BCO1

Summary

BCO1 (beta-carotene oxygenase 1, HGNC:13815) is a protein-coding gene on chromosome 16q23.2, encoding Beta,beta-carotene 15,15’-dioxygenase (Q9HAY6). Symmetrically cleaves beta-carotene into two molecules of retinal using a dioxygenase mechanism.

Vitamin A metabolism is important for vital processes such as vision, embryonic development, cell differentiation, and membrane and skin protection. The protein encoded by this gene is a key enzyme in beta-carotene metabolism to vitamin A. It catalyzes the oxidative cleavage of beta,beta-carotene into two retinal molecules.

Source: NCBI Gene 53630 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary hypercarotenemia and vitamin A deficiency (Supportive, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 172 total
• Phenotypes (HPO): 4
• MANE Select transcript: NM_017429

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13815
Approved symbol	BCO1
Name	beta-carotene oxygenase 1
Location	16q23.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10730, BCMO
Ensembl gene	ENSG00000135697
Ensembl biotype	protein_coding
OMIM	605748
Entrez	53630

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 nonsense_mediated_decay

ENST00000258168, ENST00000563804, ENST00000564552, ENST00000891665, ENST00000891666

RefSeq mRNA: 1 — MANE Select: NM_017429 NM_017429

CCDS: CCDS10934

Canonical transcript exons

ENST00000258168 — 11 exons

Exon	Start	End
ENSE00001185351	81290348	81291142
ENSE00001248143	81259676	81259805
ENSE00003466711	81245475	81245603
ENSE00003480291	81262136	81262283
ENSE00003543728	81270159	81270416
ENSE00003557715	81238689	81238972
ENSE00003562711	81285540	81285634
ENSE00003613221	81287295	81287406
ENSE00003616174	81264640	81264787
ENSE00003636995	81280857	81280962
ENSE00003640561	81267908	81268131

Expression profiles

Bgee: expression breadth ubiquitous, 130 present calls, max score 96.27.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.2510 / max 419.2864, expressed in 142 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155142	0.9129	116
155141	0.1222	33
155144	0.1014	38
155143	0.0675	19
155140	0.0469	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	96.27	gold quality
retina	UBERON:0000966	96.25	gold quality
jejunal mucosa	UBERON:0000399	82.38	gold quality
eye	UBERON:0000970	78.34	gold quality
duodenum	UBERON:0002114	74.47	gold quality
palpebral conjunctiva	UBERON:0001812	73.44	gold quality
choroid plexus epithelium	UBERON:0003911	71.50	gold quality
rectum	UBERON:0001052	70.02	gold quality
mucosa of transverse colon	UBERON:0004991	68.08	gold quality
pancreatic ductal cell	CL:0002079	66.54	silver quality
small intestine	UBERON:0002108	65.81	gold quality
small intestine Peyer’s patch	UBERON:0003454	65.05	gold quality
jejunum	UBERON:0002115	63.56	gold quality
gall bladder	UBERON:0002110	62.53	gold quality
intestine	UBERON:0000160	61.91	gold quality
transverse colon	UBERON:0001157	61.86	gold quality
islet of Langerhans	UBERON:0000006	61.51	gold quality
ileal mucosa	UBERON:0000331	61.31	silver quality
metanephros cortex	UBERON:0010533	61.27	gold quality
adult mammalian kidney	UBERON:0000082	61.24	gold quality
colon	UBERON:0001155	60.90	gold quality
large intestine	UBERON:0000059	60.87	gold quality
colonic mucosa	UBERON:0000317	60.34	gold quality
mucosa of sigmoid colon	UBERON:0004993	60.04	silver quality
nephron tubule	UBERON:0001231	60.00	silver quality
seminal vesicle	UBERON:0000998	59.73	silver quality
muscle layer of sigmoid colon	UBERON:0035805	59.35	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	58.65	gold quality
left ovary	UBERON:0002119	58.19	gold quality
kidney	UBERON:0002113	57.84	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ISX, MEF2A, MEF2C, PPARA, PPARG, RXRA, THRA

miRNA regulators (miRDB)

39 targeting BCO1, 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-4795-3P	100.00	74.62	4024
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-3682-3P	99.58	67.63	865

Literature-anchored findings (GeneRIF, showing 37)

