NPAS2

Summary

NPAS2 (neuronal PAS domain protein 2, HGNC:7895) is a protein-coding gene on chromosome 2q11.2, encoding Neuronal PAS domain-containing protein 2 (Q99743). Transcriptional activator which forms a core component of the circadian clock.

The protein encoded by this gene is a member of the basic helix-loop-helix (bHLH)-PAS family of transcription factors. A similar mouse protein may play a regulatory role in the acquisition of specific types of memory. It also may function as a part of a molecular clock operative in the mammalian forebrain.

Source: NCBI Gene 4862 — RefSeq curated summary.

At a glance

• Gene–disease (curated): azoospermia (Limited, GenCC)
• GWAS associations: 15
• Clinical variants (ClinVar): 147 total — 1 likely-pathogenic
• Transcription factor: yes — 10 downstream targets (CollecTRI)
• MANE Select transcript: NM_002518

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7895
Approved symbol	NPAS2
Name	neuronal PAS domain protein 2
Location	2q11.2
Locus type	gene with protein product
Status	Approved
Aliases	MOP4, PASD4, bHLHe9
Ensembl gene	ENSG00000170485
Ensembl biotype	protein_coding
OMIM	603347
Entrez	4862

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 12 protein_coding, 4 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000335681, ENST00000427413, ENST00000433408, ENST00000448812, ENST00000450763, ENST00000451740, ENST00000471974, ENST00000474550, ENST00000486017, ENST00000490052, ENST00000492373, ENST00000495559, ENST00000906777, ENST00000906778, ENST00000933582, ENST00000960862, ENST00000960863, ENST00000960864

RefSeq mRNA: 1 — MANE Select: NM_002518 NM_002518

CCDS: CCDS2048

Canonical transcript exons

ENST00000335681 — 21 exons

Exon	Start	End
ENSE00000771928	100965660	100965766
ENSE00001254213	100988079	100988276
ENSE00001254232	100970990	100971074
ENSE00001374878	100964861	100964943
ENSE00001471957	100820139	100820414
ENSE00001731234	100968281	100968428
ENSE00001885611	100995400	100996829
ENSE00003467877	100948235	100948355
ENSE00003492048	100932910	100933001
ENSE00003493586	100925146	100925294
ENSE00003506525	100990256	100990446
ENSE00003506758	100974803	100974944
ENSE00003514326	100990780	100990872
ENSE00003523466	100982231	100982377
ENSE00003625557	100904733	100904786
ENSE00003629074	100993347	100993527
ENSE00003633283	100949367	100949480
ENSE00003666918	100964058	100964176
ENSE00003670844	100977710	100977799
ENSE00003690856	100975458	100975567
ENSE00003790872	100937753	100937842

Expression profiles

Bgee: expression breadth ubiquitous, 266 present calls, max score 98.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.7873 / max 526.7426, expressed in 1479 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21601	20.9809	1476
21604	0.5750	308
21602	0.1389	50
202322	0.0682	34
21603	0.0243	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	98.28	gold quality
esophagus mucosa	UBERON:0002469	94.19	gold quality
body of pancreas	UBERON:0001150	93.74	gold quality
metanephros cortex	UBERON:0010533	93.19	gold quality
apex of heart	UBERON:0002098	93.04	gold quality
body of stomach	UBERON:0001161	91.35	gold quality
pancreas	UBERON:0001264	91.14	gold quality
heart left ventricle	UBERON:0002084	91.04	gold quality
skin of leg	UBERON:0001511	91.03	gold quality
esophagus	UBERON:0001043	90.77	gold quality
cardiac ventricle	UBERON:0002082	90.68	gold quality
right atrium auricular region	UBERON:0006631	90.38	gold quality
stomach	UBERON:0000945	89.83	gold quality
skin of abdomen	UBERON:0001416	89.83	gold quality
prefrontal cortex	UBERON:0000451	89.72	gold quality
cardiac atrium	UBERON:0002081	89.44	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.19	gold quality
right frontal lobe	UBERON:0002810	89.10	gold quality
heart	UBERON:0000948	89.05	gold quality
caudate nucleus	UBERON:0001873	89.02	gold quality
nucleus accumbens	UBERON:0001882	89.01	gold quality
islet of Langerhans	UBERON:0000006	88.94	gold quality
thoracic aorta	UBERON:0001515	88.29	gold quality
ascending aorta	UBERON:0001496	88.23	gold quality
minor salivary gland	UBERON:0001830	88.14	gold quality
cingulate cortex	UBERON:0003027	88.05	gold quality
anterior cingulate cortex	UBERON:0009835	87.85	gold quality
vagina	UBERON:0000996	87.81	gold quality
cartilage tissue	UBERON:0002418	87.72	gold quality
urinary bladder	UBERON:0001255	87.55	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

10 targets.

Target	Regulation
AANAT
ADCY1
BMAL1
CRY1	Unknown
CRY2	Unknown
MAOA	Unknown
NPAS2
PER1	Unknown
PER2	Unknown
RDH12

Upstream regulators (CollecTRI, top): CLOCK, KAT2B, NPAS2, NR1D1, RORA

miRNA regulators (miRDB)

120 targeting NPAS2, 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-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-526B-3P	99.88	74.06	2587

Literature-anchored findings (GeneRIF, showing 38)

• A significant difference between patients with seasonal affective disorder (SAD) and controls is found for NPAS2 protein (471 Leu/Ser) indicating a recessive effect of the leucine allele on SAD susceptibility. (PMID:12655319)
• the CLOCK(NPAS2)/BMAL1 complex is post-translationally regulated by cry1 and cry2 (PMID:16628007)
• Our results demonstrate a robust association of the variant Thr genotypes (Ala/Thr and Thr/Thr) with reduced risk of non-Hodgkin’s lymphoma. (PMID:17096334)
• With autisitc disorder, haplotype analysis of two-marker haplotypes showed that in npas2 40 out of the 136 possible two-marker combinations were significant, with the best result between markers rs1811399 and rs2117714. (PMID:17264841)
• a role of the circadian gene NPAS2 in human breast cancer, suggesting that genetic variations in circadian genes might be a novel panel of biomarkers for breast cancer risk. (PMID:17453337)
• variations associated with seasonal affective disorder (PMID:17457720)
• knockdown of NPAS2 significantly represses the expression of several cell cycle and DNA repair genes in breast and colorectal neoplasms. (PMID:18819933)
• Variations in circadian genes are associated with serum levels of androgens and IGF markers, particularly NPAS2 rs2305160:G>A(Ala394Thr). (PMID:18990770)
• The 1st list of direct transcriptional targets of NPAS2 comprises 26 genes that contain potential NPAS2 binding regions, 9 of which are involved in tumorigenesis. (PMID:19457610)
• A high level of NPAS2 expression was strongly associated with improved disease free survival & overall survival. The Ala/Ala, Ala/Thr, & Thr/Thr genotypes were also differentially distributed by tumor severity, as measured by TNM classification. (PMID:19649706)
• ARNTL and NPAS2 SNPs were associated with reproduction and with seasonal variation. (PMID:20368993)
• Data demonstrate that NPAS2 is also a RORalpha and REV-ERBalpha target gene. (PMID:20817722)
• found a novel functional SNP (rs3739008) located at 3’UTR of NPAS2 and the C to T changing of the SNP may disrupt the binding of microRNA- (miR-) 17-5p and miR-519e to the 3’UTR of NPAS2 (PMID:21140207)
• Convergent functional genomics allowed the identification of novel candidate genes, GRIK2 and NPAS2, involved in glutamatergic neurotransmission and the circadian rhythm, respectively, that are potentially associated with CFS. (PMID:21912186)
• Genetic variants of NPAS2 associate with seasonal affective disorder or winter depression. (PMID:22538398)
• Variants in NPAS2 have been associated with seasonality and seasonal affective disorder, phenotypes that could reflect circadian rhythm disruption. (PMID:23449886)
• Functional rs1053096 and rs2305160 polymorphisms in the NPAS2 gene are associated with overall survival in transcatheter arterial chemoembolization-treated hepatocellular carcinoma patients. (PMID:24754267)
• distributions of allelic, genotypic, and haplotypic variants of NPAS2 (rs2305160 and rs6725296) were not significantly different between schizophrenic patients with and without RLS (PMID:24824748)
• Two single nucleotide polymorphisms in RORA were associated with breast cancer in the whole sample and among postmenopausal women, and we also reported an association with CLOCK, RORA, and NPAS2 in the analyses at the gene level (PMID:24919398)
• NPAS2, functioned as a potential tumor suppressor gene, could serve as a promising target and potential prognostic indicator for colorectal cancer. (PMID:24978311)
• NPAS2 rs2305160 polymorphism does not appear to have any association with risk of chronic lymphocytic leukemia in our Pakistani population. (PMID:25227809)
• With whole-exome sequencing a novel mutation in NPAS2 was identified in a Turkish family with nonobstructive azoospermia. (PMID:25956372)
• Genetic variations in NPAS2 might be a biomarker for a seasonal pattern in bipolar disorders. (PMID:25989161)
• CLOCK, ARNTL, and NPAS2 gene polymorphisms may have a role in seasonal variations in mood and behavior (PMID:26134245)
• NPAS2 has a critical role in HCC cell survival and tumor growth, which is mainly mediated by transcriptional upregulation of CDC25A. (PMID:28333141)
• Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (ppathway < 0.00625). The two most significant genes were NPAS2 (pgene = 0.0062) and AANAT (pgene = 0.00078); the latter being significant after Bonferroni correction. (PMID:28699174)
• Significantly, this study is the first to show that a variant copy number GGC repeat sequence in the NPAS2 clock gene associates with melanoma risk and which may be useful in the assessment of melanoma predisposition. (PMID:28799406)
• NPAS2 hypomethylation occurs at the early stage of PD and is a moderate biomarker for distinguishing PD patients from healthy subjects. (PMID:29353016)
• Study reported an association between the risk of prostate cancer and the circadian pathway where significant associations were found for the genes NPAS2 and PER1. (PMID:30665264)
• Our findings demonstrate that NPAS2 plays a critical role in glucose metabolism reprogramming, suggesting that NPAS2 may serve as a potential therapeutic target in HCC. (PMID:31765736)
• Circadian genes polymorphisms, night work and prostate cancer risk: Findings from the EPICAP study. (PMID:32506468)
• Genetic variants in NPAS2 gene and clinical outcomes of resectable non-small-cell lung cancer. (PMID:33541123)
• Roles of NPAS2 in circadian rhythm and disease. (PMID:34415290)
• Integrative Molecular Analyses of an Individual Transcription Factor-Based Genomic Model for Lung Cancer Prognosis. (PMID:34925645)
• NPAS2 promotes aerobic glycolysis and tumor growth in prostate cancer through HIF-1A signaling. (PMID:36978001)
• Characterization of molecular subtypes based on chromatin regulators and identification of the role of NPAS2 in lung adenocarcinoma. (PMID:37120564)
• High expression of the circadian clock gene NPAS2 is associated with progression and poor prognosis of gastric cancer: A single-center study. (PMID:37398880)
• Association between glucose metabolism, the circadian cycle and hypoxia: Evaluation of the NPAS2 and Rev-Erb-alpha protein serum levels in obstructive sleep apnea patients - a pilot study. (PMID:38804230)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
mus_musculus	Npas2	ENSMUSG00000026077
rattus_norvegicus	Npas2	ENSRNOG00000013408
drosophila_melanogaster	Met	FBGN0002723
drosophila_melanogaster	Clk	FBGN0023076
drosophila_melanogaster	gce	FBGN0261703
drosophila_melanogaster	tgo	FBGN0264075
caenorhabditis_elegans	aha-1	WBGENE00000095

Paralogs (6): BMAL2 (ENSG00000029153), BMAL1 (ENSG00000133794), CLOCK (ENSG00000134852), ARNT (ENSG00000143437), PASD1 (ENSG00000166049), ARNT2 (ENSG00000172379)

Protein

Protein identifiers

Neuronal PAS domain-containing protein 2 — Q99743 (reviewed: Q99743)

Alternative names: Basic-helix-loop-helix-PAS protein MOP4, Class E basic helix-loop-helix protein 9, Member of PAS protein 4, PAS domain-containing protein 4

All UniProt accessions (7): Q99743, A2I2P5, H7BZA3, H7BZY5, H7C080, H7C0J4, H7C0Z2

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. 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. NPAS2 plays an important role in sleep homeostasis and in maintaining circadian behaviors in normal light/dark and feeding conditions and in the effective synchronization of feeding behavior with scheduled food availability. Regulates the gene transcription of key metabolic pathways in the liver and is involved in DNA damage response by regulating several cell cycle and DNA repair genes. Controls the circadian rhythm of NR0B2 expression by binding rhythmically to its promoter. Mediates the diurnal variation in the expression of GABARA1 receptor in the brain and contributes to the regulation of anxiety-like behaviors and GABAergic neurotransmission in the ventral striatum.

Subunit / interactions. Component of the circadian clock oscillator which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins. Efficient DNA binding requires dimerization with another bHLH protein. Forms a heterodimer with BMAL1 and this heterodimerization is required for E-box-dependent transactivation. Interacts with NCOA3, KAT2B, CREBBP and EP300.

Subcellular location. Nucleus.

Activity regulation. Carbon monoxide (CO) and the redox state of the cell can modulate the transcriptional activity of the NPAS2-BMAL1 heterodimer. NADH and NADPH enhance the DNA-binding activity of the heterodimer whereas CO binds the heme group in NPAS2 and inhibits the DNA-binding activity of the heterodimer.

Polymorphism. Variants in NPAS2 show a susceptibility to seasonal affective disorder (SAD) [MIM:608516]. SAD is a depressive condition resulting from seasonal changes, and with diurnal preference.

RefSeq proteins (1): NP_002509* (*=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
IPR047230	CLOCK-like	Family

Pfam: PF00010, PF00989, PF14598

UniProt features (30 total): compositionally biased region 12, region of interest 6, domain 4, sequence conflict 3, binding site 2, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99743-F1	61.78	0.34

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 (2): 119 (axial binding residue); 171 (axial binding residue)

Function

Pathways and Gene Ontology

Reactome pathways

6 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-9931509	Expression of BMAL (ARNTL), CLOCK, and NPAS2
R-HSA-9931510	Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes
R-HSA-9931521	The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex

MSigDB gene sets: 246 (showing top): GOBP_CIRCADIAN_RHYTHM, FXR_IR1_Q6, TAATAAT_MIR126, BENPORATH_ES_WITH_H3K27ME3, GOBP_BEHAVIOR, RORA1_01, TGCACTT_MIR519C_MIR519B_MIR519A, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, AREB6_01, GOBP_POSITIVE_REGULATION_OF_BEHAVIOR, TGACCTY_ERR1_Q2, GOBP_CIRCADIAN_REGULATION_OF_GENE_EXPRESSION, TAL1ALPHAE47_01, HNF1_Q6, GOBP_REGULATION_OF_DNA_REPAIR

GO Biological Process (12): regulation of transcription by RNA polymerase II (GO:0006357), DNA damage response (GO:0006974), central nervous system development (GO:0007417), response to xenobiotic stimulus (GO:0009410), circadian regulation of gene expression (GO:0032922), positive regulation of DNA repair (GO:0045739), positive regulation of DNA-templated transcription (GO:0045893), response to redox state (GO:0051775), positive regulation of behavioral fear response (GO:2000987), regulation of DNA-templated transcription (GO:0006355), regulation of gene expression (GO:0010468), rhythmic process (GO:0048511)

GO Molecular Function (9): 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), DNA-binding transcription factor activity (GO:0003700), metal ion binding (GO:0046872), protein dimerization activity (GO:0046983), Hsp90 protein binding (GO:0051879), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515)

GO Cellular Component (7): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), CLOCK-BMAL transcription complex (GO:1990513), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Circadian clock	4
Regulation of lipid metabolism by PPARalpha	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of DNA-templated transcription	3
regulation of gene expression	2
DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
transcription by RNA polymerase II	1
cellular response to stress	1
nervous system development	1
system development	1
response to chemical	1
circadian rhythm	1
DNA repair	1
regulation of DNA repair	1
positive regulation of response to stimulus	1
positive regulation of DNA metabolic process	1
positive regulation of RNA biosynthetic process	1
response to stimulus	1
behavioral fear response	1
positive regulation of defense response	1
positive regulation of behavior	1
positive regulation of fear response	1
regulation of behavioral fear response	1
regulation of RNA biosynthetic process	1
gene expression	1
regulation of macromolecule biosynthetic process	1
biological_process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
cation binding	1
protein binding	1
heat shock protein binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
binding	1
chromosome	1

Protein interactions and networks

STRING

944 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPAS2	BMAL1	O00327	991
NPAS2	CRY1	Q16526	976
NPAS2	NR1D1	P20393	972
NPAS2	BMAL2	Q8WYA1	954
NPAS2	CRY2	Q49AN0	953
NPAS2	CLOCK	O15516	943
NPAS2	NR1D2	Q14995	938
NPAS2	NFIL3	Q16649	930
NPAS2	BHLHE41	Q9C0J9	929
NPAS2	RORA	P35397	924
NPAS2	BHLHE40	O14503	921
NPAS2	RORB	Q92753	921
NPAS2	TIMELESS	Q9UNS1	883
NPAS2	CSNK1E	P49674	881
NPAS2	RORC	P51449	851

IntAct

81 interactions, top by confidence:

A	B	Type	Score
CLOCK	BMAL1	psi-mi:“MI:0914”(association)	0.880
NPAS2	BMAL1	psi-mi:“MI:0915”(physical association)	0.740
NPAS2	BMAL2	psi-mi:“MI:0915”(physical association)	0.740
BMAL1	NPAS2	psi-mi:“MI:0915”(physical association)	0.740
BMAL2	NPAS2	psi-mi:“MI:0915”(physical association)	0.740
BMAL1	CLOCK	psi-mi:“MI:0914”(association)	0.720
BMAL2	CLOCK	psi-mi:“MI:0914”(association)	0.670
BMAL1	NPAS2	psi-mi:“MI:0915”(physical association)	0.630
NPAS2	BMAL1	psi-mi:“MI:0915”(physical association)	0.630
NCK2	NPAS2	psi-mi:“MI:0915”(physical association)	0.560
NGLY1	NPAS2	psi-mi:“MI:0915”(physical association)	0.560
NPAS2	BPIFA1	psi-mi:“MI:0915”(physical association)	0.560
INCA1	NPAS2	psi-mi:“MI:0915”(physical association)	0.560
UBAP2	NPAS2	psi-mi:“MI:0915”(physical association)	0.560
FGFR3	NPAS2	psi-mi:“MI:0915”(physical association)	0.560
GRIN2C	NPAS2	psi-mi:“MI:0915”(physical association)	0.560
	NPAS2	psi-mi:“MI:0915”(physical association)	0.560
RBM25	PRPF40A	psi-mi:“MI:0914”(association)	0.560
NPAS2	Bmal1	psi-mi:“MI:0915”(physical association)	0.550

BioGRID (60): NPAS2 (Affinity Capture-RNA), NPAS2 (Two-hybrid), NPAS2 (Two-hybrid), NPAS2 (Two-hybrid), NPAS2 (Two-hybrid), NPAS2 (Two-hybrid), RORC (Two-hybrid), NPAS2 (Two-hybrid), NPAS2 (Affinity Capture-MS), NPAS2 (Affinity Capture-MS), NPAS2 (Affinity Capture-RNA), NPAS2 (Reconstituted Complex), NCOA3 (Reconstituted Complex), EP300 (Reconstituted Complex), KAT2B (Reconstituted Complex)

ESM2 similar proteins: A0AVK6, A4L9P5, B2GUN4, D2HNW6, D3ZGB1, E1BKK0, E1BP74, E1BZ85, F1LMN3, O14607, O15164, O15550, O70546, O88850, O88904, O94916, Q14B70, Q58CW6, Q58FA4, Q5RJA1, Q5ZKW8, Q64127, Q6B4Z3, Q7Z353, Q7Z3K3, Q84VX4, Q86Z02, Q8BJ34, Q8BZH4, Q8C7R7, Q8HWS3, Q8IXK0, Q8K0L9, Q8N187, Q93073, Q99743, Q99MQ1, Q99PP7, Q9BYH8, Q9ERH7

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

3 interactions.

A	Effect	B	Mechanism
NPAS2	“form complex”	BMAL1/NPAS2	binding
RORA	“up-regulates quantity by expression”	NPAS2	“transcriptional regulation”
NR1D1	“down-regulates quantity by repression”	NPAS2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 32 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes	5	125.2×	4e-08

GO biological processes:

GO term	Partners	Fold	FDR
circadian regulation of gene expression	5	43.3×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	93
Likely benign	15
Benign	10

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
242856	NM_002518.4(NPAS2):c.1363C>G (p.Pro455Ala)	Likely pathogenic

SpliceAI

4844 predictions. Top by Δscore:

Variant	Effect	Δscore
2:100904728:TGCA:T	acceptor_loss	1.0000
2:100904729:GCAG:G	acceptor_loss	1.0000
2:100904730:CAGG:C	acceptor_loss	1.0000
2:100904731:A:AG	acceptor_gain	1.0000
2:100904731:AG:A	acceptor_gain	1.0000
2:100904731:AGG:A	acceptor_loss	1.0000
2:100904732:G:GG	acceptor_gain	1.0000
2:100904732:GG:G	acceptor_gain	1.0000
2:100904732:GGAA:G	acceptor_gain	1.0000
2:100904732:GGAAA:G	acceptor_gain	1.0000
2:100922908:GAGCA:G	donor_gain	1.0000
2:100922910:GCA:G	donor_gain	1.0000
2:100922913:G:GG	donor_gain	1.0000
2:100922921:C:G	donor_gain	1.0000
2:100925141:TACAG:T	acceptor_gain	1.0000
2:100925142:ACAG:A	acceptor_loss	1.0000
2:100925142:ACAGA:A	acceptor_gain	1.0000
2:100925143:C:G	acceptor_gain	1.0000
2:100925143:CA:C	acceptor_loss	1.0000
2:100925143:CAG:C	acceptor_gain	1.0000
2:100925144:A:AG	acceptor_gain	1.0000
2:100925144:AGA:A	acceptor_gain	1.0000
2:100925145:G:GT	acceptor_gain	1.0000
2:100925145:GA:G	acceptor_gain	1.0000
2:100925145:GAG:G	acceptor_gain	1.0000
2:100925145:GAGC:G	acceptor_gain	1.0000
2:100925145:GAGCT:G	acceptor_gain	1.0000
2:100938866:G:GG	donor_gain	1.0000
2:100948233:A:AG	acceptor_gain	1.0000
2:100948233:AGTC:A	acceptor_gain	1.0000

AlphaMissense

5384 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:100904786:G:C	R11T	1.000
2:100925146:A:C	R11S	1.000
2:100925146:A:T	R11S	1.000
2:100925153:C:G	R14G	1.000
2:100925154:G:A	R14Q	1.000
2:100925154:G:C	R14P	1.000
2:100925154:G:T	R14L	1.000
2:100925156:A:G	N15D	1.000
2:100925158:C:A	N15K	1.000
2:100925158:C:G	N15K	1.000
2:100925165:G:A	E18K	1.000
2:100925166:A:T	E18V	1.000
2:100925167:G:C	E18D	1.000
2:100925167:G:T	E18D	1.000
2:100925168:A:G	K19E	1.000
2:100925170:G:C	K19N	1.000
2:100925170:G:T	K19N	1.000
2:100925174:C:A	R21S	1.000
2:100925174:C:G	R21G	1.000
2:100925174:C:T	R21C	1.000
2:100925175:G:C	R21P	1.000
2:100925177:C:G	R22G	1.000
2:100925178:G:C	R22P	1.000
2:100925186:T:C	F25L	1.000
2:100925187:T:C	F25S	1.000
2:100925188:C:A	F25L	1.000
2:100925188:C:G	F25L	1.000
2:100925191:T:A	N26K	1.000
2:100925191:T:G	N26K	1.000
2:100925196:T:C	L28P	1.000

