Human Gene Module / Chromosome 14 / NPAS3

NPAS3neuronal PAS domain protein 3

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
7 / 9
Rare Variants / Common Variants
6 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
14q13.1
Associated Disorders
-
Relevance to Autism

Chen et al., 2025 integrated cortex cell-specific cis-regulatory element annotations, a deep learning-based variant prediction model, and massively parallel reporter assays to systematically evaluate the functional impact of 227,878 non-coding de novo mutations (ncDNMs) in ASD probands from Simons Simplex Collection (SSC) and Autism Speaks MSSNG resource (MSSNG) cohorts and identified a ncDNM that down-regulated expression of the NPAS3 gene in a SSC proband. Additional de novo variants, including a loss-of-function variant and two missense variants, have been identified in the NPAS3 gene in ASD probands (De Rubeis et al., 2014; Satterstrom et al., 2020; Fu et al., 2022; Trost et al., 2022). Li et al., 2022 found that Npas3deficiency in mice resulted in impaired cortical astrogenesis, which correlated with abnormal brain development and autistic-like behaviors. Michaelson et al., 2017 found that Fmr1 and Ube3a were transcriptionally regulated by NPAS3, as was the neurogenesis regulator Notch. Rare coding variants in NPAS3, including a frameshift variant that was experimentally shown to result in loss of transcriptional activity, had been previously reported in individuals with NDDs from the Baylor Genetics clinical exome sequencing database in Rossi et al., 2021.

Molecular Function

This gene encodes a member of the basic helix-loop-helix and PAS domain-containing family of transcription factors. The encoded protein is localized to the nucleus and may regulate genes involved in neurogenesis. Chromosomal abnormalities that affect the coding potential of this gene are associated with schizophrenia and cognitive disability.

External Links
Gene CardPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser
Reports related to NPAS3 (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support - Jacob J Michaelson et al. (2017) No -
3 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
4 Support - Joseph J Rossi et al. (2021) No -
5 Support - Fu JM et al. (2022) Yes -
6 Support - Yuanyuan Li et al. (2022) Yes -
7 Support - Trost B et al. (2022) Yes -
8 Primary - Congcong Chen et al. () Yes -
9 Support - Richard G Boles et al. (2025) Yes ADHD, DD, ID
Rare Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.400C>T p.Arg134Ter stop_gained De novo - - 35982160 Fu JM et al. (2022)
c.558+9431C>T - intron_variant De novo - Simplex 40738258 Congcong Chen et al. ()
c.2106C>G p.Gly702= synonymous_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.886G>A p.Val296Met missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.1321A>T p.Thr441Ser missense_variant De novo - Unknown 36368308 Trost B et al. (2022)
c.2196C>T p.Gly732= synonymous_variant De novo - - 41010044 Richard G Boles et al. (2025)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

10/1/2025
3

Initial score established: 3

Krishnan Probability Score

Score 0.59570205951002

Ranking 442/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.98054866970654

Ranking 2114/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.9502084715043

Ranking 18401/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score -0.24487168584983

Ranking 16290/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
Submit New Gene

Report an Error