ABCG5

Summary

ABCG5 (ATP binding cassette subfamily G member 5, HGNC:13886) is a protein-coding gene on chromosome 2p21, encoding ATP-binding cassette sub-family G member 5 (Q9H222). ABCG5 and ABCG8 form an obligate heterodimer that mediates Mg(2+)- and ATP-dependent sterol transport across the cell membrane.

The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the White subfamily. The protein encoded by this gene functions as a half-transporter to limit intestinal absorption and promote biliary excretion of sterols. It is expressed in a tissue-specific manner in the liver, colon, and intestine. This gene is tandemly arrayed on chromosome 2, in a head-to-head orientation with family member ABCG8. Mutations in this gene may contribute to sterol accumulation and atheroschlerosis, and have been observed in patients with sitosterolemia.

Source: NCBI Gene 64240 — RefSeq curated summary.

At a glance

• Gene–disease (curated): sitosterolemia (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 12
• Clinical variants (ClinVar): 912 total — 46 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 43
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_022436

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13886
Approved symbol	ABCG5
Name	ATP binding cassette subfamily G member 5
Location	2p21
Locus type	gene with protein product
Status	Approved
Aliases	STSL
Ensembl gene	ENSG00000138075
Ensembl biotype	protein_coding
OMIM	605459
Entrez	64240

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 3 retained_intron

ENST00000405322, ENST00000409962, ENST00000486512, ENST00000644754, ENST00000882114, ENST00000882115, ENST00000882116, ENST00000882117

RefSeq mRNA: 1 — MANE Select: NM_022436 NM_022436

CCDS: CCDS1814

Canonical transcript exons

ENST00000405322 — 13 exons

Exon	Start	End
ENSE00000962648	43837834	43837955
ENSE00000962652	43826382	43826521
ENSE00000962653	43824889	43825018
ENSE00000962654	43824219	43824432
ENSE00001663763	43827983	43828115
ENSE00003466144	43814477	43814589
ENSE00003496657	43822797	43822935
ENSE00003508665	43819915	43820100
ENSE00003561583	43812472	43813309
ENSE00003571418	43831947	43832083
ENSE00003572351	43831769	43831867
ENSE00003597517	43823913	43824118
ENSE00003822295	43838537	43838839

Expression profiles

Bgee: expression breadth broad, 61 present calls, max score 98.68.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3023 / max 120.8763, expressed in 17 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28102	0.1086	14
28105	0.0859	14
28104	0.0410	11
28106	0.0297	11
28103	0.0248	10
28107	0.0122	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	98.68	gold quality
right lobe of liver	UBERON:0001114	95.84	gold quality
duodenum	UBERON:0002114	93.92	gold quality
liver	UBERON:0002107	93.81	gold quality
ileal mucosa	UBERON:0000331	79.08	gold quality
jejunum	UBERON:0002115	75.81	gold quality
small intestine	UBERON:0002108	64.19	gold quality
gall bladder	UBERON:0002110	64.14	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	60.43	gold quality
small intestine Peyer’s patch	UBERON:0003454	59.02	gold quality
oocyte	CL:0000023	58.14	gold quality
Brodmann (1909) area 46	UBERON:0006483	55.91	gold quality
buccal mucosa cell	CL:0002336	52.05	gold quality
prefrontal cortex	UBERON:0000451	51.82	gold quality
deltoid	UBERON:0001476	49.72	gold quality
cerebellar vermis	UBERON:0004720	49.62	gold quality
epithelial cell of pancreas	CL:0000083	49.56	gold quality
quadriceps femoris	UBERON:0001377	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
Brodmann (1909) area 9	UBERON:0013540	48.59	gold quality
vastus lateralis	UBERON:0001379	48.58	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.05

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF4A, NR1H2, NR1H3, NR1H4, NR5A2, SREBF2

miRNA regulators (miRDB)

35 targeting ABCG5, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-4774-3P	98.90	67.82	737
HSA-MIR-6889-3P	98.84	67.35	1198
HSA-MIR-942-3P	98.81	69.04	876
HSA-MIR-500A-5P	98.76	69.13	1241
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-6529-3P	98.68	66.76	1020
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-4704-3P	98.28	69.33	1300
HSA-MIR-6773-3P	98.17	65.51	1213
HSA-MIR-4294	97.86	65.72	1110
HSA-MIR-3198	97.84	65.64	579
HSA-MIR-4309	97.84	65.45	588
HSA-MIR-924	97.78	66.21	681
HSA-MIR-4639-3P	97.54	67.12	787

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• mutations in ATP-binding cassette proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia (PMID:11668628)
• New mutations - R419H and IVS12+1G –>A. (Latter is splice site mutation.) (PMID:11855938)
• In a sitosterolemia patient a novel heterozygous mutation has been found in exon 8 of the ABCG5 gene leading to a premature termination of the protein (Arg408Ter). (PMID:12124998)
• several potential regulatory elements were found for the ABCG5 and ABCG8 genes, and the intergenic region was found to act as a bidirectional promoter (PMID:12150943)
• Role of ABCG5 and ABCG8 in cholesterol secretion and absorption (PMID:12208868)
• ABCG5 and ABCG8 function as obligate heterodimers to promote sterol excretion into bile (PMID:14504269)
• in patients with hypercholesterolemia, the ABCG8 D19H variant is associated with greater LDLC-lowering response to atorvastatin therapy (PMID:14703505)
• LRH-1 is a positive transcription factor for ABCG5 and ABCG8 and, in conjunction with studies on LRH-1 activation of other promoters, identify LRH-1 as a “master regulator” for genes involved in sterol and bile acid secretion from liver and intestine (PMID:15121760)
• ABCGG5 and ABCG8 are required to modulate biliary cholesterol secretion in response to cholate and diosgenin. (PMID:15611112)
• MDR2 expression is required for ABCG5- and ABCG8-mediated biliary sterol secretion. Inactivation of MDR2 markedly attenuated the reduction in fractional sterol absorption associated with ABCG5, ABCG8 overexpression (PMID:15930516)
• Strong relationship between ABCG5 and ABCG8 gene expression is consistent with the coordinate regulation of both genes and in line with heterodimerization of both proteins into a functional transporter. (PMID:16250035)
• Two genes, ABCG5 and ABCG8, compose the sitosterolemia locus, and complete mutation in either, but not both, results in disease. (PMID:16472606)
• In diabetic patients statin therapy is associated wiwth increased mRNA. (PMID:16518588)
• ABCG5 polymorphism may play a role in the plasma response to dietary cholesterol and carotenoids. (PMID:16614398)
• Purified ABCG5 and ABCG8 had very low ATPase activities, suggesting that the hetero-dimer is the catalytically active species, and likely the active species in vivo. (PMID:16893193)
• Polymorphisms at the half-transporter ABCG5 and ABCG8 genes affect blood cholesterol concentrations in prepubertal children by influencing dietary responsiveness. (PMID:16980816)
• biochemical and functional characterization of the ABCG5/ABCG8 proteins and their possible involvement in steroid hormone transport or regulation. (PMID:17055487)
• Increased NPC1L1 and lower ABCG5 abd ABCG8 may lead to increased cholesterol and sitosterol in chylomicron particles in diabetic patients. (PMID:17102949)
• Cooperative interaction between HNF4A and GATA4 and GATA6 regulates ABCG5 and ABCG8. (PMID:17403900)
• results indicate that ABCG5/G8, unlike ABCA1, together with bile acids should participate in sterol efflux on the apical surface of Caco-2 cells. (PMID:17690481)
• changes in cholesterol metabolism after weight loss were affected by single nucleotide polymorphisms (SNPs) in ABCG5 (PMID:17827468)
• Upregulation of ABCG5/ABCG8 in gallstone patients, possibly mediated by increased liver X receptor (LXR) alpha, may contribute to the cholesterol supersaturation of bile, a prerequisite for gallstone formation. (PMID:18007013)
• Carriers of ABCG5 604Q or ABCG8 D19H polymorphisms have an increased risk of gallstone disease independent of age, sex and body mass index. (PMID:18457353)
• links between polymorphisms of ABC G5 (ABCG5) transporter gene to hypercholesterolemia and to gallstone disease risk (Review) (PMID:18522623)
• No common polymorphisms in ABCG8, ABCG5, or NPC1L1 were demonstrated between the 3 top responders and the non-respondersto plant sterol intervention. (PMID:18641716)
• Results describe the association between ABCG5/G8 and NPC1L1 genotype single nucleotide polymorphisms with sterol absorption and corresponding plasma concentrations. (PMID:18850127)
• ABCG5/G8 genetic variants modulate HDL-C concentrations, leading to an HDL-C-lowering effect and thereby a potential increased risk for atherosclerosis only in smokers. (PMID:19005228)
• In Chilean patients, the ABCG5 1950C>G polymorphism, but not the ABCG8 251A>G polymorphism, was found to be associated with hypercholesterolemia. (PMID:19012522)
• Most Asian phytosterolemia patients possess mutations in the ABCG5 gene. The site of the novel mutation was completely different from previous reports. No other mutation was found in the ABCG5 and ABCG8 genes. (PMID:19111681)
• To examine the molecular mechanisms of the regulated trafficking of ABCG5 and ABCG8, the subcellular localizations of chimeric proteins, fused with ABCG1 or ABCG2, were analyzed. (PMID:19270375)
• Insulin resistance elevates ABCG5 and increases susceptibility to cholesterol gallstones (PMID:19306529)
• The effects of ABCG5/G8 polymorphisms on HDL-cholesterol concentrations depend on ABCA1 genetic variants. (PMID:19692220)
• ABCG5/G8 polymorphisms are not associated with reduction of serum lipids by soy or dietary fiber in hyperlipidemic Mexican subjects (PMID:19917453)
• an ABCG5-G8 haplotype, which included the rs6544718 T allele, was associated with higher HDLcholesterol plasma concentrations in women. (PMID:20170916)
• Genetic variations at ABCG5/G8 genes modulate plasma lipids concentrations in patients with familial hypercholesterolemia (PMID:20172523)
• Bile acids may promote an active conformation of purified ABCG5/G8 either by global stabilization of the transporter or by binding to a specific site on ABCG5/G8. (PMID:20210363)
• five Chinese children from four separate families presented with sitosterolemia in whom we identified two new (Y329X, G269R) and three known (R446X, N437K, R389H) mutations in the ABCG5 gene (PMID:20521169)
• A systematic review and meta-analysis of ABCG5 polymorphisms and association with markers of cholesterol metabolism. (PMID:20581104)
• The associations of four ABCG5/G8 single nucleotide polymorphisms and serum lipid levels are different between the Mulao and Han populations in China, or between males and females. (PMID:22655090)
• ABCG5-R50C variant associated with cholesterol gallstone disease (PMID:22898925)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	abcg5	ENSDARG00000063078
mus_musculus	Abcg5	ENSMUSG00000040505
rattus_norvegicus	Abcg5	ENSRNOG00000005250
drosophila_melanogaster	CG11069	FBGN0039244
caenorhabditis_elegans		WBGENE00016973

Paralogs (4): ABCG2 (ENSG00000118777), ABCG8 (ENSG00000143921), ABCG1 (ENSG00000160179), ABCG4 (ENSG00000172350)

Protein

Protein identifiers

ATP-binding cassette sub-family G member 5 — Q9H222 (reviewed: Q9H222)

Alternative names: Sterolin-1

All UniProt accessions (1): Q9H222

UniProt curated annotations — full annotation on UniProt →

Function. ABCG5 and ABCG8 form an obligate heterodimer that mediates Mg(2+)- and ATP-dependent sterol transport across the cell membrane. Plays an essential role in the selective transport of dietary plant sterols and cholesterol in and out of the enterocytes and in the selective sterol excretion by the liver into bile. Required for normal sterol homeostasis. The heterodimer with ABCG8 has ATPase activity.

Subunit / interactions. Heterodimer with ABCG8.

Subcellular location. Cell membrane. Apical cell membrane.

Tissue specificity. Strongly expressed in the liver, lower levels in the small intestine and colon.

Post-translational modifications. N-glycosylated.

Disease relevance. Sitosterolemia 2 (STSL2) [MIM:618666] A form of sitosterolemia, an autosomal recessive metabolic disorder characterized by unregulated intestinal absorption of cholesterol, phytosterols and shellfish sterols, and decreased biliary excretion of dietary sterols into bile. Patients have hypercholesterolemia, very high levels of plant sterols in the plasma, and frequently develop tendon and tuberous xanthomas, accelerated atherosclerosis and premature coronary artery disease. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The ATPase activity of the heterodimer is stimulated by cholate. Taurocholate, glycocholate, taurochenodeoxycholate, glycochenodeoxycholate and taurodeoxycholate also stimulate ATPase activity, but to a lower degree. Glycodeoxycholate has no significant effect on ATPase activity. ATPase activity is inhibited by vanadate and by berillium fluoride.

Domain organisation. The Walker motif (consensus sequence G-X-X-G-X-G-K-[ST]-T) is expected to bind ATP. Within this motif, the conserved Lys is essential for transport activity mediated by the heterodimer with ABCG8.

Similarity. Belongs to the ABC transporter superfamily. ABCG family. Eye pigment precursor importer (TC 3.A.1.204) subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H222-1	1	yes
Q9H222-2	2

RefSeq proteins (1): NP_071881* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003439	ABC_transporter-like_ATP-bd	Domain
IPR003593	AAA+_ATPase	Domain
IPR013525	ABC2_TM	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR043926	ABCG_dom	Domain
IPR050352	ABCG_transporters	Family

Pfam: PF00005, PF01061, PF19055

Catalyzed reactions (Rhea), 2 shown:

• cholesterol(in) + ATP + H2O = cholesterol(out) + ADP + phosphate + H(+) (RHEA:39051)
• sitosterol(in) + ATP + H2O = sitosterol(out) + ADP + phosphate + H(+) (RHEA:39103)

UniProt features (84 total): helix 24, strand 15, sequence variant 13, turn 8, topological domain 7, transmembrane region 6, mutagenesis site 3, domain 2, glycosylation site 2, chain 1, region of interest 1, binding site 1, splice variant 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
7R89	ELECTRON MICROSCOPY	2.6
7R8A	ELECTRON MICROSCOPY	2.9
7R8B	ELECTRON MICROSCOPY	3.1
7JR7	ELECTRON MICROSCOPY	3.3
7R87	ELECTRON MICROSCOPY	3.4
7R88	ELECTRON MICROSCOPY	3.5
5DO7	X-RAY DIFFRACTION	3.93
8CUB	X-RAY DIFFRACTION	4.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H222-F1	85.48	0.58

Antibody-complex structures (SAbDab): 6 — 7JR7, 7R87, 7R88, 7R89, 7R8A, 7R8B

Functional residue map

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

Ligand- & substrate-binding residues (1): 86–93

Glycosylation sites (2): 584, 591

Mutagenesis-validated functional residues (3):

Position	Phenotype
92–93	abolishes increase of the very low basal atpase activity by cholate.
432	strongly decreases cholesterol secretion into bile.
540	strongly decreases cholesterol secretion into bile.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-1369062	ABC transporters in lipid homeostasis
R-HSA-5679090	Defective ABCG8 causes GBD4 and sitosterolemia
R-HSA-5679096	Defective ABCG5 causes sitosterolemia
R-HSA-9029569	NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-382551	Transport of small molecules
R-HSA-382556	ABC-family protein mediated transport
R-HSA-5619084	ABC transporter disorders
R-HSA-5619115	Disorders of transmembrane transporters
R-HSA-9006931	Signaling by Nuclear Receptors
R-HSA-9024446	NR1H2 and NR1H3-mediated signaling

MSigDB gene sets: 220 (showing top): GOBP_ACYLGLYCEROL_HOMEOSTASIS, GOBP_DIGESTION, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_STEROL_HOMEOSTASIS, GOBP_LIPID_DIGESTION, KEGG_ABC_TRANSPORTERS, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GOBP_LIPID_HOMEOSTASIS, GOBP_CHOLESTEROL_EFFLUX, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GATA3_01, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, MARTIN_VIRAL_GPCR_SIGNALING_UP, GOBP_RESPONSE_TO_RADIATION, GOBP_DIGESTIVE_SYSTEM_PROCESS

GO Biological Process (14): response to nutrient (GO:0007584), response to xenobiotic stimulus (GO:0009410), response to ionizing radiation (GO:0010212), negative regulation of intestinal phytosterol absorption (GO:0010949), response to muscle activity (GO:0014850), sterol transport (GO:0015918), intestinal cholesterol absorption (GO:0030299), cholesterol efflux (GO:0033344), cholesterol homeostasis (GO:0042632), negative regulation of intestinal cholesterol absorption (GO:0045796), transmembrane transport (GO:0055085), triglyceride homeostasis (GO:0070328), lipid transport (GO:0006869), response to nutrient levels (GO:0031667)

GO Molecular Function (10): ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), ATPase-coupled transmembrane transporter activity (GO:0042626), metal ion binding (GO:0046872), protein heterodimerization activity (GO:0046982), cholesterol transfer activity (GO:0120020), ABC-type transporter activity (GO:0140359), nucleotide binding (GO:0000166), protein binding (GO:0005515), protein dimerization activity (GO:0046983)

GO Cellular Component (6): plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), ATP-binding cassette (ABC) transporter complex (GO:0043190), signaling receptor complex (GO:0043235), membrane (GO:0016020), apical part of cell (GO:0045177)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
ABC transporter disorders	2
ABC-family protein mediated transport	1
NR1H2 and NR1H3-mediated signaling	1
Transport of small molecules	1
Disorders of transmembrane transporters	1
Disease	1
Signal Transduction	1
Signaling by Nuclear Receptors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to chemical	2
negative regulation of intestinal lipid absorption	2
transport	2
ATP-dependent activity	2
cellular anatomical structure	2
response to nutrient levels	1
response to radiation	1
intestinal phytosterol absorption	1
response to activity	1
lipid transport	1
organic hydroxy compound transport	1
lipid digestion	1
intestinal lipid absorption	1
cholesterol transport	1
sterol homeostasis	1
intestinal cholesterol absorption	1
regulation of intestinal cholesterol absorption	1
cellular process	1
acylglycerol homeostasis	1
lipid localization	1
response to stimulus	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
primary active transmembrane transporter activity	1
ATP hydrolysis activity	1
cation binding	1
protein dimerization activity	1
cholesterol binding	1
sterol transfer activity	1
ATPase-coupled transmembrane transporter activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
protein binding	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
ATPase dependent transmembrane transport complex	1

