduced interaction with lrp1; when associated with a-291; a-293; a-302; a-307 and a-341.
290	reduces competition with mapt for binding to lrp1; when associated with a-304.
291	strongly reduced interaction with lrp1; when associated with a-283; a-293; a-302; a-307 and a-341.
293	strongly reduced interaction with lrp1; when associated with a-283; a-291; a-302; a-307 and a-341.
302	strongly reduced interaction with lrp1; when associated with a-283; a-291; a-293; a-307 and a-341.
304	reduces competition with mapt for binding to lrp1; when associated with a-290.
307	strongly reduced interaction with lrp1; when associated with a-283; a-291; a-293; a-302 and a-341.
341	strongly reduced interaction with lrp1; when associated with a-283; a-291; a-293; a-302 and a-307.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 224 (showing top): STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOCC_CELL_SURFACE, GOBP_NEGATIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, FERREIRA_EWINGS_SARCOMA_UNSTABLE_VS_STABLE_DN, TERAMOTO_OPN_TARGETS_CLUSTER_4, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, GOBP_PLASMA_LIPOPROTEIN_PARTICLE_CLEARANCE, GOBP_REGULATION_OF_RECEPTOR_INTERNALIZATION, GOBP_REGULATION_OF_RECEPTOR_MEDIATED_ENDOCYTOSIS, GOBP_EXTRACELLULAR_REGULATION_OF_SIGNAL_TRANSDUCTION, SCHAEFFER_PROSTATE_DEVELOPMENT_AND_CANCER_BOX4_DN

GO Biological Process (8): negative regulation of receptor internalization (GO:0002091), signal transduction (GO:0007165), negative regulation of very-low-density lipoprotein particle clearance (GO:0010916), regulation of receptor-mediated endocytosis (GO:0048259), amyloid-beta clearance by transcytosis (GO:0150093), extracellular negative regulation of signal transduction (GO:1900116), negative regulation of amyloid-beta clearance (GO:1900222), positive regulation of amyloid-beta clearance (GO:1900223)

GO Molecular Function (9): amyloid-beta binding (GO:0001540), signaling receptor binding (GO:0005102), heparin binding (GO:0008201), lipase binding (GO:0035473), receptor ligand activity (GO:0048018), receptor antagonist activity (GO:0048019), low-density lipoprotein particle receptor binding (GO:0050750), very-low-density lipoprotein particle receptor binding (GO:0070326), protein binding (GO:0005515)

GO Cellular Component (13): extracellular region (GO:0005576), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), endoplasmic reticulum-Golgi intermediate compartment (GO:0005793), Golgi apparatus (GO:0005794), Golgi lumen (GO:0005796), cis-Golgi network (GO:0005801), plasma membrane (GO:0005886), cell surface (GO:0009986), endomembrane system (GO:0012505), endosome lumen (GO:0031904), rough endoplasmic reticulum lumen (GO:0048237), vesicle (GO:0031982)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	4
amyloid-beta clearance	3
cellular anatomical structure	3
endomembrane system	3
cytoplasm	3
regulation of amyloid-beta clearance	2
signaling receptor binding	2
lipoprotein particle receptor binding	2
Golgi apparatus	2
intracellular organelle lumen	2
regulation of receptor internalization	1
receptor internalization	1
negative regulation of receptor-mediated endocytosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
regulation of very-low-density lipoprotein particle clearance	1
negative regulation of lipoprotein particle clearance	1
very-low-density lipoprotein particle clearance	1
receptor-mediated endocytosis	1
regulation of endocytosis	1
transcytosis	1
extracellular region	1
negative regulation of signal transduction	1
extracellular regulation of signal transduction	1
negative regulation of multicellular organismal process	1
positive regulation of multicellular organismal process	1
peptide binding	1
protein binding	1
glycosaminoglycan binding	1
sulfur compound binding	1
enzyme binding	1
signal transduction	1
signaling receptor activator activity	1
signaling receptor inhibitor activity	1
binding	1
cytoplasmic vesicle	1
membrane	1

Protein interactions and networks

STRING

1286 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRPAP1	RALGDS	Q12967	996
LRPAP1	RAPGEF4	Q8WZA2	950
LRPAP1	RAPGEF3	O95398	901
LRPAP1	RALA	P11233	881
LRPAP1	LRP1	Q07954	868
LRPAP1	MYCBP2	O75592	850
LRPAP1	RAP1A	P10113	845
LRPAP1	RAP2A	P10114	832
LRPAP1	LRP2	P98164	827
LRPAP1	RAP1B	P09526	824
LRPAP1	RGS14	O43566	818
LRPAP1	RALGAPA1	Q6GYQ0	810
LRPAP1	RASIP1	Q5U651	783
LRPAP1	SLCO6A1	Q86UG4	777
LRPAP1	LRP3	O75074	733

IntAct

95 interactions, top by confidence:

