BMAL1

Summary

BMAL1 (basic helix-loop-helix ARNT like 1, HGNC:701) is a protein-coding gene on chromosome 11p15.3, encoding Basic helix-loop-helix ARNT-like protein 1 (O00327). Transcriptional activator which forms a core component of the circadian clock.

The protein encoded by this gene is a basic helix-loop-helix protein that forms a heterodimer with CLOCK. This heterodimer binds E-box enhancer elements upstream of Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2) genes and activates transcription of these genes. PER and CRY proteins heterodimerize and repress their own transcription by interacting in a feedback loop with CLOCK/ARNTL complexes. Defects in this gene have been linked to infertility, problems with gluconeogenesis and lipogenesis, and altered sleep patterns. The protein regulates interferon-stimulated gene expression and is an important factor in viral infection, including COVID-19.

Source: NCBI Gene 406 — RefSeq curated summary.

At a glance

• GWAS associations: 67
• Clinical variants (ClinVar): 71 total
• Transcription factor: yes — 71 downstream targets (CollecTRI)
• MANE Select transcript: NM_001297719

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:701
Approved symbol	BMAL1
Name	basic helix-loop-helix ARNT like 1
Location	11p15.3
Locus type	gene with protein product
Status	Approved
Aliases	MOP3, JAP3, PASD3, bHLHe5, ARNTL1
Ensembl gene	ENSG00000133794
Ensembl biotype	protein_coding
OMIM	602550
Entrez	406

Gene structure

Transcript identifiers

Ensembl transcripts: 69 — 53 protein_coding, 10 nonsense_mediated_decay, 5 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000389707, ENST00000401424, ENST00000403290, ENST00000403482, ENST00000403510, ENST00000472842, ENST00000480685, ENST00000482049, ENST00000485918, ENST00000497429, ENST00000524392, ENST00000527998, ENST00000529050, ENST00000529388, ENST00000529390, ENST00000529825, ENST00000530357, ENST00000531665, ENST00000533520, ENST00000534102, ENST00000534544, ENST00000673626, ENST00000673817, ENST00000673834, ENST00000673868, ENST00000673888, ENST00000673892, ENST00000674108, ENST00000873778, ENST00000873779, ENST00000873780, ENST00000873781, ENST00000873782, ENST00000873783, ENST00000873784, ENST00000873785, ENST00000873786, ENST00000873787, ENST00000873788, ENST00000873790, ENST00000873791, ENST00000873792, ENST00000873793, ENST00000922493, ENST00000957601, ENST00000957602, ENST00000957603, ENST00000957604, ENST00000957605, ENST00000957606, ENST00000957607, ENST00000957608, ENST00000957609, ENST00000957610, ENST00000957611, ENST00000957612, ENST00000957613, ENST00000957614, ENST00000957615, ENST00000957616, ENST00000957617, ENST00000957618, ENST00000957619, ENST00000957620, ENST00000957621, ENST00000957622, ENST00000957623, ENST00000957624, ENST00000957625

RefSeq mRNA: 27 — MANE Select: NM_001297719 NM_001030272, NM_001030273, NM_001178, NM_001297719, NM_001297722, NM_001297724, NM_001351804, NM_001351805, NM_001351806, NM_001351807, NM_001351808, NM_001351809, NM_001351810, NM_001351811, NM_001351812, NM_001351813, NM_001351814, NM_001351815, NM_001351816, NM_001351817, NM_001351818, NM_001351819, NM_001351820, NM_001351821, NM_001351822, NM_001351823, NM_001351824

CCDS: CCDS44543, CCDS73259, CCDS91444

Canonical transcript exons

ENST00000403290 — 20 exons

Exon	Start	End
ENSE00001258861	13309987	13310059
ENSE00001259368	13349945	13350070
ENSE00001525102	13326413	13326467
ENSE00001712237	13369618	13369767
ENSE00001804038	13372163	13372409
ENSE00002187606	13277790	13277923
ENSE00003479107	13386596	13387266
ENSE00003519729	13376640	13376728
ENSE00003547098	13385689	13385791
ENSE00003548986	13378337	13378445
ENSE00003551704	13381161	13381254
ENSE00003577946	13354301	13354448
ENSE00003579415	13366665	13366782
ENSE00003586718	13360345	13360424
ENSE00003656077	13358434	13358591
ENSE00003658333	13375612	13375762
ENSE00003691919	13374095	13374201
ENSE00003786996	13357055	13357096
ENSE00003788814	13356739	13356777
ENSE00003790235	13365500	13365592

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 92.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.0919 / max 368.0087, expressed in 1703 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
113171	13.0919	1703

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ovary	UBERON:0002119	92.07	gold quality
right lobe of thyroid gland	UBERON:0001119	91.92	gold quality
middle temporal gyrus	UBERON:0002771	91.66	gold quality
right lung	UBERON:0002167	91.65	gold quality
skin of abdomen	UBERON:0001416	91.50	gold quality
blood	UBERON:0000178	91.44	gold quality
granulocyte	CL:0000094	91.37	gold quality
skin of leg	UBERON:0001511	91.08	gold quality
lateral nuclear group of thalamus	UBERON:0002736	90.85	silver quality
left lobe of thyroid gland	UBERON:0001120	90.80	gold quality
upper lobe of left lung	UBERON:0008952	90.73	gold quality
gastrocnemius	UBERON:0001388	90.71	gold quality
lower esophagus mucosa	UBERON:0035834	90.36	gold quality
primary visual cortex	UBERON:0002436	90.25	gold quality
upper lobe of lung	UBERON:0008948	90.11	gold quality
thyroid gland	UBERON:0002046	90.07	gold quality
right frontal lobe	UBERON:0002810	90.00	gold quality
zone of skin	UBERON:0000014	89.99	gold quality
calcaneal tendon	UBERON:0003701	89.92	gold quality
right ovary	UBERON:0002118	89.91	gold quality
Brodmann (1909) area 23	UBERON:0013554	89.81	gold quality
occipital lobe	UBERON:0002021	89.67	gold quality
postcentral gyrus	UBERON:0002581	89.57	gold quality
right lobe of liver	UBERON:0001114	89.46	gold quality
adrenal tissue	UBERON:0018303	89.42	gold quality
lower esophagus	UBERON:0013473	89.36	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.36	gold quality
superior frontal gyrus	UBERON:0002661	89.34	gold quality
Brodmann (1909) area 46	UBERON:0006483	89.34	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.29	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.45

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

71 targets.

