NPAS4

Chr 11

neuronal PAS domain protein 4

Also known as: Le-PAS, NXF, PASD10, bHLHe79

NCBI Gene: 266743ENSG00000174576UniProt: Q8IUM7

NXF is a member of the basic helix-loop-helix-PER (MIM 602260)-ARNT (MIM 126110)-SIM (see SIM2; MIM 600892) (bHLH-PAS) class of transcriptional regulators, which are involved in a wide range of physiologic and developmental events (Ooe et al., 2004 [PubMed 14701734]).[supplied by OMIM, Mar 2008]

112
ClinVar variants
11
Pathogenic / LP
0.97
pLI score· haploinsufficient
0
Active trials
Clinical Summary— NPAS4
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
11 Pathogenic / Likely Pathogenic· 93 VUS of 112 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.32LOEUF
pLI 0.973
Z-score 4.28
OE 0.14 (0.07–0.32)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.52Z-score
OE missense 0.80 (0.73–0.87)
348 obs / 437.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.14 (0.07–0.32)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.80 (0.73–0.87)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.09
0≤1.21.6
LoF obs/exp: 4 / 28.8Missense obs/exp: 348 / 437.7Syn Z: -0.97

ClinVar Variant Classifications

112 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic2
VUS93
Likely Benign5
Benign3
9
Pathogenic
2
Likely Pathogenic
93
VUS
5
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
9
0
9
Likely Pathogenic
0
0
2
0
2
VUS
1
83
9
0
93
Likely Benign
0
5
0
0
5
Benign
0
0
0
3
3
Total188203112

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

NPAS4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Exploring autoantigens in autoimmune limbic encephalitis using phage immunoprecipitation sequencing.
Kherbek H et al.·J Neurol
2025
Downregulated NPAS4 in multiple brain regions is associated with major depressive disorder.
Selçuk B et al.·Sci Rep
2023
Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders.
Rossi JJ et al.·Sci Rep
2021
Improvement of Depressed Mood with Green Tea Intake.
Unno K et al.·Nutrients
2022
The BDNF Val66Met variant affects gene expression through miR-146b.
Hsu PK et al.·Neurobiol Dis
2015
Modeling epilepsy by loss-of-function of the CUG-binding protein Elav-like family member 2 in zebrafish with multi-omics analysis.
Wang X et al.·Chin Med J (Engl)
2026Functional
Transcriptomic analysis reveals the molecular mechanism of Alzheimer-related neuropathology induced by sevoflurane in mice.
Ge X et al.·J Cell Biochem
2019Functional
Clinical Value Screening, Prognostic Significance, and Key Gene Identification of TrkB in Laryngeal Carcinoma.
Zhang J et al.·Dis Markers
2022
Whole transcriptome profiling of the human hippocampus suggests an involvement of the KIBRA rs17070145 polymorphism in differential activation of the MAPK signaling pathway.
Piras IS et al.·Hippocampus
2017
The Intranigral Infusion of Human-Alpha Synuclein Oligomers Induces a Cognitive Impairment in Rats Associated with Changes in Neuronal Firing and Neuroinflammation in the Anterior Cingulate Cortex.
Palmas MF et al.·Cells
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
HF-rTMS improves swallowing function in rats with poststroke dysphagia by increasing nucleus tractus solitarius excitability through the NMDAR1-Npas4-Nav1.1 pathway.
Chen J et al.·Exp Neurol
2025
Propofol induces neuronal damage in developing mice by inhibiting EGR4 transcription and regulating NPAS4 expression.
Han J et al.·Toxicol Res (Camb)
2025
Deletion of NPAS4 in olfactory bulb principal neurons alters E/I balance and impairs decoding of chemically similar odour molecules.
Wolf D et al.·J Physiol
2026🔓 Open Access
Combinative Protein Expression of Immediate Early Genes c-Fos, Arc, and Npas4 Along Aversive and Appetitive Experience-Related Neural Networks.
Arai M et al.·Hippocampus
2025🔓 Open Access
Npas4 drives the effects of early social isolation on social behaviors and prefrontal parvalbumin neurons.
Jindal K et al.·Prog Neurobiol
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

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External Resources

Links to major genomics databases and tools