Human Gene Module / Chromosome X / SMARCA1

SMARCA1SNF2 related chromatin remodeling ATPase 1

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
3 / 4
Rare Variants / Common Variants
29 / 0
Aliases
-
Associated Syndromes
Rett syndrome, ASD, DD, epilepsy/seizures
Chromosome Band
Xq25-q26.1
Associated Disorders
-
Relevance to Autism

Mirzaa et al., 2025 described 35 individuals from 26 families with de novo or maternally-inherited variants in the SMARCA1 gene presenting with an X-linked neurodevelopmental disorder characterized by mild to severe developmental delay/intellectual disability, delayed or regressive speech development, behavioral abnormalities, facial dysmorphisms, and other variable features, including macrocephaly; almost one-third of patients (31%; 11/35) received an ASD diagnosis. Mirzaa et al., 2025 also demonstrated that individuals with SMARCA1 truncating variants exhibited a mildly unique genome-wide DNA methylation profile with a high penetrance of macrocephaly, while genetic dissection of the NURF complex using single and double knockouts of Smarca1 and other NURF complex genes demonstrated the importance of NURF compositon and dosage for proper forebrain development. Damaging de novo missense variants in the SMARCA1 gene have also been identified in a female ASD proband from the SPARK cohort (Zhou et al., 2022), as well as in a severely autistic Portuguese female with a clinical presentation significantly overlapping Rett syndrome (Lopes et al., 2016).

Molecular Function

This gene encodes a member of the SWI/SNF family of proteins. The encoded protein is an ATPase which is expressed in diverse tissues and contributes to the chromatin remodeling complex that is involved in transcription. The protein may also play a role in DNA damage, growth inhibition and apoptosis of cancer cells.

External Links
Gene CardPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Reports related to SMARCA1 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Identification of novel genetic causes of Rett syndrome-like phenotypes Lopes F , et al. (2016) Yes -
2 Support - Zhou X et al. (2022) Yes -
3 Support - Paola Granata et al. (2024) Yes -
4 Primary - Ghayda M Mirzaa et al. (2025) No ASD, ADHD, epilepsy/seizures
Rare Variants   (29)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2897G>T p.Gly966Val missense_variant De novo - - 26740508 Lopes F , et al. (2016)
c.565C>T p.Arg189Ter stop_gained De novo - - 41213919 Ghayda M Mirzaa et al. (2025)
c.1971dupT p.Asn658Ter stop_gained Unknown - - 41213919 Ghayda M Mirzaa et al. (2025)
c.353C>T p.Thr118Ile missense_variant De novo - - 41213919 Ghayda M Mirzaa et al. (2025)
c.566G>A p.Arg189Gln missense_variant De novo - - 41213919 Ghayda M Mirzaa et al. (2025)
c.3079A>T p.Asn1027Tyr missense_variant Unknown - - 39654053 Paola Granata et al. (2024)
c.1680T>A p.Phe560Leu missense_variant De novo - - 41213919 Ghayda M Mirzaa et al. (2025)
c.1861C>T p.Arg621Cys missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.3152C>T p.Ser1039Leu missense_variant Unknown - - 41213919 Ghayda M Mirzaa et al. (2025)
c.271C>T p.Arg91Ter stop_gained Familial Maternal - 41213919 Ghayda M Mirzaa et al. (2025)
c.916C>T p.Arg306Ter stop_gained Familial Maternal - 41213919 Ghayda M Mirzaa et al. (2025)
c.685C>T p.Arg229Ter stop_gained Unknown - Multiplex 41213919 Ghayda M Mirzaa et al. (2025)
c.407A>G p.Gln136Arg missense_variant Familial Maternal - 41213919 Ghayda M Mirzaa et al. (2025)
c.775C>G p.Arg259Gly missense_variant Familial Maternal - 41213919 Ghayda M Mirzaa et al. (2025)
c.1514T>C p.Val505Ala missense_variant Familial Maternal - 41213919 Ghayda M Mirzaa et al. (2025)
c.1940T>C p.Ile647Thr missense_variant Familial Maternal - 41213919 Ghayda M Mirzaa et al. (2025)
c.2161G>A p.Asp721Asn missense_variant Familial Maternal - 41213919 Ghayda M Mirzaa et al. (2025)
c.2311G>A p.Glu771Lys missense_variant Familial Maternal - 41213919 Ghayda M Mirzaa et al. (2025)
c.2681A>T p.Glu894Val missense_variant Familial Maternal - 41213919 Ghayda M Mirzaa et al. (2025)
c.2252G>A p.Arg751Gln missense_variant Unknown - Multiplex 41213919 Ghayda M Mirzaa et al. (2025)
c.3007T>C p.Phe1003Leu missense_variant Familial Maternal - 41213919 Ghayda M Mirzaa et al. (2025)
c.757C>T p.Arg253Ter stop_gained Familial Maternal Multiplex 41213919 Ghayda M Mirzaa et al. (2025)
c.1070T>G p.Leu357Ter stop_gained Familial Maternal Multiplex 41213919 Ghayda M Mirzaa et al. (2025)
c.1071dupA p.Leu358IlefsTer3 frameshift_variant Familial Maternal - 41213919 Ghayda M Mirzaa et al. (2025)
c.1295T>C p.Met432Thr missense_variant Familial Maternal Multiplex 41213919 Ghayda M Mirzaa et al. (2025)
c.2471C>T p.Pro824Leu missense_variant Familial Maternal Multiplex 41213919 Ghayda M Mirzaa et al. (2025)
c.543dupG p.Pro182AlafsTer18 frameshift_variant Unknown - Multiplex 41213919 Ghayda M Mirzaa et al. (2025)
c.271C>T p.Arg91Ter stop_gained Familial Maternal Extended multiplex 41213919 Ghayda M Mirzaa et al. (2025)
c.3103_3106del p.Arg1035GlnfsTer13 frameshift_variant Familial Maternal - 41213919 Ghayda M Mirzaa et al. (2025)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2025
1

Initial score established: 1

Krishnan Probability Score

Score 0.56560263086077

Ranking 1236/25841 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 0.99994664589762

Ranking 596/18225 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 0.94171147481884

Ranking 15034/18665 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 0.44348620562476

Ranking 986/20870 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
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