• Study demonstrates that human intestinal cell BCMO1 expression is dependent on the functional cooperation between peroxisome proliferator-activated receptor-gamma and myocyte enhancer factor 2 isoforms. (PMID:16504037)
• Haploinsufficiency of the CMO1 enzyme caused hypercarotenemia and hypovitaminosis A in individuals consuming a carotenoid-containing and vitamin A-deficient diet. (PMID:17951468)
• T3 is an important hormone for the regulation of vitamin A and beta-carotene metabolism-related gene expression in human small intestinal cells. (PMID:18282583)
• Two common single nucleotide polymorphisms in the gene encoding BCOM1 alter beta-carotene metabolism in female volunteers. (PMID:19103647)
• Identification of novel common variants associated with circulating carotenoid levels and known lipid variants associated with alpha-tocopherol levels in variations of this enzyme. (PMID:19185284)
• Hydrophobic mutations (K108F and K108L) at this position substantially decreased the affinity of the enzyme for substrates with ionone rings at both ends, such as alpha-carotene, beta-carotene, and beta-cryptoxanthine. (PMID:20221844)
• non-synonymous single nucleotide polymorphisms in the BCMO1 gene have been discovered causing observably reduced BCMO1 activity (PMID:20599666)
• These results suggest that BCMO1 and CD36 are implicated in plasma and retina concentrations of lutein and that genetic variants in these genes can modulate blood and retina concentrations of lutein. (PMID:21091228)
• investigated the effects of 4 identified SNP 5’ upstream from the BCMO1 gene on beta-carotene conversion efficiency; found that three of the four intronic SNPs reduced the catalytic activity of BCMO1 in female volunteers (PMID:22113863)
• genetic association study in US women of European descent: Data suggest that 2 SNP in BCMO1 (rs4889286; rs12934922) are associated with plasma carotenoid level (i.e., alpha-carotene, beta-carotene, lutein, zeaxanthin). (data from Nurses Health Study) (PMID:23134893)
• Individual responsiveness to dietary carotenoids was associated with genetic variants of the carotenoid metabolizing enzyme beta-carotene 15,15’-monooxygenase 1. (PMID:23517913)
• BCMO1 SNP had a statistically significant association with HDL plasma levels. (PMID:23656756)
• Purified BCMO1 is a monomeric enzymatically active soluble protein that does not require cofactors and displays a turnover rate of about 8 molecules of beta,beta-carotene per second. (PMID:23727499)
• Inhibition of BCMO1 expression is associated with increased invasiveness of colon cancer cells and increased expression of MMP7 and MMP28. beta-Carotene can upregulate BCMO1 and reverse these effects. (PMID:23803888)
• CMO1 is expressed in human alveolar epithelial (A549) cells and converts beta-carotene into retinal and biologically active retinoic acids. (PMID:24071514)
• a stepwise cleavage by BCO2 and BCO1 with APO10ol as an intermediate could provide a mechanism to tailor asymmetric carotenoids such as beta-cryptoxanthin for vitamin A production. (PMID:24106281)
• Substrate specificity of purified recombinant human beta-carotene 15,15’-oxygenase (BCO1). (PMID:24187135)
• Specific BCMO1 SNPs should be determined when assessing the effects of carotenoid supplementation on macular pigment and that their expression may be influenced by retinal disease. (PMID:24586510)
• Incubation of beta-carotene and recombinant human BCMO1 in either H2(18)O-(16)O2 or H2(16)O-(18)O2 medium yields two retinal products both of which contain oxygen atoms originating solely from O2 gas. The results show that BCMO1 is a dioxygenase and not a monooxygenase as previously thought. (PMID:24668807)
• Together with the data from (18)O-retinal-H2(16)O and (16)O-retinal-H2(18)O incubations to account for nonenzymatic oxygen exchange, our results show that BCO1 incorporates only oxygen from O2 into retinal. Thus, BCO1 is a dioxygenase. (PMID:24668807)
