NPAS4

neuronal PAS domain protein 4, the group of PAS domain containing|Basic helix-loop-helix proteins

Basic information

Region (hg38): 11:66421035-66426707

Links

ENSG00000174576NCBI:266743OMIM:608554HGNC:18983Uniprot:Q8IUM7AlphaFoldGenCCjaxSfariGnomADPubmedClinVar

Phenotypes

GenCC

Source: genCC

  • complex neurodevelopmental disorder (Limited), mode of inheritance: AD

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NPAS4 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NPAS4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type Pathogenic Likely pathogenic VUS Likely benign Benign Sum
synonymous
3
clinvar
3
missense
46
clinvar
3
clinvar
49
nonsense
1
clinvar
1
start loss
0
frameshift
1
clinvar
1
inframe indel
0
splice donor/acceptor (+/-2bp)
0
splice region
0
non coding
0
Total 0 0 48 3 3

Variants in NPAS4

This is a list of pathogenic ClinVar variants found in the NPAS4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position Type Phenotype Significance ClinVar
11-66421345-T-C not specified Uncertain significance (Apr 26, 2024)3300592
11-66422141-C-A not specified Uncertain significance (Dec 11, 2024)3880661
11-66422146-C-T not specified Uncertain significance (Oct 12, 2021)2254695
11-66422155-G-T not specified Uncertain significance (Aug 09, 2021)2241706
11-66422263-C-A not specified Uncertain significance (Jul 06, 2021)2234859
11-66422266-T-C not specified Uncertain significance (Apr 20, 2024)3300591
11-66422484-G-A not specified Uncertain significance (Aug 28, 2023)2622112
11-66422529-A-G not specified Uncertain significance (Mar 29, 2022)2280073
11-66422686-G-A not specified Uncertain significance (Nov 20, 2024)3407122
11-66422720-CCAGAGTG-C Microcephaly Uncertain significance (Mar 23, 2023)2498188
11-66422745-C-T not specified Uncertain significance (Apr 04, 2024)3300590
11-66422776-C-A not specified Uncertain significance (Feb 22, 2025)3880670
11-66422776-C-T not specified Uncertain significance (Dec 25, 2024)3880666
11-66422841-C-T not specified Uncertain significance (May 21, 2024)3300593
11-66422848-G-T not specified Uncertain significance (Oct 26, 2021)2356718
11-66422853-G-A not specified Uncertain significance (Mar 18, 2024)3300589
11-66423132-C-G Uncertain significance (Dec 05, 2024)3726577
11-66423199-C-G not specified Uncertain significance (Feb 10, 2025)3880664
11-66423208-G-A not specified Uncertain significance (Apr 07, 2023)2535127
11-66423644-C-T Likely benign (Oct 01, 2023)2641990
11-66423718-G-T Uncertain significance (Dec 05, 2024)3726578
11-66423839-A-G not specified Uncertain significance (Jun 28, 2022)2298645
11-66423840-T-A not specified Uncertain significance (Apr 25, 2022)2285752
11-66423851-A-G not specified Uncertain significance (Jun 27, 2023)2606754
11-66423857-C-T not specified Uncertain significance (Feb 01, 2025)3880662

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
NPAS4protein_codingprotein_codingENST00000311034 85704
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
0.9730.0267125744041257480.0000159
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense1.523484380.7950.00002345163
Missense in Polyphen75134.280.558511549
Synonymous-0.9742061891.090.00001051703
Loss of Function4.28428.80.1390.00000145322

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.000.00
Ashkenazi Jewish0.0001020.0000992
East Asian0.00005440.0000544
Finnish0.000.00
European (Non-Finnish)0.000008800.00000879
Middle Eastern0.00005440.0000544
South Asian0.00003270.0000327
Other0.000.00

dbNSFP

Source: dbNSFP

Function
FUNCTION: Transcription factor expressed in neurons of the brain that regulates the excitatory-inhibitory balance within neural circuits and is required for contextual memory in the hyppocampus (By similarity). Plays a key role in the structural and functional plasticity of neurons (By similarity). Acts as an early-response transcription factor in both excitatory and inhibitory neurons, where it induces distinct but overlapping sets of late-response genes in these two types of neurons, allowing the synapses that form on inhibitory and excitatory neurons to be modified by neuronal activity in a manner specific to their function within a circuit, thereby facilitating appropriate circuit responses to sensory experience (By similarity). In excitatory neurons, activates transcription of BDNF, which in turn controls the number of GABA-releasing synapses that form on excitatory neurons, thereby promoting an increased number of inhibitory synapses on excitatory neurons (By similarity). In inhibitory neurons, regulates a distinct set of target genes that serve to increase excitatory input onto somatostatin neurons, probably resulting in enhanced feedback inhibition within cortical circuits (By similarity). The excitatory and inhibitory balance in neurons affects a number of processes, such as short-term and long-term memory, acquisition of experience, fear memory, response to stress and social behavior (By similarity). Acts as a regulator of dendritic spine development in olfactory bulb granule cells in a sensory-experience-dependent manner by regulating expression of MDM2 (By similarity). Efficient DNA binding requires dimerization with another bHLH protein, such as ARNT, ARNT2 or BMAL1 (PubMed:14701734). Can activate the CME (CNS midline enhancer) element (PubMed:14701734). {ECO:0000250|UniProtKB:Q8BGD7, ECO:0000269|PubMed:14701734}.;

Recessive Scores

pRec
0.115

Intolerance Scores

loftool
0.246
rvis_EVS
-0.66
rvis_percentile_EVS
15.95

Haploinsufficiency Scores

pHI
0.540
hipred
Y
hipred_score
0.726
ghis
0.504

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
N
gene_indispensability_pred
E
gene_indispensability_score
0.900

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Npas4
Phenotype
mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype;

Zebrafish Information Network

Gene name
npas4a
Affected structure
brain
Phenotype tag
abnormal
Phenotype quality
increased process quality

Gene ontology

Biological process
regulation of transcription by RNA polymerase II;learning;short-term memory;long-term memory;cell differentiation;regulation of synaptic transmission, GABAergic;social behavior;positive regulation of transcription by RNA polymerase II;regulation of synaptic plasticity;excitatory postsynaptic potential;inhibitory postsynaptic potential;cellular response to corticosterone stimulus;inhibitory synapse assembly
Cellular component
nucleus;transcription factor complex;postsynapse
Molecular function
RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;protein binding;protein heterodimerization activity