Protein interactions and networks

STRING

1985 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ABCG5	ABCG8	Q9H221	988
ABCG5	SREBF2	Q12772	920
ABCG5	XPR1	Q9UBH6	918
ABCG5	CYP7A1	P22680	887
ABCG5	NPC1L1	Q9UHC9	886
ABCG5	NR1H3	Q13133	847
ABCG5	NR1H4	Q96RI1	841
ABCG5	NR1H2	P55055	822
ABCG5	CYP7B1	O75881	810
ABCG5	SREBF1	P36956	798
ABCG5	HMGCR	P04035	744
ABCG5	APOB	P04114	707
ABCG5	SCARB1	Q8WTV0	707
ABCG5	CYP8B1	Q9UNU6	679
ABCG5	LDLRAP1	Q5SW96	679

IntAct

8 interactions, top by confidence:

A	B	Type	Score
ABCG5	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
NCK1	ABCG5	psi-mi:“MI:0915”(physical association)	0.400
ABCG5	PIK3R1	psi-mi:“MI:0915”(physical association)	0.400
ABCG1	ABCG5	psi-mi:“MI:0915”(physical association)	0.400
ABCG5	ABCG8	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (3): ABCG5 (Positive Genetic), ABCG8 (Affinity Capture-Western), ABCG5 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A0G2K1Q8, B2RX12, E9PU17, E9PX95, F1MWM0, O00329, O15438, O35600, O75899, O88563, O88871, O94911, O95477, P41233, P55205, P58428, P78363, Q09427, Q09428, Q09429, Q2NKY8, Q5BJS0, Q5R607, Q5ZI74, Q6TL19, Q7L2E3, Q7TNJ2, Q80T41, Q84M24, Q8CF82, Q8IUA7, Q8K440, Q8K441, Q8K442, Q8K448, Q8K449, Q8LPK0, Q8N139, Q8NCL4, Q8R420

Diamond homologs: A0A059J0G5, A0A0M3R8G1, A0A0M4FLW6, A0A1L9WQK0, A0A1U8QKX8, A0A1U8QT10, A0A1V0QSE4, A0A1V1GB10, A0A1Y0BRF0, A0A2H1A768, A0A2U8U2K9, A0A481WQK1, A0A4P8GG95, A0A8K1AW53, A1C8C8, A1CFM0, A9YWR6, B6HV31, B6RAL1, B8NDS8, B9G5Y5, D3GE74, D4AYW0, E9RBG1, F2PLH2, F2RSQ6, F2SG60, F2SHL1, G3JF11, I1RL06, J9VME1, J9VPA2, M2UCE5, O42690, O65934, O74208, O74676, P25371, P32568, P33302

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SREBF2	“down-regulates quantity by repression”	ABCG5	“transcriptional regulation”
HNF4A	“down-regulates quantity by repression”	ABCG5	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	46
Likely pathogenic	26
Uncertain significance	441
Likely benign	266
Benign	39