Target	Regulation
AANAT
ACOX1	Unknown
ADAM17
ADCY1
ADRB1
ANGPTL2
ARSE
ATF5	Repression
ATG14
AVP	Unknown
BHLHE40	Activation
BHLHE41	Activation
BMAL1
CCL2	Unknown
CD44
CDKN1A	Unknown
CIART
CLOCK	Activation
CREBBP
CRY1	Activation
CRY2	Activation
CRYL1
CSNK1E
CST6
DBP	Activation
DEFB1	Unknown
DLST
DUSP1
EGR1	Activation
EP300	Unknown

Upstream regulators (CollecTRI, top): BHLHE40, BHLHE41, BMAL1, CLOCK, DBP, EPAS1, ID2, KLF10, MTA1, MYC, NCOA2, NCOR1, NFYA, NPAS2, NR0B2, NR1D1, NR1D2, NR3C1, PPARA, PPARG, PPARGC1A, RAI1, RORA, RORB, RORC, RXRA, SP1, TP63, ZFHX4

miRNA regulators (miRDB)

85 targeting BMAL1, 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-6873-3P	100.00	71.42	2626
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
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-4666A-3P	99.96	71.71	3434
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-4320	99.75	65.80	793
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-5700	99.64	69.88	2280

Literature-anchored findings (GeneRIF, showing 40)

• The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iepsilon. (PMID:11875063)
• BMAL1 and CLOCK have roles in circadian system control (PMID:12897057)
• Transcripts of BMAL1 underwent circadian oscillation. (PMID:14750904)
• a molecular genetic screen in mammalian cells to identify mutants of the circadian transcriptional activators CLOCK and BMAL1. (PMID:16474406)
• the CLOCK(NPAS2)/BMAL1 complex is post-translationally regulated by cry1 and cry2 (PMID:16628007)
• We have examined the circadian expression of clock genes in human leukocytes and found that Bmal1 mRNA showed weak rhythm. (PMID:17274950)
• variations associated with seasonal affective disorder (PMID:17457720)
• rat models to human provides evidence of a causative role of Bmal1 variants in pathological components of the metabolic syndrome (PMID:17728404)
• CLOCK/BMAL1-mediated activation of PER1 by AP1 and E-Box elements is distinct from peripheral transcriptional modulation via cAMP-induced CREB and C/EBP. (PMID:17994337)
• DEC1, along with DEC2, plays a role in the finer regulation and robustness of the molecular clock CLOCK/BMAL1 (PMID:18411297)
• The regulators of clock-controlled transcription PER2, CRY1 and CRY2 differ in their capacity to interact with each single component of the BMAL1-CLOCK heterodimer and, in the case of BMAL1, also in their interaction sites. (PMID:18430226)
• Individual PER3 rhythms correlated significantly with sleep-wake timing and the timing of melatonin and cortisol, but those of PER2 and BMAL1 did not reach significance. (PMID:18517031)
• The transcription of human nocturnin gene displayed circadian oscillations in Huh7 cells (a human hepatoma cell line) and was regulated by CLOCK/BMAL1 heterodimer via the E-box of nocturnin promoter. (PMID:18587630)
• Several new polymorphisms in ARNTL gene are reported. (PMID:18663240)
• The shRNA barcode screening technique identified ARNTL as being involved in p53 regulation. cells having suppressed ARNTL are unable to arrest upon p53 activation associated with an inability to activate the p53 target gene p21(CIP1). (PMID:19277210)
• expression of BMAL1 is significantly associated with lymph node metastasis and poor prognosis in breast cancer (PMID:19296127)
• Epigenetic inactivation of the circadian clock gene BMAL1 is associated with hematologic malignancies. (PMID:19861541)
• BMAL1 mRNA levels were correlated only with age (beta = -.50, p < .001). (PMID:19861640)
• results suggest that a peripheral molecular clock, as reflected in the dampened expression of the clock genes BMAL1 in total leukocytes, is altered in Parkinson’s disease patients (PMID:19912323)
• There was no circadian rhythm of bmal1(brain and muscle ARNT-like 1) and cry1(cryptochrome 1) in PBMC of preterm neonates (PMID:20222832)
• ARNTL and NPAS2 SNPs were associated with reproduction and with seasonal variation. (PMID:20368993)
• In this salivary gland cell line, there is a rhythm in the core oscillator components BMAL1 and REV-ERBalpha, an indication that circadian-based transcriptional regulation can be modelled in this peripheral cell type. (PMID:20446921)
• ID2 can interact with the canonical clock components CLOCK and BMAL1 and mediate inhibitory effects on mPer1 expression (PMID:20861012)
• Data indicate that fetal adrenal gland showed circadian expression of Bmal-1 and Per-2 as well as of Mt1 and Egr-1. (PMID:21363938)
• Overexpression of the Bmal1 gene and reduced expression of the Per1 gene may thus be useful predictors of liver metastasis. (PMID:21380491)
• Lean individuals exhibited significant (P < 0.05) temporal changes of core clock (PER1, PER2, PER3, CRY2, BMAL1, and DBP) and metabolic (REVERBalpha, RIP140, and PGC1alpha) genes. (PMID:21411511)
• rhythmic modulation of circulating microRNAs targeting Bmal1 (PMID:21799909)
• Data conclude that BMAL1 is a crucial factor in the regulation of energy homeostasis, and disorders of the functions of BMAL1 lead to the development of metabolic syndrome. (PMID:21966465)
• Examines the effect of acute sleep deprivation under light conditions on the expression of hPer2 and hBmal1. 40-hour acute sleep deprivation under light conditions may affect the expression of hPer2 in PBMCs. (PMID:21990077)
• This study demonistraed that BMAL1 exhibited rhythmic expression in the control group, but not the Adult attention-deficit hyperactivity disorder group. (PMID:22105622)
• treatment with isoprenaline or dexamethasone induces circadian expression of hPer1, hPer2, hPer3, and hBMAL1 (PMID:22217103)
• findings indicate that BMAL1 has a critical role in MPM and could serve as an attractive therapeutic target for MPM (PMID:22510946)
• Data indicate that SNPs in SERPINE1 and ARNTL and an nucleotide polymorphisms (SNPs) associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1. (PMID:22990020)
• DNA methylation levels at different CpG sites of CLOCK, BMAL1 and PER2 genes were analyzed in sixty normal-weight, overweight and obese women following a 16-week weight reduction program. (PMID:23003921)
• Data indicate that Clock-Bmal1 regulates the response to glucocorticoids in peripheral tissues through acetylation of the glucocorticoid receptor (GR), possibly antagonizing the biologic actions of diurnally fluctuating circulating cortisol. (PMID:23033538)
• Expression of the CLOCK, BMAL1, and PER1 circadian genes in human oral mucosa cells as dependent on CLOCK gene polymorphic variants. (PMID:23129285)
• The data suggest that the impairment of the BMAL1 clock gene expression is closely associated with GDM susceptibility. (PMID:23206673)
• The phospho-mimicking S78E mutant of BMAL1 efficiently blocks DNA binding, which provides a molecular rationale for the possibility of rhythmic binding of CLOCK-BMAL1 during circadian cycle. (PMID:23229515)
• These data document for the first time that the expression of BMAL1, PER3, PPARD and CRY2 genes is altered in gestational diabetes compared to normal pregnant women. deranged expression of clock genes may play a pathogenic role in GDM. (PMID:23323702)
• this study demonstrated that BMAL1 was modified with an O-linked beta-N-acetylglucosamine (O-GlcNAc), which stabilized BMAL1 and enhanced its transcriptional activity. (PMID:23337503)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	bmal1a	ENSDARG00000006791
danio_rerio	bmal1b	ENSDARG00000035732
mus_musculus	Bmal1	ENSMUSG00000055116
rattus_norvegicus	Bmal1	ENSRNOG00000014448
drosophila_melanogaster	Met	FBGN0002723
drosophila_melanogaster	gce	FBGN0261703
drosophila_melanogaster	tgo	FBGN0264075
caenorhabditis_elegans	aha-1	WBGENE00000095