dbSNP variants (sampled 300 via entrez): RS1000002027 (2:100976864 A>G), RS1000002731 (2:100983579 G>A,T), RS1000012549 (2:100897426 A>T), RS1000045001 (2:100897601 C>T), RS1000048614 (2:100873945 A>T), RS1000096204 (2:100956508 T>C), RS1000139205 (2:100878331 A>G), RS1000142226 (2:100924333 C>G), RS1000152629 (2:100850844 T>C,G), RS1000199911 (2:100820375 C>A,G,T), RS1000223601 (2:100833414 A>C,T), RS1000229720 (2:100954242 C>G,T), RS1000238879 (2:100873988 G>T), RS1000240864 (2:100954729 A>C), RS1000255406 (2:100874558 A>G)

Disease associations

OMIM: gene MIM:603347 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
azoospermia	Limited	Autosomal recessive

Mondo (1): azoospermia (MONDO:0100459)

Orphanet (0):

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST001334_6	Creutzfeldt-Jakob disease (variant)	4.000000e-08
GCST002598_48	Educational attainment	8.000000e-06
GCST006394_47	Intraocular pressure	2.000000e-08
GCST007096_129	Pulse pressure	1.000000e-08
GCST007576_320	Chronotype	1.000000e-12
GCST009391_200	Metabolite levels	7.000000e-06
GCST009413_16	Intraocular pressure	5.000000e-08
GCST009415_1	Intraocular pressure and central corneal thickness (multi-trait analysis)	1.000000e-07
GCST009725_74	Intraocular pressure	6.000000e-08
GCST012194_9	Obsessive-compulsive traits	8.000000e-07
GCST90002401_380	Platelet distribution width	1.000000e-10
GCST90002407_54	White blood cell count	9.000000e-10
GCST90011899_52	Aspartate aminotransferase levels	5.000000e-09
GCST90020028_64	Hip circumference adjusted for BMI	1.000000e-09
GCST90020028_65	Hip circumference adjusted for BMI	3.000000e-08

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004784	self reported educational attainment
EFO:0004695	intraocular pressure measurement
EFO:0005763	pulse pressure measurement
EFO:0008328	chronotype measurement
EFO:0010483	gentisic acid measurement
EFO:0005213	central corneal thickness
EFO:0007984	platelet component distribution width
EFO:0004736	aspartate aminotransferase measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D053713	Azoospermia	C12.100.500.430.380; C12.100.750.700.380; C12.200.294.430.380

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression, affects splicing	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
nickel sulfate	increases expression	2
Resveratrol	increases expression	2
Temozolomide	affects response to substance, decreases expression	2
Valproic Acid	decreases methylation, increases methylation	2
Cyclosporine	increases expression	2
Aflatoxin B1	increases methylation, decreases methylation	2
Particulate Matter	increases expression, increases methylation	2
aristolochic acid I	decreases expression	1
dicrotophos	increases expression	1
dihydroouabain	affects binding, increases reaction, increases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	decreases expression	1
hydroxyhydroquinone	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
cobaltous chloride	decreases expression	1
potassium chromate(VI)	increases expression	1
aflatoxin B2	increases methylation	1
cupric chloride	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression, affects response to substance, increases expression	1
avobenzone	increases expression	1
CGP 52608	affects binding, increases reaction	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
jinfukang	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Sunitinib	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Caffeine	increases phosphorylation	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A4R8	SEES3-1V human NPAS2, clone1	Embryonic stem cell	Male
CVCL_A4R9	SEES3-1V human NPAS2, clone2	Embryonic stem cell	Male
CVCL_A4S0	SEES3-1V human NPAS2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02307994	PHASE4	UNKNOWN	Clinical Research on Effectiveness and Safety of Treatment of Severe Oligospermia or Azoospermia With uFSH
NCT02275169	PHASE3	UNKNOWN	FSH Treatment for Non-obstructive Azoospermic Patients
NCT02544191	PHASE2	UNKNOWN	GnRHa Combined With hCG and hMG for Treatment of Patients With Non-obstructive Azoospermia
NCT03762967	PHASE2	UNKNOWN	Autologous Adipose-Derived Adult Stromal Vascular Cell Administration for Male Patients With Infertility
NCT02041910	PHASE1/PHASE2	UNKNOWN	Testicular Injection of Autologous Stem Cells for Treatment of Patients With Azoospermia
NCT00282477	Not specified	UNKNOWN	Trial to Evaluate Erectile Function, Fertility and Sperm Count in Male Cyclists Compared to Age Matched Controls
NCT00484081	Not specified	COMPLETED	Microdissection Testicular Sperm Extraction (MicroTESE) and IVF-ICSI Outcome in Non-Obstructive Azoospermia (NOA)
NCT00548977	Not specified	COMPLETED	Genetic Studies Spermatogenic Failure
NCT01375062	Not specified	COMPLETED	Obtaining Undifferentiated Cells From Testis Biopsy
NCT01509482	Not specified	COMPLETED	Insulin Resistance in Idiopathic Oligospermia and Azoospermia
NCT02008799	Not specified	UNKNOWN	Intra Testicular Artery Injection of Bone Marrow Stem Cell in Management of Azoospermia
NCT02339272	Not specified	COMPLETED	Study of Synapsis and Recombination in Male Meiosis and the Implications in Infertility
NCT02414295	Not specified	COMPLETED	Sperm Production in Kleinfelter Syndrome Patients After Mesenchymal Stem Cell Injection
NCT02418832	Not specified	RECRUITING	Testis Needle Aspiration of Sperm in Men With Azoospermia
NCT02617173	Not specified	UNKNOWN	The Effect of Low Electrical Current on Testicular Spermatocyte Count
NCT02773498	Not specified	TERMINATED	Comparison of Medical Results of Testicular Sperm Extraction by Conventional Surgery and Microsurgical Track
NCT03497728	Not specified	TERMINATED	Detection of Microdeletions in the Azoospermia Factor (AZF) Regions in Infertile Male Patients
NCT04675164	Not specified	COMPLETED	Laser Assisted Sperm Selection of Viable Immotile Testicular Sperm in Azoospermic Infertile Men
NCT05479474	Not specified	RECRUITING	Platelet Rich Plasma Testis Treatment for Infertile Men
NCT05628987	Not specified	RECRUITING	The Association of Gut Microbiota and Spermatogenic Dysfunction
NCT05866484	Not specified	COMPLETED	Testicular Sperm Aspiration (TESA) vs. Microfluidic Sperm Separation (MSS)
NCT06524258	Not specified	COMPLETED	Testicular Elastography for Microscopic Testicular Sperm Extraction
NCT06841328	Not specified	RECRUITING	Fertility Enhancement Through Regenerative Treatment in Ovaries and Testes
NCT06941922	Not specified	RECRUITING	Testicular Evaluation of Azoospermia Using Micro-Ultrasound
NCT07074015	Not specified	RECRUITING	IntelliWell: An AI-Assisted Imaging Platform for Detection and Location of Ultra-Rare Testicular Sperm in Surgical Specimens
NCT07357701	Not specified	RECRUITING	Identifying Genome Variants in Non-Obstructive Azoospermia (NOA) or Primary Ovarian Insufficiency (POI)
NCT07542626	Not specified	RECRUITING	Fertility Restoration With Autografting of Cryopreserved Immature Testicular Tissue