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1120119	NM_022436.3(ABCG5):c.751C>T (p.Gln251Ter)	Pathogenic
1328058	NM_022436.3(ABCG5):c.774+1G>T	Pathogenic
1437547	NM_022436.3(ABCG5):c.1138del (p.Leu379_Val380insTer)	Pathogenic
1514001	NC_000002.11:g.(?44040255)(44041748_?)del	Pathogenic
155615	GRCh38/hg38 2p25.3-21(chr2:236816-45983232)x3	Pathogenic
1704642	NM_022436.3(ABCG5):c.64C>T (p.Gln22Ter)	Pathogenic
1771014	NM_022436.3(ABCG5):c.136del (p.Ser46fs)	Pathogenic
1907244	NM_022436.3(ABCG5):c.1657C>T (p.Gln553Ter)	Pathogenic
2023964	NM_022436.3(ABCG5):c.1573C>T (p.Gln525Ter)	Pathogenic
2111434	NM_022436.3(ABCG5):c.1681dup (p.Ile561fs)	Pathogenic
212767	NM_016008.4(DYNC2LI1):c.1000G>T (p.Glu334Ter)	Pathogenic
2203052	NM_022436.3(ABCG5):c.1528del (p.His510fs)	Pathogenic
2203054	NM_022436.3(ABCG5):c.1311C>G (p.Asn437Lys)	Pathogenic
2616584	NM_022436.3(ABCG5):c.335dup (p.Val113fs)	Pathogenic
2722141	NM_022436.3(ABCG5):c.1763-1G>A	Pathogenic
2740333	NM_022436.3(ABCG5):c.367G>T (p.Glu123Ter)	Pathogenic
2889432	NM_022436.3(ABCG5):c.1273C>T (p.Gln425Ter)	Pathogenic
2903014	NM_022436.3(ABCG5):c.1528dup (p.His510fs)	Pathogenic
2989355	NM_022437.3(ABCG8):c.52C>T (p.Gln18Ter)	Pathogenic
30484	NM_022436.3(ABCG5):c.46C>T (p.Gln16Ter)	Pathogenic
3247168	NC_000002.11:g.(?44065656)(44105052_?)del	Pathogenic
3247230	NC_000002.11:g.(?44001278)(45236249_?)del	Pathogenic
3627815	NM_022436.3(ABCG5):c.1735G>T (p.Glu579Ter)	Pathogenic
3671907	NM_022436.3(ABCG5):c.145del (p.His49fs)	Pathogenic
3715753	NM_022436.3(ABCG5):c.187C>T (p.Gln63Ter)	Pathogenic
3720320	NM_022436.3(ABCG5):c.436G>T (p.Glu146Ter)	Pathogenic
3720321	NM_022436.3(ABCG5):c.144-1G>A	Pathogenic
3886530	NM_022436.3(ABCG5):c.1489_1501del (p.Ala497fs)	Pathogenic
3992479	NM_022436.3(ABCG5):c.321del (p.Thr108fs)	Pathogenic
402127	GRCh37/hg19 2p23.3-16.1(chr2:27861707-60790985)x3	Pathogenic

SpliceAI

1866 predictions. Top by Δscore:

Variant	Effect	Δscore
2:43814591:T:C	acceptor_gain	1.0000
2:43822808:A:AC	donor_gain	1.0000
2:43822809:C:CC	donor_gain	1.0000
2:43822809:CTG:C	donor_gain	1.0000
2:43822936:C:CC	acceptor_gain	1.0000
2:43823911:A:AC	donor_gain	1.0000
2:43823912:C:CC	donor_gain	1.0000
2:43823912:CA:C	donor_gain	1.0000
2:43824887:A:AC	donor_gain	1.0000
2:43824888:C:CC	donor_gain	1.0000
2:43824888:CTA:C	donor_gain	1.0000
2:43825024:C:CT	acceptor_gain	1.0000
2:43827976:CACTT:C	donor_loss	1.0000
2:43827977:ACTTA:A	donor_loss	1.0000
2:43827979:TTAC:T	donor_loss	1.0000
2:43827980:TACTA:T	donor_loss	1.0000
2:43827981:A:AC	donor_gain	1.0000
2:43827981:A:T	donor_loss	1.0000
2:43827982:C:CT	donor_gain	1.0000
2:43827982:CT:C	donor_gain	1.0000
2:43827982:CTA:C	donor_gain	1.0000
2:43827982:CTAGG:C	donor_gain	1.0000
2:43828112:CCAC:C	acceptor_gain	1.0000
2:43828113:CAC:C	acceptor_gain	1.0000
2:43828113:CACC:C	acceptor_gain	1.0000
2:43828115:CCTG:C	acceptor_loss	1.0000
2:43828116:CTG:C	acceptor_loss	1.0000
2:43828117:T:C	acceptor_loss	1.0000
2:43829823:TGTGG:T	donor_gain	1.0000
2:43831764:CCCA:C	donor_loss	1.0000

AlphaMissense

4253 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:43832074:T:A	K92I	0.994
2:43822811:G:C	S483R	0.992
2:43822811:G:T	S483R	0.992
2:43822813:T:G	S483R	0.992
2:43822835:G:C	S475R	0.991
2:43822835:G:T	S475R	0.991
2:43822837:T:G	S475R	0.991
2:43828018:C:G	R200P	0.990
2:43826474:C:G	A228P	0.986
2:43828006:G:T	A204E	0.986
2:43832071:G:A	T93I	0.986
2:43824974:G:C	F273L	0.985
2:43824974:G:T	F273L	0.985
2:43824976:A:G	F273L	0.985
2:43828021:C:G	R199P	0.985
2:43820026:C:T	G513D	0.983
2:43823925:C:G	A438P	0.983
2:43823937:C:G	G434R	0.983
2:43828015:A:T	V201D	0.983
2:43823981:C:G	R419P	0.982
2:43820027:C:G	G513R	0.981
2:43823936:C:T	G434D	0.980
2:43831833:T:A	E146V	0.979
2:43826408:G:C	H250D	0.978
2:43828087:A:G	L177P	0.978
2:43827997:A:G	L207P	0.977
2:43828007:C:G	A204P	0.977
2:43826500:G:C	P219R	0.976
2:43826488:A:G	L223P	0.975
2:43832073:T:A	K92N	0.975