Paralogs (6): BMAL2 (ENSG00000029153), CLOCK (ENSG00000134852), ARNT (ENSG00000143437), PASD1 (ENSG00000166049), NPAS2 (ENSG00000170485), ARNT2 (ENSG00000172379)

Protein

Protein identifiers

Basic helix-loop-helix ARNT-like protein 1 — O00327 (reviewed: O00327)

Alternative names: Aryl hydrocarbon receptor nuclear translocator-like protein 1, Basic-helix-loop-helix-PAS protein MOP3, Brain and muscle ARNT-like 1, Class E basic helix-loop-helix protein 5, Member of PAS protein 3, PAS domain-containing protein 3, bHLH-PAS protein JAP3

All UniProt accessions (14): A0A140VKD3, A0A669KAV4, A0A669KAX2, A0A669KB07, A0A669KBF4, E9PI92, E9PKG7, E9PKN1, E9PL54, E9PNI4, E9PRB1, E9PSD2, O00327, H0YER9

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots ‘circa’ (about) and ‘diem’ (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for ’timegivers’). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5’-CACGTG-3’) within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. BMAL1 positively regulates myogenesis and negatively regulates adipogenesis via the transcriptional control of the genes of the canonical Wnt signaling pathway. Plays a role in normal pancreatic beta-cell function; regulates glucose-stimulated insulin secretion via the regulation of antioxidant genes NFE2L2/NRF2 and its targets SESN2, PRDX3, CCLC and CCLM. Negatively regulates the mTORC1 signaling pathway; regulates the expression of MTOR and DEPTOR. Controls diurnal oscillations of Ly6C inflammatory monocytes; rhythmic recruitment of the PRC2 complex imparts diurnal variation to chemokine expression that is necessary to sustain Ly6C monocyte rhythms. Regulates the expression of HSD3B2, STAR, PTGS2, CYP11A1, CYP19A1 and LHCGR in the ovary and also the genes involved in hair growth. Plays an important role in adult hippocampal neurogenesis by regulating the timely entry of neural stem/progenitor cells (NSPCs) into the cell cycle and the number of cell divisions that take place prior to cell-cycle exit. Regulates the circadian expression of CIART and KLF11. The CLOCK-BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated in glucose and lipid metabolism. Promotes rhythmic chromatin opening, regulating the DNA accessibility of other transcription factors. The NPAS2-BMAL1 heterodimer positively regulates the expression of MAOA, F7 and LDHA and modulates the circadian rhythm of daytime contrast sensitivity by regulating the rhythmic expression of adenylate cyclase type 1 (ADCY1) in the retina. The preferred binding motif for the CLOCK-BMAL1 heterodimer is 5’-CACGTGA-3’, which contains a flanking adenine nucleotide at the 3-prime end of the canonical 6-nucleotide E-box sequence. CLOCK specifically binds to the half-site 5’-CAC-3’, while BMAL1 binds to the half-site 5’-GTGA-3’. The CLOCK-BMAL1 heterodimer also recognizes the non-canonical E-box motifs 5’-AACGTGA-3’ and 5’-CATGTGA-3’. Essential for the rhythmic interaction of CLOCK with ASS1 and plays a critical role in positively regulating CLOCK-mediated acetylation of ASS1. Plays a role in protecting against lethal sepsis by limiting the expression of immune checkpoint protein CD274 in macrophages in a PKM2-dependent manner. Regulates the diurnal rhythms of skeletal muscle metabolism via transcriptional activation of genes promoting triglyceride synthesis (DGAT2) and metabolic efficiency (COQ10B). (Microbial infection) Regulates SARS coronavirus-2/SARS-CoV-2 entry and replication in lung epithelial cells probably through the post-transcriptional regulation of ACE2 and interferon-stimulated gene expression.