• Data suggest that beta-cryptoxanthin is a poorer substrate for BCMO1 than is beta-carotene; however, the comparatively high bioavailability of beta-cryptoxanthin from foods makes beta-cryptoxanthin-rich fruits good sources of vitamin A. [REVIEW] (PMID:25270992)
• This study indicates that the competitive actions of HNF-1alpha and HNF-4alpha on their overlapping binding sites in the human BCMO1 gene promoter oppositely regulate BCMO1 gene expression in the human small intestine. (PMID:25445224)
• study revealed circulating beta-carotene levels were significantly higher in rs6564851 GG homozygotes; daily intake of beta-cryptoxanthin was positively associated with circulating beta-carotene levels in female GG homozygotes of rs6564851 and the daily intake of alpha- and beta-carotenes, and beta-cryptoxanthin was significantly lower in female rs6564851 T allele carries than in female GG homozygotes (PMID:28005968)
• Study reports a molecular mechanism by which glucocorticoid-induced PPARalpha expression negatively affects the activity of PPARgamma and downregulates BCO1 gene expression. Results explicate novel aspects of local glucocorticoid:retinoid interactions that may contribute to alveolar tissue remodeling in chronic lung diseases that affect children and, possibly, adults. (PMID:28732066)
• Single nucleotide polymorphism rs1501299 in the gene ADIPOQ (P=0.0010, OR=0.41, 95% C.I.:0.24-0.70) and rs7501331 in the gene BCMO1 (P=0.0106, OR=0.24, 95% C.I.:0.21-0.71), are significantly associated (the latter marginally significant) with the decrease of the risk of polycystic ovary syndrome. (PMID:29428584)
• We did not observe associations of BCMO1 variants and lung cancer. (PMID:29673335)
• Two BCO1 single nucleotide polymorphism (SNP) genotypes were significant predictors of the change in plasma lycopene associated with consumption of a tomato-soy beverage, with SNP effects differing in magnitude and direction, depending on the level of juice intake. (PMID:30801647)
• In dyslipidemia patients, polymorphisms (rs12934922 and rs11646692) in the BCO1 gene may influence the development of coronary atherosclerosis. (PMID:30896431)
• beta-Carotene 15,15’-oxygenase inhibits cancer cell stemness and metastasis by regulating differentiation-related miRNAs in human neuroblastoma. (PMID:31048207)
• Enzymology of vertebrate carotenoid oxygenases. (PMID:32035229)
• Evolutionary aspects and enzymology of metazoan carotenoid cleavage oxygenases. (PMID:32061750)
• beta-Carotene Oxygenase 1 Activity Modulates Circulating Cholesterol Concentrations in Mice and Humans. (PMID:32433733)
• SNP rs6564851 in the BCO1 Gene Is Associated with Varying Provitamin a Plasma Concentrations but Not with Retinol Concentrations among Adolescents from Rural Ghana. (PMID:32560166)
• ALDH2, ADCY3 and BCMO1 polymorphisms and lifestyle-induced traits are jointly associated with CAD risk in Chinese Han people. (PMID:34481002)
• Common variant rs6564851 near the beta-carotene oxygenase 1 gene is associated with plasma triglycerides levels in middle-aged Mexican men adults. (PMID:35461060)
• Association of TGFB1 rs1800469 and BCMO1 rs6564851 with coronary heart disease and IL1B rs16944 with all-cause mortality in men from the Northern Ireland PRIME study. (PMID:35994463)
• Association of MARC1, ADCY5, and BCO1 Variants with the Lipid Profile, Suggests an Additive Effect for Hypertriglyceridemia in Mexican Adult Men. (PMID:36233117)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	bco1	ENSDARG00000104256
mus_musculus	Bco1	ENSMUSG00000031845
rattus_norvegicus	Bco1	ENSRNOG00000012027
drosophila_melanogaster	ninaB	FBGN0002937
caenorhabditis_elegans		WBGENE00012914
caenorhabditis_elegans		WBGENE00018755