A	B	Type	Score
SORT1	LRPAP1	psi-mi:“MI:0407”(direct interaction)	0.810
LRPAP1	LRP1	psi-mi:“MI:0407”(direct interaction)	0.810
LRP1	LRPAP1	psi-mi:“MI:0407”(direct interaction)	0.810
LRP1	LRPAP1	psi-mi:“MI:0915”(physical association)	0.810
LRPAP1	SORL1	psi-mi:“MI:0407”(direct interaction)	0.800
SORL1	LRPAP1	psi-mi:“MI:0915”(physical association)	0.800
VLDLR	LRPAP1	psi-mi:“MI:0915”(physical association)	0.770
LRPAP1	VLDLR	psi-mi:“MI:0407”(direct interaction)	0.770
LDLR	LRPAP1	psi-mi:“MI:0407”(direct interaction)	0.740
LRPAP1	LDLR	psi-mi:“MI:0407”(direct interaction)	0.740
SORL1	CNTFR	psi-mi:“MI:0915”(physical association)	0.670
SRPK1	SNRPC	psi-mi:“MI:0914”(association)	0.640
SORT1	CNTF	psi-mi:“MI:0915”(physical association)	0.570
LRPAP1	LRP8	psi-mi:“MI:0915”(physical association)	0.560
ASPH	LRPAP1	psi-mi:“MI:0915”(physical association)	0.560
LRPAP1	ASPH	psi-mi:“MI:0915”(physical association)	0.560
APP	LRPAP1	psi-mi:“MI:0915”(physical association)	0.560
SORT1	TG	psi-mi:“MI:0915”(physical association)	0.540
LRPAP1	LRP4	psi-mi:“MI:0914”(association)	0.530
CD4	CCDC85C	psi-mi:“MI:0914”(association)	0.530
IL1R2	EXOC5	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530

BioGRID (226): LRPAP1 (Proximity Label-MS), LRPAP1 (Proximity Label-MS), LRPAP1 (Reconstituted Complex), VLDLR (Affinity Capture-MS), LRP1B (Affinity Capture-MS), LRP4 (Affinity Capture-MS), SORL1 (Affinity Capture-MS), ROCK2 (Affinity Capture-MS), LDLR (Affinity Capture-MS), LRP8 (Affinity Capture-MS), LRP1 (Affinity Capture-MS), LRP2 (Affinity Capture-MS), LRPAP1 (Affinity Capture-MS), LRPAP1 (Affinity Capture-RNA), LRPAP1 (Affinity Capture-MS)

ESM2 similar proteins: A0PJT0, A4FV45, D3Z2R5, D3ZND0, G9G127, O14525, O70367, O73683, O75829, O77770, O93279, P05067, P08592, P12023, P15943, P17404, P30533, P51693, P53601, P55302, P79307, Q02818, Q02819, Q03157, Q06335, Q06481, Q0P569, Q16891, Q1JPG0, Q28F39, Q32KV6, Q5IS80, Q5M862, Q5R4U1, Q60495, Q61137, Q63083, Q6DFC2, Q6NVC9, Q7L4E1

Diamond homologs: P30533, P55302, Q99068

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PLK2	“up-regulates activity”	LRPAP1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	51
Likely benign	12
Benign	6

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1526247	NM_002337.4(LRPAP1):c.705_708del (p.Asp236fs)	Pathogenic
65460	NM_002337.4(LRPAP1):c.605del (p.Asn202fs)	Pathogenic

SpliceAI

2202 predictions. Top by Δscore:

Variant	Effect	Δscore
4:3512946:C:A	donor_gain	1.0000
4:3514705:T:TA	donor_gain	1.0000
4:3514747:CGCA:C	donor_loss	1.0000
4:3514748:GCAC:G	donor_loss	1.0000
4:3514749:CACCG:C	donor_loss	1.0000
4:3514750:A:AC	donor_gain	1.0000
4:3514750:A:AT	donor_loss	1.0000
4:3514751:C:CA	donor_loss	1.0000
4:3514751:C:CC	donor_gain	1.0000
4:3514796:T:TA	donor_gain	1.0000
4:3514924:TCCTC:T	acceptor_gain	1.0000
4:3514925:CCTCC:C	acceptor_gain	1.0000
4:3514926:CTC:C	acceptor_gain	1.0000
4:3514926:CTCCT:C	acceptor_loss	1.0000
4:3514927:TCCTG:T	acceptor_loss	1.0000
4:3514928:CCTGG:C	acceptor_loss	1.0000
4:3514929:C:CC	acceptor_gain	1.0000
4:3514929:C:CG	acceptor_loss	1.0000
4:3514930:T:C	acceptor_loss	1.0000
4:3516197:CT:C	acceptor_gain	1.0000
4:3516199:C:CC	acceptor_gain	1.0000
4:3518030:TCACC:T	donor_loss	1.0000
4:3518032:A:AC	donor_gain	1.0000
4:3518032:AC:A	donor_gain	1.0000
4:3518032:ACCA:A	donor_loss	1.0000
4:3518032:ACCAG:A	donor_gain	1.0000
4:3518033:C:CA	donor_gain	1.0000
4:3518033:CC:C	donor_gain	1.0000
4:3518033:CCA:C	donor_gain	1.0000
4:3518033:CCAG:C	donor_gain	1.0000