Subunit / interactions. Component of the circadian clock oscillator which includes the CRY1/2 proteins, CLOCK or NPAS2,BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER1/2/3 proteins. Forms a heterodimer with CLOCK. The CLOCK-BMAL1 heterodimer is required for E-box-dependent transactivation, for CLOCK nuclear translocation and degradation, and, for phosphorylation of both CLOCK and BMAL1. Part of a nuclear complex which also includes RACK1 and PRKCA; RACK1 and PRKCA are recruited to the complex in a circadian manner. Interacts with NPAS2. Interacts with EZH2. Interacts with SUMO3. Interacts with SIRT1. Interacts with AHR. Interacts with ID1, ID2 and ID3. Interacts with DDX4. Interacts with OGT. Interacts with EED and SUZ12. Interacts with MTA1. Interacts with CIART. Interacts with HSP90. Interacts with KAT2B and EP300. Interacts with BHLHE40/DEC1 and BHLHE41/DEC2. Interacts with RELB and the interaction is enhanced in the presence of CLOCK. Interacts with PER1, PER2, CRY1 and CRY2 and this interaction requires a translocation to the nucleus. Interaction of the CLOCK-BMAL1 heterodimer with PER or CRY inhibits transcription activation. Interaction of the CLOCK-BMAL1 with CRY1 is independent of DNA but with PER2 is off DNA. The CLOCK-BMAL1 heterodimer interacts with GSK3B. Interacts with KDM5A. Interacts with KMT2A; in a circadian manner. Interacts with UBE3A. Interacts with PRKCG. Interacts with MAGEL2. Interacts with NCOA2. Interacts with THRAP3. The CLOCK-BMAL1 heterodimer interacts with PASD1. Interacts with PASD1. Interacts with USP9X. Interacts with PIWIL2 (via PIWI domain). Interacts with HDAC3. Interacts with HNF4A.

Subcellular location. Nucleus. Cytoplasm. PML body.

Tissue specificity. Hair follicles (at protein level). Highly expressed in the adult brain, skeletal muscle and heart.

Post-translational modifications. Ubiquitinated, leading to its proteasomal degradation. Deubiquitinated by USP9X. O-glycosylated; contains O-GlcNAc. O-glycosylation by OGT prevents protein degradation by inhibiting ubiquitination. It also stabilizes the CLOCK-BMAL1 heterodimer thereby increasing CLOCK-BMAL1-mediated transcription of genes in the negative loop of the circadian clock such as PER1/2/3 and CRY1/2. Acetylated on Lys-538 by CLOCK during the repression phase of the circadian cycle. Acetylation facilitates recruitment of CRY1 protein and initiates the repression phase of the circadian cycle. Acetylated at Lys-538 by KAT5 during the activation phase of the cycle, leading to recruitment of the positive transcription elongation factor b (P-TEFb) and BRD4, followed by productive elongation of circadian transcripts. Deacetylated by SIRT1, which may result in decreased protein stability. Phosphorylated upon dimerization with CLOCK. Phosphorylation enhances the transcriptional activity, alters the subcellular localization and decreases the stability of the CLOCK-BMAL1 heterodimer by promoting its degradation. Phosphorylation shows circadian variations in the liver with a peak between CT10 to CT14. Phosphorylation at Ser-90 by CK2 is essential for its nuclear localization, its interaction with CLOCK and controls CLOCK nuclear entry. Dephosphorylation at Ser-78 is important for dimerization with CLOCK and transcriptional activity. Sumoylated on Lys-259 upon dimerization with CLOCK. Predominantly conjugated to poly-SUMO2/3 rather than SUMO1 and the level of these conjugates undergo rhythmic variation, peaking at CT9-CT12. Sumoylation localizes it exclusively to the PML body and promotes its ubiquitination in the PML body, ubiquitin-dependent proteasomal degradation and the transcriptional activity of the CLOCK-BMAL1 heterodimer. Undergoes lysosome-mediated degradation in a time-dependent manner in the liver.

Activity regulation. There is conflicting data about the effect of NAD cofactors on activity. PubMed:11441146 suggests that the redox state of the cell can modulate the transcriptional activity of the CLOCK-BMAL1 heterodimer; NADH and NADPH enhance the DNA-binding activity of the heterodimer. PubMed:23229515 reports that NADH and NADPH have no significant effect on DNA-binding activity of the CLOCK-BMAL1 heterodimer.