Paralogs (2): RPE65 (ENSG00000116745), BCO2 (ENSG00000197580)

Protein

Protein identifiers

Beta,beta-carotene 15,15’-dioxygenase — Q9HAY6 (reviewed: Q9HAY6)

Alternative names: Beta-carotene dioxygenase 1, Beta-carotene oxygenase 1

All UniProt accessions (3): Q9HAY6, H3BPA2, H3BV18

UniProt curated annotations — full annotation on UniProt →

Function. Symmetrically cleaves beta-carotene into two molecules of retinal using a dioxygenase mechanism.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Highly expressed in retinal pigment epithelium. Also expressed in kidney, testis, liver, brain, small intestine and colon.

Disease relevance. Hypercarotenemia and vitamin A deficiency, autosomal dominant (HCVAD) [MIM:115300] A disorder characterized by increased serum beta-carotene, decreased conversion of beta-carotene to vitamin A and decreased serum vitamin A. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 Fe(2+) ion per subunit.

Pathway. Cofactor metabolism; retinol metabolism.

Similarity. Belongs to the carotenoid oxygenase family.

RefSeq proteins (1): NP_059125* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004294	Carotenoid_Oase	Family

Pfam: PF03055

Enzyme classification (BRENDA):

• EC 1.13.11.63 — beta-carotene 15,15’-dioxygenase (BRENDA: 23 organisms, 74 substrates, 58 inhibitors, 48 Km, 20 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BETA-CAROTENE	0.0009–0.215	23
ALPHA-CAROTENE	0.0062–0.37	4
BETA-CRYPTOXANTHIN	0.0067–0.29	4
BETA-APO-8’-CAROTENAL	0.0077–0.0085	2
GAMMA-CAROTENE	0.382–0.69	2
13-CIS-BETA-CAROTENE	0.0035	1
ALL-TRANS-BETA-CAROTENE	0.0057	1
BETA-APO-10’-CAROTENAL	0.0092	1
BETA-APO-10’-CAROTENOL + O2	0.067	1
BETA-APO-4’-CAROTENAL	0.147	1
BETA-APO-4’CAROTENAL	0.18	1
BETA-APO-8’CAROTENAL	0.19	1

Catalyzed reactions (Rhea), 1 shown:

• all-trans-beta-carotene + O2 = 2 all-trans-retinal (RHEA:32887)

UniProt features (11 total): binding site 4, sequence variant 3, chain 1, region of interest 1, sequence conflict 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HAY6-F1	90.03	0.77

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 (4): 172; 237; 308; 514

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-975634	Retinoid metabolism and transport
R-HSA-1430728	Metabolism
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-2187338	Visual phototransduction
R-HSA-6806667	Metabolism of fat-soluble vitamins
R-HSA-9709957	Sensory Perception

MSigDB gene sets: 92 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_RETINOL_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, GATA6_01, GOBP_VITAMIN_BIOSYNTHETIC_PROCESS, GOBP_RETINAL_METABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ALDEHYDE_METABOLIC_PROCESS, GOBP_LIPID_BIOSYNTHETIC_PROCESS, GOBP_ISOPRENOID_BIOSYNTHETIC_PROCESS, GOBP_LIPID_CATABOLIC_PROCESS, GOBP_VITAMIN_METABOLIC_PROCESS, GOBP_ISOPRENOID_METABOLIC_PROCESS

GO Biological Process (7): retinoid metabolic process (GO:0001523), carotene catabolic process (GO:0016121), vitamin A biosynthetic process (GO:0035238), retinol metabolic process (GO:0042572), retinal metabolic process (GO:0042574), beta-carotene metabolic process (GO:1901810), lipid metabolic process (GO:0006629)

GO Molecular Function (6): beta-carotene 15,15’-dioxygenase activity (GO:0003834), carotenoid dioxygenase activity (GO:0010436), metal ion binding (GO:0046872), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen (GO:0016702), dioxygenase activity (GO:0051213)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Visual phototransduction	1
Metabolism of fat-soluble vitamins	1
Metabolism	1
Sensory Perception	1
Metabolism of vitamins and cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
carotene metabolic process	2
retinoid metabolic process	2
olefinic compound metabolic process	2
oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen	2
cellular anatomical structure	2
diterpenoid metabolic process	1
terpene catabolic process	1
vitamin A metabolic process	1
diterpenoid biosynthetic process	1
fat-soluble vitamin biosynthetic process	1
primary alcohol metabolic process	1
hormone metabolic process	1
aldehyde metabolic process	1
carotenoid metabolic process	1
primary metabolic process	1
cation binding	1
catalytic activity	1
oxidoreductase activity, acting on single donors with incorporation of molecular oxygen	1
dioxygenase activity	1
oxidoreductase activity	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

812 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BCO1	ISX	Q2M1V0	985
BCO1	SCARB1	Q8WTV0	791
BCO1	RBP4	P02753	750
BCO1	LRAT	O95237	745
BCO1	RARS1	P54136	640
BCO1	STRA6	Q9BX79	596
BCO1	STARD3	Q14849	568
BCO1	CYP26A1	O43174	552
BCO1	RETSAT	Q6NUM9	539
BCO1	RDH10	Q8IZV5	532
BCO1	RBP1	P09455	520
BCO1	RDH12	Q96NR8	517
BCO1	RBP2	P50120	503
BCO1	ALDH1A2	O94788	503
BCO1	ALDH1A3	P47895	502

IntAct

5 interactions, top by confidence:

A	B	Type	Score
CHMP2A	DECR1	psi-mi:“MI:0914”(association)	0.530
BCO1	ABLIM1	psi-mi:“MI:0915”(physical association)	0.400
MYC		psi-mi:“MI:0914”(association)	0.350

BioGRID (4): ABLIM1 (Affinity Capture-MS), ABLIM1 (Affinity Capture-MS), BCO1 (Affinity Capture-MS), BCO1 (Affinity Capture-MS)

ESM2 similar proteins: A1KQY3, A4XES9, A5HV13, A8Y9I2, C3VA26, C3VEQ4, O24592, O43837, O49505, O49675, O77784, P17571, P41565, P51553, P70404, P74334, P9WPR4, P9WPR5, Q28479, Q4W9H1, Q58CP0, Q5MBR3, Q5MBR5, Q5MBR6, Q5RBT4, Q5RF16, Q68FX0, Q69NX5, Q6PBW5, Q6QT07, Q6YVJ0, Q80YA7, Q84K96, Q8AXN9, Q8HXG8, Q8K4Y7, Q8LIY8, Q8VCF1, Q8VY26, Q8WVQ1

Diamond homologs: A8Y9I2, A9C3R8, A9C3R9, O70276, Q16518, Q28175, Q5RF16, Q6PBW5, Q6QT07, Q8AXN9, Q8HXG8, Q91XT5, Q91ZQ5, Q99NF1, Q9BYV7, Q9HAY6, Q9I993, Q9JJS6, Q9TVB8, Q9VFS2, Q9XT71, Q9YGX2, Q9YI25, Q93VD5, Q8VY26

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	118
Likely benign	15
Benign	33

Top pathogenic / likely-pathogenic (0)

SpliceAI

1779 predictions. Top by Δscore:

Variant	Effect	Δscore
16:81245600:GACG:G	donor_gain	1.0000
16:81259750:GTGTC:G	donor_gain	1.0000
16:81259751:TGTCT:T	donor_gain	1.0000
16:81259752:GTCTG:G	donor_gain	1.0000
16:81259806:G:GG	donor_gain	1.0000
16:81262133:CAGAG:C	acceptor_loss	1.0000
16:81262134:A:AG	acceptor_gain	1.0000
16:81262134:A:T	acceptor_loss	1.0000
16:81262135:G:GG	acceptor_gain	1.0000
16:81262135:GA:G	acceptor_gain	1.0000
16:81262135:GAGC:G	acceptor_gain	1.0000
16:81262135:GAGCT:G	acceptor_gain	1.0000
16:81262247:G:GT	donor_gain	1.0000
16:81262248:A:T	donor_gain	1.0000
16:81267906:AGAG:A	acceptor_gain	1.0000
16:81267907:GA:G	acceptor_gain	1.0000
16:81267907:GAGG:G	acceptor_gain	1.0000
16:81270156:CAGAC:C	acceptor_loss	1.0000
16:81270157:A:AG	acceptor_gain	1.0000
16:81270157:A:C	acceptor_loss	1.0000
16:81270158:G:GA	acceptor_gain	1.0000
16:81270158:GA:G	acceptor_gain	1.0000
16:81270158:GAC:G	acceptor_gain	1.0000
16:81270158:GACT:G	acceptor_gain	1.0000
16:81270158:GACTT:G	acceptor_gain	1.0000
16:81270386:G:GT	donor_gain	1.0000
16:81270413:CAAG:C	donor_loss	1.0000
16:81270414:AAGG:A	donor_loss	1.0000
16:81270415:AGG:A	donor_loss	1.0000
16:81270416:GGTAA:G	donor_loss	1.0000