AlphaMissense

2348 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:3525008:A:G	L83P	0.998
4:3514921:A:G	L281P	0.996
4:3514921:A:T	L281H	0.995
4:3516167:C:A	W261C	0.995
4:3516167:C:G	W261C	0.995
4:3516171:A:G	L260P	0.995
4:3516194:G:C	F252L	0.995
4:3516194:G:T	F252L	0.995
4:3516196:A:G	F252L	0.995
4:3516195:A:C	F252C	0.994
4:3532251:G:C	F54L	0.994
4:3532251:G:T	F54L	0.994
4:3532253:A:G	F54L	0.994
4:3516169:A:G	W261R	0.993
4:3516169:A:T	W261R	0.993
4:3516159:G:T	A264E	0.992
4:3516195:A:G	F252S	0.991
4:3518971:G:C	F164L	0.991
4:3518971:G:T	F164L	0.991
4:3518973:A:G	F164L	0.991
4:3514893:C:A	K290N	0.990
4:3514893:C:G	K290N	0.990
4:3514912:A:G	F284S	0.990
4:3516160:C:G	A264P	0.989
4:3518991:C:G	A158P	0.989
4:3525020:A:G	L79P	0.988
4:3532252:A:C	F54C	0.988
4:3532252:A:G	F54S	0.988
4:3513014:A:G	L345P	0.987
4:3520078:C:A	W155C	0.987

dbSNP variants (sampled 300 via entrez): RS1000059294 (4:3523582 C>T), RS1000063787 (4:3531898 T>A,C), RS1000125586 (4:3532825 G>A,T), RS1000159556 (4:3523700 C>T), RS10001975 (4:3509042 G>A), RS10002108 (4:3509230 G>A,C,T), RS1000275763 (4:3527229 C>T), RS1000281552 (4:3527430 G>A), RS1000409349 (4:3531254 T>C), RS1000414533 (4:3512811 C>T), RS1000461747 (4:3531479 C>T), RS1000483431 (4:3506357 A>C), RS1000514460 (4:3519535 A>G), RS1000539653 (4:3532121 C>A,T), RS1000595663 (4:3515876 G>A)

Disease associations

OMIM: gene MIM:104225 | disease phenotypes: MIM:615431

GenCC curated gene-disease

Disease	Classification	Inheritance
myopia 23, autosomal recessive	Definitive	Autosomal recessive

Mondo (2): myopia 23, autosomal recessive (MONDO:0014183), prostate cancer (MONDO:0008315)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000505	Visual impairment
HP:0007663	Reduced visual acuity
HP:0007800	Increased axial length of the globe
HP:0011003	High myopia

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST002147_9	Fibrinogen	2.000000e-08
GCST002216_34	Triglycerides	2.000000e-12
GCST002221_21	Cholesterol, total	1.000000e-10
GCST002222_36	LDL cholesterol	2.000000e-08
GCST002896_35	Cholesterol, total	1.000000e-10
GCST002897_35	Triglycerides	1.000000e-10
GCST004233_28	LDL cholesterol levels	3.000000e-09
GCST004235_35	Total cholesterol levels	1.000000e-11
GCST004237_41	Triglyceride levels	3.000000e-15
GCST004923_3	Tuberculosis	3.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004574	total cholesterol measurement
EFO:0004611	low density lipoprotein cholesterol measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases expression, increases methylation	5
bisphenol F	increases expression, affects cotreatment, decreases expression	2
bisphenol A	decreases expression, affects cotreatment, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	2
Doxorubicin	increases expression	2
Lead	decreases expression, increases expression	2
Tretinoin	affects cotreatment, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
lead acetate	affects cotreatment, increases expression	1
potassium perchlorate	increases expression	1
chromous chloride	affects cotreatment, increases expression	1
sodium arsenite	affects cotreatment, increases expression	1
chromic oxide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Arsenic Trioxide	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Ethanol	affects cotreatment, increases abundance, increases expression	1
Asbestos	affects expression	1
Carbamazepine	affects expression	1
Dexamethasone	affects cotreatment, increases expression, decreases expression	1
Diethylstilbestrol	decreases expression	1
Diuron	decreases expression	1
Ethyl Methanesulfonate	increases expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C0CX	WAe009-A-L	Embryonic stem cell	Female
CVCL_E2BF	HAP1 LRPAP1 (-) 1	Cancer cell line	Male
CVCL_E2BG	HAP1 LRPAP1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer