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

ENSG00000174576 ∙ NCBI:266743 ∙ OMIM:608554 ∙ HGNC:18983 ∙ Uniprot:Q8IUM7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

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	3
missense			46	3		49
nonsense			1			1
start loss						0
frameshift			1			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)
11-66422141-C-A		not specified	Uncertain significance (Dec 11, 2024)
11-66422146-C-T		not specified	Uncertain significance (Oct 12, 2021)
11-66422155-G-T		not specified	Uncertain significance (Aug 09, 2021)
11-66422263-C-A		not specified	Uncertain significance (Jul 06, 2021)
11-66422266-T-C		not specified	Uncertain significance (Apr 20, 2024)
11-66422484-G-A		not specified	Uncertain significance (Aug 28, 2023)
11-66422529-A-G		not specified	Uncertain significance (Mar 29, 2022)
11-66422686-G-A		not specified	Uncertain significance (Nov 20, 2024)
11-66422720-CCAGAGTG-C		Microcephaly	Uncertain significance (Mar 23, 2023)
11-66422745-C-T		not specified	Uncertain significance (Apr 04, 2024)
11-66422776-C-A		not specified	Uncertain significance (Feb 22, 2025)
11-66422776-C-T		not specified	Uncertain significance (Dec 25, 2024)
11-66422841-C-T		not specified	Uncertain significance (May 21, 2024)
11-66422848-G-T		not specified	Uncertain significance (Oct 26, 2021)
11-66422853-G-A		not specified	Uncertain significance (Mar 18, 2024)
11-66423132-C-G			Uncertain significance (Dec 05, 2024)
11-66423199-C-G		not specified	Uncertain significance (Feb 10, 2025)
11-66423208-G-A		not specified	Uncertain significance (Apr 07, 2023)
11-66423644-C-T			Likely benign (Oct 01, 2023)
11-66423718-G-T			Uncertain significance (Dec 05, 2024)
11-66423839-A-G		not specified	Uncertain significance (Jun 28, 2022)
11-66423840-T-A		not specified	Uncertain significance (Apr 25, 2022)
11-66423851-A-G		not specified	Uncertain significance (Jun 27, 2023)
11-66423857-C-T		not specified	Uncertain significance (Feb 01, 2025)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NPAS4	protein_coding	protein_coding	ENST00000311034	8	5704

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.973	0.0267	125744	0	4	125748	0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.52	348	438	0.795	0.0000234	5163
Missense in Polyphen		75	134.28	0.55851		1549
Synonymous	-0.974	206	189	1.09	0.0000105	1703
Loss of Function	4.28	4	28.8	0.139	0.00000145	322

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.000102	0.0000992
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.00000880	0.00000879
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

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

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

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