AlphaMissense

3632 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:81268000:A:C	S238R	0.997
16:81268002:C:A	S238R	0.997
16:81268002:C:G	S238R	0.997
16:81259708:A:C	S76R	0.996
16:81259710:C:A	S76R	0.996
16:81259710:C:G	S76R	0.996
16:81245511:G:C	R34P	0.995
16:81262181:C:A	N123K	0.995
16:81262181:C:G	N123K	0.995
16:81262184:C:G	C124W	0.995
16:81267997:C:G	H237D	0.995
16:81267988:A:C	S234R	0.994
16:81267990:C:A	S234R	0.994
16:81267990:C:G	S234R	0.994
16:81262176:G:C	D122H	0.992
16:81262231:A:T	E140V	0.991
16:81245565:A:T	D52V	0.990
16:81264721:G:C	G185R	0.990
16:81267999:C:A	H237Q	0.990
16:81267999:C:G	H237Q	0.990
16:81268001:G:T	S238I	0.990
16:81290438:G:C	R502P	0.990
16:81245577:T:C	L56P	0.989
16:81270249:G:C	A312P	0.989
16:81245558:T:A	W50R	0.988
16:81245558:T:C	W50R	0.988
16:81259709:G:T	S76I	0.988
16:81264682:C:G	H172D	0.988
16:81270237:C:G	H308D	0.988
16:81245516:G:T	G36W	0.987

dbSNP variants (sampled 300 via entrez): RS1000021684 (16:81269350 C>G,T), RS1000052727 (16:81252479 C>G,T), RS1000074342 (16:81269138 T>A), RS1000119654 (16:81269153 C>G), RS1000128435 (16:81240454 C>G,T), RS1000138679 (16:81262057 A>C,G), RS1000188700 (16:81237909 C>G), RS1000198583 (16:81238089 C>G), RS1000199501 (16:81239689 CAG>C), RS1000245982 (16:81236820 A>T), RS1000256488 (16:81273176 T>C), RS1000298862 (16:81264605 A>C,G), RS1000378998 (16:81255879 T>A), RS1000409666 (16:81260453 G>A,C), RS1000502359 (16:81240338 G>A,C)

Disease associations

OMIM: gene MIM:605748 | disease phenotypes: MIM:115300, MIM:614468

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary hypercarotenemia and vitamin A deficiency	Supportive	Autosomal dominant

Mondo (3): primary ovarian failure (MONDO:0005387), hereditary hypercarotenemia and vitamin A deficiency (MONDO:0007272), familial cold autoinflammatory syndrome 3 (MONDO:0013766)

Orphanet (3): Hereditary hypercarotenemia and vitamin A deficiency (Orphanet:199285), PLCG2-associated antibody deficiency and immune dysregulation (Orphanet:300359), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000951	Abnormality of the skin
HP:0004905	Reduced circulating vitamin A concentration
HP:0430074	Increased circulating beta-carotene concentration

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000324_2	Carotenoid and tocopherol levels	2.000000e-24
GCST005958_20	Waist-to-hip ratio adjusted for BMI (age >50)	4.000000e-06
GCST005962_30	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-06
GCST009160_2	Carotenoid levels	7.000000e-11
GCST009160_3	Carotenoid levels	8.000000e-14
GCST012020_471	Serum metabolite levels	4.000000e-23
GCST012020_472	Serum metabolite levels	8.000000e-15

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004737	carotenoid measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0007894	beta-carotene measurement
EFO:0007895	lutein measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C567296	Hypercarotenemia And Vitamin A Deficiency, Autosomal Dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases methylation	6
trichostatin A	affects cotreatment, decreases expression	3
methylmercuric chloride	decreases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	decreases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
bisphenol A	decreases methylation, increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
Ro 41-5253	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Arsenic Trioxide	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Silicon Dioxide	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	affects expression	1
Aflatoxin B1	increases methylation	1
beta Carotene	increases activity, increases expression	1
Okadaic Acid	increases expression	1
p-Chloromercuribenzoic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure
NCT00006156	Not specified	COMPLETED	Feasibility Study for Development of an Early Test for Ovarian Failure
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists