NPAS1

Summary

NPAS1 (neuronal PAS domain protein 1, HGNC:7894) is a protein-coding gene on chromosome 19q13.32, encoding Neuronal PAS domain-containing protein 1 (Q99742). May control regulatory pathways relevant to schizophrenia and to psychotic illness.

The protein encoded by this gene is a member of the basic helix-loop-helix (bHLH)-PAS family of transcription factors. Studies of a related mouse gene suggest that it functions in neurons. The exact function of this gene is unclear, but it may play protective or modulatory roles during late embryogenesis and postnatal development.

Source: NCBI Gene 4861 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 86 total
• MANE Select transcript: NM_002517

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7894
Approved symbol	NPAS1
Name	neuronal PAS domain protein 1
Location	19q13.32
Locus type	gene with protein product
Status	Approved
Aliases	MOP5, PASD5, bHLHe11
Ensembl gene	ENSG00000130751
Ensembl biotype	protein_coding
OMIM	603346
Entrez	4861

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000439365, ENST00000449844, ENST00000594257, ENST00000594670, ENST00000600352, ENST00000601169, ENST00000602189, ENST00000602212, ENST00000906440, ENST00000906441, ENST00000940003, ENST00000941427, ENST00000941428

RefSeq mRNA: 2 — MANE Select: NM_002517 NM_001321086, NM_002517

CCDS: CCDS12694, CCDS82371

Canonical transcript exons

ENST00000602212 — 12 exons

Exon	Start	End
ENSE00000895953	47039036	47039151
ENSE00002237784	47021612	47021847
ENSE00003033461	47019837	47019997
ENSE00003192883	47045191	47045775
ENSE00003201377	47021006	47021169
ENSE00003463399	47040978	47041125
ENSE00003471055	47032278	47032351
ENSE00003497051	47042810	47042904
ENSE00003512242	47039407	47039564
ENSE00003541771	47035964	47036129
ENSE00003603750	47032643	47032732
ENSE00003643430	47040444	47040550

Expression profiles

Bgee: expression breadth ubiquitous, 168 present calls, max score 85.96.

FANTOM5 (CAGE): breadth broad, TPM avg 2.8455 / max 94.0971, expressed in 798 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176623	1.9994	552
176624	0.7387	338
176622	0.1074	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	85.96	silver quality
right frontal lobe	UBERON:0002810	81.20	gold quality
prefrontal cortex	UBERON:0000451	80.86	gold quality
cingulate cortex	UBERON:0003027	79.72	gold quality
anterior cingulate cortex	UBERON:0009835	79.53	gold quality
tendon of biceps brachii	UBERON:0008188	79.01	silver quality
amygdala	UBERON:0001876	77.89	gold quality
frontal cortex	UBERON:0001870	77.35	gold quality
neocortex	UBERON:0001950	77.35	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.65	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	76.57	gold quality
Brodmann (1909) area 9	UBERON:0013540	76.44	gold quality
skin of leg	UBERON:0001511	76.39	gold quality
pancreatic ductal cell	CL:0002079	76.33	silver quality
triceps brachii	UBERON:0001509	76.27	gold quality
skin of abdomen	UBERON:0001416	75.98	gold quality
cerebral cortex	UBERON:0000956	75.19	gold quality
gluteal muscle	UBERON:0002000	75.11	gold quality
ganglionic eminence	UBERON:0004023	73.78	gold quality
zone of skin	UBERON:0000014	73.57	gold quality
Ammon’s horn	UBERON:0001954	73.14	gold quality
cortical plate	UBERON:0005343	72.85	gold quality
temporal lobe	UBERON:0001871	72.21	gold quality
lower esophagus mucosa	UBERON:0035834	71.83	gold quality
parotid gland	UBERON:0001831	71.70	gold quality
telencephalon	UBERON:0001893	71.67	gold quality
descending thoracic aorta	UBERON:0002345	71.16	gold quality
secondary oocyte	CL:0000655	71.14	gold quality
ventricular zone	UBERON:0003053	70.94	gold quality
forebrain	UBERON:0001890	70.67	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.07

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
ARNT	Repression
ARNT2	Repression
EPO	Unknown
TH	Repression

miRNA regulators (miRDB)

2 targeting NPAS1, 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-5571-5P	99.49	66.99	1764
HSA-MIR-324-3P	99.26	66.31	1034

Literature-anchored findings (GeneRIF, showing 2)

• Here the authors examined the crystal structures of multi-domain NPAS1-ARNT and NPAS3-ARNT-DNA complexes, discovering each to contain four putative ligand-binding pockets. (PMID:27782878)
• Study provides a clear, unbiased view of the full spectrum of genes regulated by NPAS1 and NPAS3 and shows that these transcription factors are master regulators of neuropsychiatric function. These findings expose the molecular pathophysiology of NPAS1/3 mutations and provide a striking example of the shared, combinatorial nature of molecular pathways that underlie diagnostically distinct neuropsychiatric conditions. (PMID:28499489)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	npas1	ENSDARG00000015876
mus_musculus	Npas1	ENSMUSG00000001988
rattus_norvegicus	Npas1	ENSRNOG00000015376
drosophila_melanogaster	trh	FBGN0262139
caenorhabditis_elegans		WBGENE00001851

Paralogs (7): HIF1A (ENSG00000100644), SIM1 (ENSG00000112246), EPAS1 (ENSG00000116016), HIF3A (ENSG00000124440), NPAS3 (ENSG00000151322), SIM2 (ENSG00000159263), NPAS4 (ENSG00000174576)

Protein

Protein identifiers

Neuronal PAS domain-containing protein 1 — Q99742 (reviewed: Q99742)

Alternative names: Basic-helix-loop-helix-PAS protein MOP5, Class E basic helix-loop-helix protein 11, Member of PAS protein 5, PAS domain-containing protein 5

All UniProt accessions (4): Q99742, M0QX32, M0R1R8, M0R2M8

UniProt curated annotations — full annotation on UniProt →

Function. May control regulatory pathways relevant to schizophrenia and to psychotic illness. May play a role in late central nervous system development by modulating EPO expression in response to cellular oxygen level. Forms a heterodimer that binds core DNA sequence 5’-TACGTG-3’ within the hypoxia response element (HRE) leading to transcriptional repression on its target gene TH.

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein. Interacts with ARNT; forms a heterodimer that binds core DNA sequence 5’-[AG]CGTG-3’ within the hypoxia response element (HRE) leading to a transcriptional repressor on its target gene TH.

Subcellular location. Nucleus.

Isoforms (2)

UniProt ID	Names	Canonical?
Q99742-1	1	yes
Q99742-2	2

RefSeq proteins (2): NP_001308015, NP_002508* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR011598	bHLH_dom	Domain
IPR013655	PAS_fold_3	Domain
IPR013767	PAS_fold	Domain
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00989, PF08447, PF23171

UniProt features (18 total): sequence conflict 5, domain 4, splice variant 3, compositionally biased region 3, region of interest 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99742-F1	67.23	0.44

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 106 (showing top): MODULE_52, BENPORATH_ES_WITH_H3K27ME3, GOBP_BEHAVIOR, MODULE_118, GOBP_STARTLE_RESPONSE, GOBP_PARENTAL_BEHAVIOR, GOBP_REPRODUCTIVE_BEHAVIOR, MODULE_123, MODULE_165, MODULE_497, MODULE_98, MODULE_18, GOBP_NEUROMUSCULAR_PROCESS, GOMF_PROTEIN_HETERODIMERIZATION_ACTIVITY, GOMF_PROTEIN_DIMERIZATION_ACTIVITY

GO Biological Process (7): negative regulation of transcription by RNA polymerase II (GO:0000122), startle response (GO:0001964), regulation of transcription by RNA polymerase II (GO:0006357), central nervous system development (GO:0007417), maternal behavior (GO:0042711), negative regulation of DNA-templated transcription (GO:0045892), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (7): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription factor activity (GO:0003700), protein heterodimerization activity (GO:0046982), DNA binding (GO:0003677), protein binding (GO:0005515), protein dimerization activity (GO:0046983)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
DNA-templated transcription	2
transcription cis-regulatory region binding	2
negative regulation of DNA-templated transcription	1
response to external stimulus	1
neuromuscular process	1
nervous system development	1
system development	1
parental behavior	1
negative regulation of RNA biosynthetic process	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
transcription regulator activity	1
protein dimerization activity	1
nucleic acid binding	1
binding	1
protein binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

818 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPAS1	LHX6	Q9UPM6	669
NPAS1	PER1	O15534	631
NPAS1	ARNT	P27540	584
NPAS1	GYPE	P15421	570
NPAS1	BHLHE41	Q9C0J9	543
NPAS1	PVALB	P20472	514
NPAS1	ESRRG	P62508	506
NPAS1	MEPE	Q9NQ76	486
NPAS1	AKT3	Q9Y243	460
NPAS1	NKX2-1	P43699	447
NPAS1	LHX8	Q68G74	446
NPAS1	NPAS2	Q99743	419
NPAS1	NPAS4	Q8IUM7	417
NPAS1	MCHR2	Q969V1	414
NPAS1	PASD1	Q8IV76	405

IntAct

7 interactions, top by confidence:

A	B	Type	Score
NPAS1	DNAJB5	psi-mi:“MI:0914”(association)	0.530
NPAS1	DNAJB6	psi-mi:“MI:0914”(association)	0.350
NPAS1	CIBAR1	psi-mi:“MI:0914”(association)	0.350
NHSL2	PSMA8	psi-mi:“MI:0914”(association)	0.350
CHRND	CHRNB1	psi-mi:“MI:0914”(association)	0.350
NPAS1	VWA8	psi-mi:“MI:0914”(association)	0.350

BioGRID (257): ARNT (Affinity Capture-MS), ARNT2 (Affinity Capture-MS), TUBB1 (Affinity Capture-MS), SMG7 (Affinity Capture-MS), AKAP1 (Affinity Capture-MS), ATG2B (Affinity Capture-MS), PRUNE (Affinity Capture-MS), CRYBG3 (Affinity Capture-MS), DNAJB5 (Affinity Capture-MS), PRKACB (Affinity Capture-MS), HAUS6 (Affinity Capture-MS), TUBB3 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), PPP6R1 (Affinity Capture-MS), FAM83D (Affinity Capture-MS)

ESM2 similar proteins: A2A9Q0, A2RRU4, A4D2P6, A6NCQ9, A6QM06, A9JSM3, D4A2Q0, E1BDF2, E7ERA6, F2Z333, O43566, P0CG25, P97260, Q0IIA6, Q12770, Q16512, Q29RT8, Q2MJR0, Q3UV31, Q5MNU5, Q5SNT2, Q69YZ2, Q69Z89, Q6GQT6, Q6NS60, Q6P6N5, Q7L591, Q7Z6J2, Q86UD0, Q86UR1, Q8BX43, Q8IUW3, Q8K2Y3, Q8N1F8, Q8N6N2, Q8QZV0, Q8R4T5, Q8TF61, Q8WXF8, Q969Z4

Diamond homologs: A1YFY6, A2T6X9, A9YTQ3, O09000, O35800, P05709, P81133, P97459, P97481, Q0PGG7, Q0VBL6, Q14190, Q16665, Q24119, Q24167, Q309Z6, Q61045, Q61079, Q61221, Q8IXF0, Q98SJ5, Q98SW2, Q99742, Q99814, Q9I8A9, Q9JHS1, Q9JHS2, Q9QZQ0, Q9XTA5, Q9Y2N7, Q9YIB9, E7FFX1, O02747, O44712, O57539, O61734, P30561, P35869, P41738, P70365

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NPAS1	“down-regulates quantity by repression”	TH	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	79
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2439 predictions. Top by Δscore:

Variant	Effect	Δscore
19:47019974:G:GG	donor_gain	1.0000
19:47032267:A:AG	acceptor_gain	1.0000
19:47032267:ATCT:A	acceptor_gain	1.0000
19:47032268:T:G	acceptor_gain	1.0000
19:47032270:T:TA	acceptor_gain	1.0000
19:47032273:CCCA:C	acceptor_loss	1.0000
19:47032275:CA:C	acceptor_loss	1.0000
19:47032276:A:AG	acceptor_gain	1.0000
19:47032277:G:GT	acceptor_gain	1.0000
19:47032277:GC:G	acceptor_gain	1.0000
19:47032277:GCCCC:G	acceptor_gain	1.0000
19:47032352:GTG:G	donor_loss	1.0000
19:47032353:T:A	donor_loss	1.0000
19:47035838:A:AG	acceptor_gain	1.0000
19:47036125:GATCG:G	donor_gain	1.0000
19:47040442:A:AG	acceptor_gain	1.0000
19:47040443:G:GG	acceptor_gain	1.0000
19:47040443:GA:G	acceptor_gain	1.0000
19:47040443:GAGTC:G	acceptor_gain	1.0000
19:47040551:G:GG	donor_gain	1.0000
19:47040623:G:GT	donor_gain	1.0000
19:47040695:G:GT	donor_gain	1.0000
19:47040708:GAGAC:G	donor_gain	1.0000
19:47040728:G:GT	donor_gain	1.0000
19:47042805:CCCA:C	acceptor_loss	1.0000
19:47042808:A:AG	acceptor_gain	1.0000
19:47042809:G:GA	acceptor_gain	1.0000
19:47042809:GC:G	acceptor_gain	1.0000
19:47042809:GCC:G	acceptor_gain	1.0000
19:47042809:GCCA:G	acceptor_gain	1.0000

AlphaMissense

3755 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:47021741:G:C	K84N	1.000
19:47021741:G:T	K84N	1.000
19:47021737:A:C	D83A	0.999
19:47021737:A:T	D83V	0.999
19:47021740:A:T	K84M	0.999
19:47021745:T:C	S86P	0.999
19:47021758:T:C	L90P	0.999
19:47032655:T:C	F149L	0.999
19:47032656:T:C	F149S	0.999
19:47032657:T:A	F149L	0.999
19:47032657:T:G	F149L	0.999
19:47032701:A:T	E164V	0.999
19:47032707:T:A	V166D	0.999
19:47021661:C:A	R58S	0.998
19:47021692:T:C	L68P	0.998
19:47021734:T:C	L82P	0.998
19:47021736:G:C	D83H	0.998
19:47021739:A:C	K84Q	0.998
19:47021739:A:G	K84E	0.998
19:47021760:A:C	S91R	0.998
19:47021762:C:A	S91R	0.998
19:47021762:C:G	S91R	0.998
19:47032653:G:A	G148D	0.998
19:47032686:T:C	F159S	0.998
19:47032691:T:G	Y161D	0.998
19:47032697:T:C	S163P	0.998
19:47032721:G:C	G171R	0.998
19:47032722:G:A	G171D	0.998
19:47021630:G:C	K47N	0.997
19:47021630:G:T	K47N	0.997

dbSNP variants (sampled 300 via entrez): RS1000091127 (19:47021019 C>T), RS1000201627 (19:47043298 T>A,C), RS1000260615 (19:47022929 G>C), RS1000369133 (19:47042192 C>G,T), RS1000608007 (19:47023920 C>A,T), RS1000810853 (19:47044469 C>A,T), RS1000823079 (19:47042007 A>G,T), RS1000858409 (19:47044767 C>T), RS1001238131 (19:47045752 T>C), RS1001252850 (19:47038456 G>A), RS1001294541 (19:47026525 G>A), RS1001305417 (19:47038731 G>A), RS1001507237 (19:47032821 A>G), RS1001541777 (19:47039182 C>T), RS1001552818 (19:47026690 C>T)

Disease associations

OMIM: gene MIM:603346 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010703_65	Brain morphology (MOSTest)	2.000000e-08
GCST011126_33	Caffeine consumption from coffee or tea	1.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0006781	coffee consumption measurement
EFO:0010091	tea consumption measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, affects methylation, decreases methylation	4
Valproic Acid	increases expression, increases methylation	2
sotorasib	affects cotreatment, decreases expression	1
methyleugenol	increases expression	1
propionaldehyde	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
tobacco tar	decreases expression	1
aflatoxin B2	affects methylation	1
pentanal	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	increases expression	1
bisphenol S	increases expression	1
jinfukang	increases expression, affects cotreatment	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Aldehydes	increases expression	1
Camptothecin	increases expression	1
Carmustine	decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Diazinon	increases methylation	1
Etoposide	increases expression	1

Clinical trials (associated diseases)

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