Miscellaneous. CLOCK-BMAL1 double mutations within the PAS domains result in synergistic desensitization to high levels of CRY on repression of CLOCK-BMAL1 transcriptional activity of PER1 and, disrupt circadian rhythmicity.

Isoforms (9)

UniProt ID	Names	Canonical?
O00327-2	BMAL1B, JAP3	yes
O00327-1	BMAL1A
O00327-3	BMAL1C
O00327-4	BMAL1D
O00327-5	BMAL1E
O00327-6	BMAL1F
O00327-7	MOP3
O00327-8	8
O00327-9	9

RefSeq proteins (27): NP_001025443, NP_001025444, NP_001169, NP_001284648, NP_001284651, NP_001284653, NP_001338733, NP_001338734, NP_001338735, NP_001338736, NP_001338737, NP_001338738, NP_001338739, NP_001338740, NP_001338741, NP_001338742, NP_001338743, NP_001338744, NP_001338745, NP_001338746, NP_001338747, NP_001338748, NP_001338749, NP_001338750, NP_001338751, NP_001338752, NP_001338753 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR001067	Nuc_translocat	Family
IPR001610	PAC	Repeat
IPR011598	bHLH_dom	Domain
IPR013767	PAS_fold	Domain
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR050933	Circadian_TF	Family

Pfam: PF00010, PF00989, PF14598

UniProt features (69 total): splice variant 10, mutagenesis site 10, helix 8, sequence conflict 7, site 5, modified residue 5, strand 5, domain 4, compositionally biased region 4, region of interest 4, short sequence motif 3, cross-link 2, chain 1, turn 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8RW6	X-RAY DIFFRACTION	1.83
8RW8	X-RAY DIFFRACTION	2.16
4H10	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00327-F1	67.00	0.35

Functional residue map

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

Catalytic / active sites (5): 77 (interaction with e-box dna); 80 (interaction with e-box dna); 81 (interaction with e-box dna); 85 (interaction with e-box dna); 125 (important for interaction with clock)

Post-translational modifications (7): 17, 21, 78, 90, 538, 252, 259

Mutagenesis-validated functional residues (10):

Position	Phenotype
9	enhanced per1 reporter activity by clock-bmal1.
9	2-2.5-fold increase in clock-bmal1 transcriptional activity in the absence of cry1. no change in repression activity in
10	enhanced per1 reporter activity by clock-bmal1.
10	2-2.5-fold increase in clock-bmal1 transcriptional activity in the absence of cry1. no change in repression activity in
78	phosphomimetic mutant which severely impairs dna binding and clock-bmal1 transcriptional activity.
88	no effect on clock binding.
90	phosphomimetic mutant with no effect on dna binding or clock-bmal1 transcriptional activity.
125	impaired clock binding.
611	increased desensitization to cry1, in the presence of clock. approximately 2-fold increase in clock-bmal1 transcriptiona
612	increased desensitization to cry1, in the presence of clock. approximately 2-fold increase in clock-bmal1 transcriptiona

Function

Pathways and Gene Ontology

Reactome pathways

19 pathways

ID	Pathway
R-HSA-1368108	BMAL1:CLOCK,NPAS2 activates circadian expression
R-HSA-1989781	PPARA activates gene expression
R-HSA-9707616	Heme signaling
R-HSA-9768919	NPAS4 regulates expression of target genes
R-HSA-9931509	Expression of BMAL (ARNTL), CLOCK, and NPAS2
R-HSA-9931510	Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes
R-HSA-9931512	Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters
R-HSA-9931521	The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex
R-HSA-9931529	Phosphorylation and nuclear translocation of BMAL1 (ARNTL) and CLOCK
R-HSA-1430728	Metabolism
R-HSA-212436	Generic Transcription Pathway
R-HSA-2262752	Cellular responses to stress
R-HSA-400206	Regulation of lipid metabolism by PPARalpha
R-HSA-400253
R-HSA-556833	Metabolism of lipids
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9634815	Transcriptional Regulation by NPAS4

MSigDB gene sets: 478 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_CIRCADIAN_RHYTHM, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_REGULATION_OF_SKELETAL_MUSCLE_CELL_DIFFERENTIATION, RORA1_01, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, CMYB_01, GOBP_INSULIN_SECRETION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_TYPE_B_PANCREATIC_CELL_DEVELOPMENT

GO Biological Process (27): regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), spermatogenesis (GO:0007283), circadian rhythm (GO:0007623), negative regulation of TOR signaling (GO:0032007), circadian regulation of gene expression (GO:0032922), regulation of hair cycle (GO:0042634), positive regulation of circadian rhythm (GO:0042753), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of fat cell differentiation (GO:0045599), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of neurogenesis (GO:0050767), regulation of insulin secretion (GO:0050796), regulation of cell cycle (GO:0051726), response to redox state (GO:0051775), positive regulation of canonical Wnt signaling pathway (GO:0090263), oxidative stress-induced premature senescence (GO:0090403), energy homeostasis (GO:0097009), negative regulation of cold-induced thermogenesis (GO:0120163), positive regulation of protein acetylation (GO:1901985), regulation of type B pancreatic cell development (GO:2000074), negative regulation of nuclear receptor-mediated glucocorticoid signaling pathway (GO:2000323), regulation of cellular senescence (GO:2000772), positive regulation of skeletal muscle cell differentiation (GO:2001016), rhythmic process (GO:0048511)

GO Molecular Function (14): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), transcription coregulator activity (GO:0003712), aryl hydrocarbon receptor binding (GO:0017162), sequence-specific DNA binding (GO:0043565), protein dimerization activity (GO:0046983), Hsp90 protein binding (GO:0051879), E-box binding (GO:0070888), DNA-binding transcription factor binding (GO:0140297), sequence-specific double-stranded DNA binding (GO:1990837), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (9): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), PML body (GO:0016605), chromatoid body (GO:0033391), aryl hydrocarbon receptor complex (GO:0034751), CLOCK-BMAL transcription complex (GO:1990513), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Circadian clock	6
Regulation of lipid metabolism by PPARalpha	1
Cellular responses to stress	1
Transcriptional Regulation by NPAS4	1
RNA Polymerase II Transcription	1
Cellular responses to stimuli	1
Metabolism of lipids	1
Metabolism	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	4
DNA-templated transcription	3
cellular anatomical structure	3
regulation of gene expression	2
transcription by RNA polymerase II	2
circadian rhythm	2
regulation of transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
transcription regulator activity	2
regulation of RNA biosynthetic process	1
developmental process involved in reproduction	1
male gamete generation	1
rhythmic process	1
TOR signaling	1
regulation of TOR signaling	1
negative regulation of intracellular signal transduction	1
hair cycle	1
regulation of multicellular organismal process	1
regulation of circadian rhythm	1
positive regulation of biological process	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
fat cell differentiation	1
negative regulation of cell differentiation	1
regulation of fat cell differentiation	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
neurogenesis	1
regulation of nervous system development	1
regulation of cell development	1
insulin secretion	1
regulation of protein secretion	1
regulation of peptide hormone secretion	1
cell cycle	1
regulation of cellular process	1
response to stimulus	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1

Protein interactions and networks

STRING

2112 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BMAL1	CRY1	Q16526	998
BMAL1	NPAS2	Q99743	991
BMAL1	CLOCK	O15516	991
BMAL1	SIRT1	Q96EB6	988
BMAL1	CRY2	Q49AN0	983
BMAL1	KDM5A	P29375	982
BMAL1	BHLHE41	Q9C0J9	979
BMAL1	NR1D1	P20393	979
BMAL1	BHLHE40	O14503	965
BMAL1	CREBBP	Q92793	965
BMAL1	EP300	Q09472	963
BMAL1	NR1D2	Q14995	950
BMAL1	NFIL3	Q16649	946
BMAL1	CSNK1E	P49674	927
BMAL1	RORB	Q92753	925

IntAct

69 interactions, top by confidence:

A	B	Type	Score
CLOCK	BMAL1	psi-mi:“MI:0915”(physical association)	0.880
BMAL1	CLOCK	psi-mi:“MI:0914”(association)	0.880
CLOCK	BMAL1	psi-mi:“MI:0914”(association)	0.880
BMAL1	CLOCK	psi-mi:“MI:0915”(physical association)	0.880
BMAL1	NPAS2	psi-mi:“MI:0915”(physical association)	0.630
NPAS2	BMAL1	psi-mi:“MI:0915”(physical association)	0.630
BMAL1	PASD1	psi-mi:“MI:0915”(physical association)	0.610
HIF1A	BMAL1	psi-mi:“MI:0915”(physical association)	0.560
BMAL1	HIF1A	psi-mi:“MI:0915”(physical association)	0.560
DYRK1B	BMAL1	psi-mi:“MI:0914”(association)	0.530
CREBBP	BMAL1	psi-mi:“MI:0915”(physical association)	0.400
BMAL1	HMGA1	psi-mi:“MI:0915”(physical association)	0.400
HNF4A	BMAL1	psi-mi:“MI:0915”(physical association)	0.400
	BMAL1	psi-mi:“MI:0915”(physical association)	0.370
EPAS1	BMAL1	psi-mi:“MI:0915”(physical association)	0.370
BMAL1	HIF1A	psi-mi:“MI:0915”(physical association)	0.370
BMAL1	ECE1	psi-mi:“MI:0915”(physical association)	0.370
ECE1	BMAL1	psi-mi:“MI:0915”(physical association)	0.370
Cry2	BMAL1	psi-mi:“MI:0914”(association)	0.350

BioGRID (159): CLOCK (Two-hybrid), CRY1 (Two-hybrid), CRY2 (Two-hybrid), CSNK2B (Two-hybrid), DEC1 (Two-hybrid), NPAS2 (Two-hybrid), WDR5 (Two-hybrid), RORC (Two-hybrid), CSNK1E (Two-hybrid), CLOCK (Affinity Capture-Luminescence), ARNTL (Affinity Capture-Luminescence), ARNTL (Affinity Capture-Luminescence), ARNTL (Affinity Capture-Luminescence), ARNTL (Affinity Capture-Western), UBE3A (Affinity Capture-Western)

ESM2 similar proteins: A0MLS5, G5EGD2, O00327, O02219, O02747, O02748, O15945, O35800, O44712, O88529, P27540, P30561, P35869, P41738, P41739, P53762, P56645, P79832, P97481, Q0PGG7, Q16665, Q17062, Q2VPD4, Q309Z6, Q5R4T2, Q61221, Q61324, Q6YGZ5, Q78E60, Q8K3T2, Q8QGQ7, Q8QGQ8, Q8R4S2, Q8R4S4, Q8R4S5, Q8R4S6, Q8R4S7, Q8WYA1, Q91YA9, Q95LD9

Diamond homologs: A0MLS5, A6NFD8, O00327, O02219, O02748, O08785, O15516, O15945, O61734, O88529, P27540, P41739, P53762, P79832, P90953, P97460, Q2NL18, Q2VPD4, Q5R4T2, Q5RAK8, Q5ZQU2, Q61324, Q6YGZ4, Q6YGZ5, Q78E60, Q7TS99, Q8BGD7, Q8IUM7, Q8QGQ6, Q8QGQ7, Q8WYA1, Q91YA8, Q91YA9, Q91YB0, Q91YB2, Q99743, Q9BE97, Q9DBX7, Q9DG12, Q9EPW1

SIGNOR signaling

26 interactions.

A	Effect	B	Mechanism
GSK3B	down-regulates	ARNTL	phosphorylation
ARNTL	“down-regulates activity”	MAGEL2	binding
NR1D1	“down-regulates quantity by repression”	ARNTL	“transcriptional regulation”
RORB	“up-regulates quantity by expression”	ARNTL	“transcriptional regulation”
RORA	“up-regulates quantity by expression”	ARNTL	“transcriptional regulation”
RORC	“up-regulates quantity by expression”	ARNTL	“transcriptional regulation”
NR1D2	“down-regulates quantity by repression”	ARNTL	“transcriptional regulation”
PPARGC1A	“up-regulates quantity by expression”	ARNTL	“transcriptional regulation”
AKT2	“down-regulates activity”	ARNTL	phosphorylation
ARNTL	“down-regulates quantity by repression”	VWF	“transcriptional regulation”
RAI1	“up-regulates quantity by expression”	ARNTL	“transcriptional regulation”
PPARA	“up-regulates quantity by expression”	ARNTL	“transcriptional regulation”
ARNTL	“up-regulates quantity by expression”	PPARA	“transcriptional regulation”
PPARG	“up-regulates quantity by expression”	ARNTL	“transcriptional regulation”
TOP1	“down-regulates quantity by repression”	ARNTL	“transcriptional regulation”
ARNTL	“up-regulates quantity by expression”	CRY1	“transcriptional regulation”
ARNTL	“up-regulates quantity by expression”	CRY2	“transcriptional regulation”
ARNTL	“up-regulates quantity by expression”	PER1	“transcriptional regulation”
ARNTL	“up-regulates quantity by expression”	PER2	“transcriptional regulation”
ARNTL	“up-regulates quantity by expression”	PER3	“transcriptional regulation”
ARNTL	“form complex”	CLOCK/BMAL1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	44
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3658 predictions. Top by Δscore:

Variant	Effect	Δscore
11:13354449:G:GG	donor_gain	1.0000
11:13356775:A:T	donor_gain	1.0000
11:13358433:GGGAA:G	acceptor_gain	1.0000
11:13358587:AAGAG:A	donor_loss	1.0000
11:13358588:AGAGG:A	donor_loss	1.0000
11:13358589:GAG:G	donor_gain	1.0000
11:13358589:GAGGT:G	donor_loss	1.0000
11:13358590:AGGTG:A	donor_loss	1.0000
11:13358591:GGTGA:G	donor_loss	1.0000
11:13358592:G:GA	donor_loss	1.0000
11:13358593:T:A	donor_loss	1.0000
11:13360343:A:G	acceptor_gain	1.0000
11:13360423:GG:G	donor_gain	1.0000
11:13360424:GG:G	donor_gain	1.0000
11:13366655:A:AG	acceptor_gain	1.0000
11:13366656:T:G	acceptor_gain	1.0000
11:13366662:CAG:C	acceptor_loss	1.0000
11:13366663:A:AG	acceptor_gain	1.0000
11:13366663:AGAAT:A	acceptor_gain	1.0000
11:13366664:G:GA	acceptor_gain	1.0000
11:13366664:G:T	acceptor_loss	1.0000
11:13366664:GA:G	acceptor_gain	1.0000
11:13366664:GAA:G	acceptor_gain	1.0000
11:13366664:GAAT:G	acceptor_gain	1.0000
11:13366664:GAATG:G	acceptor_gain	1.0000
11:13366779:AAAA:A	donor_gain	1.0000
11:13366780:AAA:A	donor_gain	1.0000
11:13366781:AA:A	donor_gain	1.0000
11:13366781:AAG:A	donor_loss	1.0000
11:13366782:AG:A	donor_loss	1.0000

AlphaMissense

4146 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:13358441:C:G	H77D	1.000
11:13358443:C:A	H77Q	1.000
11:13358443:C:G	H77Q	1.000
11:13358453:G:A	E81K	1.000
11:13358454:A:T	E81V	1.000
11:13358455:A:C	E81D	1.000
11:13358455:A:T	E81D	1.000
11:13358456:A:G	K82E	1.000
11:13358458:G:C	K82N	1.000
11:13358458:G:T	K82N	1.000
11:13358460:G:C	R83P	1.000
11:13358462:C:A	R84S	1.000
11:13358462:C:G	R84G	1.000
11:13358462:C:T	R84C	1.000
11:13358463:G:C	R84P	1.000
11:13358465:C:G	R85G	1.000
11:13358465:C:T	R85W	1.000
11:13358466:G:A	R85Q	1.000
11:13358466:G:C	R85P	1.000
11:13358466:G:T	R85L	1.000
11:13358475:T:A	M88K	1.000
11:13358475:T:C	M88T	1.000
11:13358475:T:G	M88R	1.000
11:13358476:G:A	M88I	1.000
11:13358476:G:C	M88I	1.000
11:13358476:G:T	M88I	1.000
11:13358477:A:G	N89D	1.000
11:13358479:C:A	N89K	1.000
11:13358479:C:G	N89K	1.000
11:13358487:T:A	I92K	1.000

dbSNP variants (sampled 300 via entrez): RS1000018255 (11:13328441 T>C), RS1000018455 (11:13365151 T>A,G), RS1000077389 (11:13314668 T>G), RS1000082255 (11:13335813 A>G), RS1000119372 (11:13339569 A>G), RS1000134636 (11:13336058 C>T), RS1000144267 (11:13290162 G>T), RS1000161453 (11:13354660 C>T), RS1000202020 (11:13383633 G>A), RS1000226993 (11:13349049 A>G), RS1000382599 (11:13342143 C>T), RS1000461094 (11:13324186 G>A,C), RS1000474488 (11:13328813 A>C), RS1000486585 (11:13302206 A>G), RS1000493711 (11:13291539 A>G)

Disease associations

OMIM: gene MIM:602550 | disease phenotypes:

GenCC curated gene-disease

Mondo (2): neurodevelopmental disorder (MONDO:0700092), primary ovarian failure (MONDO:0005387)

Orphanet (1): NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

67 associations (top):

Study	Trait	p-value
GCST000880_20	Menarche (age at onset)	2.000000e-08
GCST001684_3	Plasminogen activator inhibitor type 1 levels (PAI-1)	2.000000e-10
GCST001839_1	Schizophrenia	5.000000e-06
GCST002541_84	Menarche (age at onset)	7.000000e-20
GCST002678_6	Iron status biomarkers (transferrin levels)	4.000000e-10
GCST002783_247	Body mass index	6.000000e-06
GCST002783_426	Body mass index	8.000000e-06
GCST003681_3	C-reactive protein levels or triglyceride levels (pleiotropy)	9.000000e-09
GCST003993_18	Menarche (age at onset)	1.000000e-06
GCST004787_10	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	5.000000e-08
GCST005195_22	Coronary artery disease	9.000000e-09
GCST005196_46	Coronary artery disease	7.000000e-08
GCST006187_31	Diastolic blood pressure (cigarette smoking interaction)	7.000000e-18
GCST006188_10	Systolic blood pressure (cigarette smoking interaction)	9.000000e-14
GCST006227_11	Diastolic blood pressure	2.000000e-08
GCST006611_65	HDL cholesterol	1.000000e-10
GCST006666_4	Lipid traits (pleiotropy) (HIPO component 1)	4.000000e-12
GCST006940_149	Neurociticism	9.000000e-13
GCST006943_4	Feeling miserable	9.000000e-09
GCST006945_21	Feeling guilty	8.000000e-12
GCST006946_5	Worry too long after an embarrassing experience	2.000000e-16
GCST007094_119	Diastolic blood pressure	2.000000e-08
GCST007325_272	General risk tolerance (MTAG)	1.000000e-13
GCST007540_7	PEG-asparaginase hypersensitivity without enzyme activity in childhood acute lymphoblastic leukaemia	7.000000e-06
GCST007576_325	Chronotype	5.000000e-10
GCST007576_388	Chronotype	9.000000e-09
GCST007614_21	C-reactive protein levels	4.000000e-12
GCST007615_31	C-reactive protein levels	3.000000e-08
GCST007692_108	Chronic obstructive pulmonary disease	4.000000e-09
GCST007704_43	Diastolic blood pressure	3.000000e-07

EFO canonical traits (32, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0004792	plasminogen activator inhibitor 1 measurement
EFO:0004461	iron biomarker measurement
EFO:0006341	transferrin measurement
EFO:0004340	body mass index
EFO:0004458	C-reactive protein measurement
EFO:0004530	triglyceride measurement
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement
EFO:0006335	systolic blood pressure
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0007660	neuroticism measurement
EFO:0009598	feeling miserable measurement
EFO:0009595	guilt measurement
EFO:0009589	worry measurement
EFO:0008579	risk-taking behaviour
EFO:0004881	asparaginase hypersensitivity
EFO:0008328	chronotype measurement
EFO:0006340	mean arterial pressure
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0004329	alcohol drinking
EFO:0010091	tea consumption measurement
EFO:0004874	memory performance
EFO:0000195	metabolic syndrome
EFO:0008111	diet measurement
EFO:0009592	social interaction measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1982350	BMAL1		0.00	0
rs2278749	BMAL1		0.00	0
rs2279287	BMAL1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	9
Benzo(a)pyrene	decreases expression, affects methylation	4
sodium arsenite	decreases expression, increases expression	2
epigallocatechin gallate	affects cotreatment, affects localization, increases expression, affects reaction, decreases expression (+3 more)	2
Dexamethasone	affects cotreatment, increases expression, affects expression	2
Gallic Acid	affects cotreatment, affects reaction, decreases expression, decreases phosphorylation, increases expression (+3 more)	2
Hydrogen Peroxide	affects cotreatment, affects reaction, decreases expression, decreases reaction, decreases phosphorylation (+1 more)	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
bisphenol A	increases expression, affects cotreatment	1
geraniol	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
1,3-dichloro-2-propanol	decreases expression, decreases localization, decreases reaction	1
gadolinium chloride	increases abundance, increases expression	1
gallocatechol	affects cotreatment, decreases expression, decreases reaction, affects expression, affects localization (+3 more)	1
2-(4-(2-carboxyethyl)phenethylamino)-5’-N-ethylcarboxamidoadenosine	affects cotreatment, increases expression	1
epicatechin gallate	affects reaction, decreases expression, increases expression, affects cotreatment, affects localization (+3 more)	1
CGP 52608	increases reaction, affects binding	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
NSC 689534	increases expression, affects binding	1
(+)-JQ1 compound	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
KL001	decreases expression, decreases reaction, increases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1
Aminooxyacetic Acid	affects reaction, affects expression, increases expression	1

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1K2	Abcam HeLa ARNTL KO	Cancer cell line	Female
CVCL_B8BI	Abcam HCT 116 ARNTL KO	Cancer cell line	Male
CVCL_B9DL	Abcam A-549 ARNTL KO	Cancer cell line	Male
CVCL_D1UZ	Abcam MCF-7 ARNTL KO	Cancer cell line	Female
CVCL_SD54	HAP1 ARNTL (-) 1	Cancer cell line	Male
CVCL_XL53	HAP1 ARNTL (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
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
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
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
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
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
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game