dbSNP variants (sampled 300 via entrez): RS1000012088 (2:43828830 G>A), RS1000300619 (2:43833877 T>G), RS1000316499 (2:43810315 C>T), RS1000371294 (2:43829195 A>G), RS1000372087 (2:43818951 G>A), RS1000532803 (2:43807997 G>A), RS1000554858 (2:43808988 C>A), RS1000572273 (2:43823637 A>G), RS1000805277 (2:43839273 G>A), RS1000953240 (2:43813556 C>T), RS1000961814 (2:43819160 G>C), RS1001051249 (2:43809138 C>T), RS1001057408 (2:43813996 G>A), RS1001109925 (2:43814154 A>G), RS1001173239 (2:43838550 A>C)

Disease associations

OMIM: gene MIM:605459 | disease phenotypes: MIM:210250, MIM:215250, MIM:618666, MIM:208500, MIM:617088, MIM:617056, MIM:157170, MIM:611465

GenCC curated gene-disease

Disease	Classification	Inheritance
sitosterolemia 1	Definitive	Autosomal recessive
sitosterolemia 2	Definitive	Autosomal recessive
sitosterolemia	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
sitosterolemia	Definitive	AR

Mondo (11): sitosterolemia (MONDO:0008863), sitosterolemia 2 (MONDO:0020748), sitosterolemia 1 (MONDO:0020747), asphyxiating thoracic dystrophy 1 (MONDO:0008831), short-rib thoracic dysplasia 15 with polydactyly (MONDO:0014907), thrombocytopenia (MONDO:0002049), hyperuricemic nephropathy, familial juvenile type 4 (MONDO:0014891), holoprosencephaly 2 (MONDO:0007999), gallstones (MONDO:0005346), gallbladder disease 4 (MONDO:1010151), familial hemolytic anemia (MONDO:0003689)

Orphanet (4): Sitosterolemia (Orphanet:2882), Jeune syndrome (Orphanet:474), Holoprosencephaly (Orphanet:2162), Mediterranean macrothrombocytopenia (Orphanet:101022)

HPO phenotypes

43 total (30 of 43 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:0001650	Aortic valve stenosis
HP:0001653	Mitral regurgitation
HP:0001658	Myocardial infarction
HP:0001677	Coronary artery atherosclerosis
HP:0001681	Angina pectoris
HP:0001744	Splenomegaly
HP:0001878	Hemolytic anemia
HP:0001902	Giant platelets
HP:0001920	Renal artery stenosis
HP:0002094	Dyspnea
HP:0002829	Arthralgia
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003077	Hyperlipidemia
HP:0003124	Hypercholesterolemia
HP:0003141	Increased LDL cholesterol concentration
HP:0004381	Supravalvular aortic stenosis
HP:0004416	Precocious atherosclerosis
HP:0004446	Stomatocytosis
HP:0004950	Peripheral arterial stenosis
HP:0004963	Calcification of the aorta
HP:0005059	Arthralgia/arthritis
HP:0005162	Abnormal left ventricular function
HP:0005177	Premature arteriosclerosis

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST000282_10	LDL cholesterol	3.000000e-10
GCST000285_10	Cholesterol, total	2.000000e-11
GCST000533_53	Lipid metabolism phenotypes	2.000000e-08
GCST000759_27	LDL cholesterol	2.000000e-47
GCST000760_6	Cholesterol, total	4.000000e-45
GCST002221_5	Cholesterol, total	3.000000e-73
GCST002222_12	LDL cholesterol	4.000000e-72
GCST003678_13	C-reactive protein levels or total cholesterol levels (pleiotropy)	4.000000e-09
GCST004787_46	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	6.000000e-10
GCST005194_42	Coronary artery disease	5.000000e-17
GCST005195_129	Coronary artery disease	2.000000e-18
GCST005196_202	Coronary artery disease	6.000000e-19

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004529	lipid measurement
EFO:0004458	C-reactive protein measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D000745	Anemia, Hemolytic, Congenital	C15.378.050.141.150; C16.320.070
D042882	Gallstones	C06.130.409.633; C06.130.564.332.500; C23.300.175.525
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
C563579	Holoprosencephaly 2 (supp.)
C537345	Sitosterolemia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11887534	ABCG5, ABCG8	3	0.25	1	atorvastatin
rs6720173	ABCG5, DYNC2LI1		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — ABCG subfamily

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression, affects cotreatment	4
Acetaminophen	decreases expression, affects cotreatment	3
Chenodeoxycholic Acid	affects cotreatment, decreases expression, increases expression	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
pregna-4,17-diene-3,16-dione	decreases expression, decreases reaction, increases expression	2
perfluorooctane sulfonic acid	decreases expression	2
tebuconazole	decreases expression	2
alisol B 23-acetate	decreases reaction, increases expression	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Deoxycholic Acid	increases expression, affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Valproic Acid	decreases expression	2
7-ketocholesterol	affects cotreatment, decreases expression	1
methyleugenol	decreases expression	1
propionaldehyde	decreases expression	1
potassium perchlorate	increases expression	1
3-DOXYLANDROSTANOL	affects binding, increases activity	1
sulforaphane	decreases expression	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	decreases expression	1
propiconazole	decreases expression	1
nefazodone	affects cotreatment, decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
GW 4064	decreases reaction, increases expression, decreases expression	1
2,4,6-trimethyl-N-((3’-(methylsulfonyl)-4-biphenylyl)methyl)-N-((5-(trifluoromethyl)-2-furanyl)methyl)benzenesulfonamide	decreases reaction, increases expression	1
Dasatinib	decreases reaction, increases expression, increases phosphorylation	1
Atazanavir Sulfate	affects cotreatment, decreases expression	1
Temozolomide	affects response to substance	1
Bosentan	affects expression	1
Leflunomide	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT01822262	PHASE4	UNKNOWN	Contrastive Study for Minimally Invasive Cholecystolithotomy With Gallbladder Reservation and Laparoscopic Cholecystectomy
NCT02472509	PHASE4	TERMINATED	The Role of Ursodeoxycholic Acid in Treatment of Gallstones in Hemolytic Disorders
NCT00037791	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00039910	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00073580	PHASE3	COMPLETED	Angiomax in Patients With HIT/HITTS Type II Undergoing Off-Pump Coronary Artery Bypass Grafting (CABG) (CHOOSE)
NCT00102323	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Refractory to Splenectomy
NCT00102336	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Prior to Splenectomy
NCT00116688	PHASE3	COMPLETED	Open Label Extension Study of Romiplostim (AMG 531) in Thrombocytopenic Patients With Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
NCT00128713	PHASE3	COMPLETED	Optimal Platelet Dose Strategy for Management of Thrombocytopenia
NCT00151866	PHASE3	COMPLETED	Efficacy of Transfusions With Platelets Stored in Platelet Additive Solution II Versus Plasma
NCT00261924	PHASE3	COMPLETED	Efficacy and Safety Study of Platelets Treated for Pathogen Inactivation and Stored for Up to Seven Days
NCT00415532	PHASE3	COMPLETED	Romiplostim (AMG 531) Versus Medical Standard of Care for Immune (Idiopathic) Thrombocytopenic Purpura
NCT00420914	PHASE3	TERMINATED	Strategies for Transfusion of Platelets (SToP)
NCT00501345	PHASE3	TERMINATED	Aspirin in Patients With Myocardial Infarction and Thrombocytopenia
NCT00508820	PHASE3	COMPLETED	An Open Label Study of Romiplostim in Adult Thrombocytopenic Subjects With ITP
NCT00678587	PHASE3	TERMINATED	Eltrombopag To Reduce The Need For Platelet Transfusion In Subjects With Chronic Liver Disease And Thrombocytopenia Undergoing Elective Invasive Procedures
NCT01438840	PHASE3	COMPLETED	Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults With Chronic Immune Thrombocytopenia (Amendment 02)
NCT01444417	PHASE3	COMPLETED	Safety and Efficacy Study of Romiplostim to Treat Immune Thrombocytopenia (ITP) in Pediatric Patients
NCT01805648	PHASE3	UNKNOWN	Efficacy and Safety Study of Maintenance Treatment With rhTPO in Thrombocytopenic Subjects With ITP
NCT02244658	PHASE3	UNKNOWN	Recombinant Human Thrombopoietin (rhTPO) in Management of Chemotherapy-induced Thrombocytopenia in Acute Myelocytic Leukemia
NCT02389621	PHASE3	COMPLETED	Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures
NCT02444728	PHASE3	TERMINATED	Cyclophosphamide and Hydroxychloroquine for Thrombocytopenia in SLE
NCT02487563	PHASE3	COMPLETED	Prospective Study of Patients With Thrombocytopenia Following HSCT
NCT02578901	PHASE3	COMPLETED	American Trial Using Tranexamic Acid in Thrombocytopenia
NCT03326843	PHASE3	TERMINATED	Avatrombopag for the Treatment of Thrombocytopenia in Adults Scheduled for a Surgical Procedure
NCT03515096	PHASE3	COMPLETED	Eltrombopag vs. rhTPO to Increase Platelet Level After HSCT