Gene: SMARCA4 -
Human Gene Module
/ Chromosome 19 /
SMARCA4
SMARCA4
SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4
SFARI Gene Score
High Confidence
Criteria 1.1
Autism Reports /
Total Reports
13
/ 27
Rare Variants /
Common Variants
60
/ 0
Aliases
SMARCA4, BAF190,  BAF190A,  BRG1,  CSS4,  MRD16,  RTPS2,  SNF2,  SNF2L4,  SNF2LB,  SWI2,  hSNF2b
Associated Syndromes
Coffin-Siris syndrome-4 (CSS4), Coffin-Siris syndrome-4, Coffin-Siris syndrome 4, DD, ID, epilepsy/seizures
Chromosome Band
19p13.2
Associated Disorders
ADHD, ASD
Relevance to Autism
Two de novo missense variants in the SMARCA4 gene were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014; both of these variants were later determined to be postzygotic mosaic mutations (PZMs) in Lim et al., 2017. A third non-synonymous PZM in SMARCA4 was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (3/571 observed vs. 11/84,448 expected; hypergeometric P-value of 4.9E-05). Furthermore, Lim et al., 2017 demonstrated that overexpression of SMARCA4 mutants in mouse neuroblastoma (N2A) cells resulted in significantly lower expression of GRIN2B compared to wild-type SMARCA4.
Molecular Function
The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. Mutations in this gene are associated with Coffin-Siris syndrome 4 (CSS4; OMIM 614609).
External Links
Gene Card
Open Targets Platform
gnomAD browser
PubMed
Human
Entrez Gene
OMIM
UniProt
HumanBase
VariCarta
SFARI Genomic Platforms
GPF browser
SFARI genome browser
Reports (27)
Variants (60)
Gene Score
Reports related to SMARCA4
(27 Reports)
Type
Title
Author, Year
Autism Report
Associated Disorders
Highly Cited
Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome
Tsurusaki Y , et al. (2012)
No
Support
Clinical correlations of mutations affecting six components of the SWI/SNF complex: detailed description of 21 patients and a review of the literature
Kosho T , et al. (2013)
No
Support
Genotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A
Kosho T , et al. (2014)
No
Primary
Synaptic, transcriptional and chromatin genes disrupted in autism
De Rubeis S , et al. (2014)
Yes
Recent Recommendation
Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder
Lim ET , et al. (2017)
Yes
Support
Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability
Zhao JJ , et al. (2017)
No
Hypotonia, dysmorphic features
Support
Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes
Feliciano P et al. (2019)
Yes
Support
The variability of SMARCA4-related Coffin-Siris syndrome: Do nonsense candidate variants add to milder phenotypes?
Li D et al. (2020)
No
ADHD, ASD
Support
Brunet T et al. (2021)
No
10
Support
Hiraide T et al. (2021)
Yes
11
Support
Mahjani B et al. (2021)
Yes
12
Support
Lee Y et al. (2021)
No
13
Recent Recommendation
Qian Y et al. (2021)
No
ASD or autistic features, ADHD
14
Support
Jin Y et al. (2022)
No
15
Support
England) (02/1)
Yes
16
Support
Hu C et al. (2022)
Yes
17
Support
Levchenko O et al. (2022)
No
Epilepsy/seizures
18
Support
Zhou X et al. (2022)
Yes
19
Support
Miyake N et al. (2023)
Yes
20
Support
Cirnigliaro M et al. (2023)
Yes
21
Support
Sanchis-Juan A et al. (2023)
No
22
Support
Lowther C et al. (2023)
Yes
23
Support
M Cecilia Poli et al. ()
No
24
Support
Kirsten Furley et al. ()
No
ID
25
Support
Sawako Furukawa et al. (2025)
Yes
26
Support
Steven Laurie et al. (2025)
No
Autistic behavior, stereotypy
27
Support
Suzanne M Musgrave et al. (2024)
Yes
Rare Variants
(60)
Status
Allele Change
Residue Change
Variant Type
Inheritance Pattern
Parental Transmission
Family Type
PubMed ID
Author, Year
c.715G>C
p.Gly239Arg
missense_variant
Unknown
35699097
England) (02/1)
c.3310C>T
p.Gln1104Ter
stop_gained
De novo
32686290
Li D et al. (2020)
c.4200C>G
p.Ile1400Met
stop_gained
Unknown
32686290
Li D et al. (2020)
copy_number_gain
Unknown
Simplex
39825153
Steven Laurie et al. (2025)
c.1018G>A
p.Ala340Thr
missense_variant
Unknown
35699097
England) (02/1)
c.1351C>T
p.Arg451Cys
missense_variant
De novo
32686290
Li D et al. (2020)
c.2477C>T
p.Ala826Val
missense_variant
De novo
32686290
Li D et al. (2020)
c.2654G>A
p.Arg885His
missense_variant
De novo
32686290
Li D et al. (2020)
c.2681C>T
p.Thr894Met
missense_variant
De novo
32686290
Li D et al. (2020)
c.2851G>A
p.Gly951Arg
missense_variant
De novo
32686290
Li D et al. (2020)
c.2900G>C
p.Arg967Pro
missense_variant
Unknown
32686290
Li D et al. (2020)
c.2936G>A
p.Arg979Gln
missense_variant
De novo
32686290
Li D et al. (2020)
c.1429A>G
p.Asn477Asp
missense_variant
De novo
35741772
Hu C et al. (2022)
c.3508A>G
p.Thr1170Ala
missense_variant
De novo
32686290
Li D et al. (2020)
c.3512T>G
p.Val1171Gly
missense_variant
De novo
32686290
Li D et al. (2020)
c.3641T>C
p.Ile1214Thr
missense_variant
De novo
32686290
Li D et al. (2020)
c.3728G>A
p.Arg1243Gln
missense_variant
De novo
32686290
Li D et al. (2020)
c.1778_1780del
p.Glu593del
inframe_deletion
Unknown
35699097
England) (02/1)
c.1273C>T
p.Arg425Trp
missense_variant
Unknown
34813034
Qian Y et al. (2021)
c.1429A>G
p.Asn477Asp
missense_variant
De novo
34813034
Qian Y et al. (2021)
c.2777A>G
p.Asn926Ser
missense_variant
Unknown
34813034
Qian Y et al. (2021)
c.2900G>A
p.Arg967His
missense_variant
De novo
34813034
Qian Y et al. (2021)
c.2460C>T
p.Tyr820=
synonymous_variant
De novo
35982159
Zhou X et al. (2022)
c.70C>G
p.Pro24Ala
missense_variant
Familial
Paternal
35699097
England) (02/1)
c.3355C>T
p.Arg1119Cys
missense_variant
De novo
34813034
Qian Y et al. (2021)
c.3476G>C
p.Gly1159Ala
missense_variant
Unknown
34813034
Qian Y et al. (2021)
c.3730C>T
p.Arg1244Cys
missense_variant
Unknown
34813034
Qian Y et al. (2021)
c.4213C>T
p.Arg1405Trp
missense_variant
De novo
35982159
Zhou X et al. (2022)
c.602A>T
p.Gln201Leu
missense_variant
Familial
Paternal
35699097
England) (02/1)
c.2437T>G
p.Ser813Ala
missense_variant
Unknown
34615535
Mahjani B et al. (2021)
c.3922C>T
p.Arg1308Trp
missense_variant
Unknown
34615535
Mahjani B et al. (2021)
c.2597A>T
p.Asp866Val
missense_variant
Unknown
38536866
Kirsten Furley et al. ()
c.3712T>G
p.Ser1238Ala
missense_variant
De novo
38177409
M Cecilia Poli et al. ()
c.326C>T
p.Pro109Leu
missense_variant
De novo
25363760
De Rubeis S , et al. (2014)
c.551T>C
p.Ile184Thr
missense_variant
De novo
25363760
De Rubeis S , et al. (2014)
c.2576C>T
p.Thr859Met
missense_variant
De novo
22426308
Tsurusaki Y , et al. (2012)
c.2653C>T
p.Arg885Cys
missense_variant
De novo
22426308
Tsurusaki Y , et al. (2012)
c.2761C>T
p.Leu921Phe
missense_variant
De novo
22426308
Tsurusaki Y , et al. (2012)
c.3128G>T
p.Arg1043Leu
missense_variant
De novo
Simplex
34706719
Lee Y et al. (2021)
c.1365G>T
p.Lys455Asn
missense_variant
De novo
Simplex
35982159
Zhou X et al. (2022)
c.2716C>T
p.Arg906Cys
missense_variant
De novo
Simplex
35982159
Zhou X et al. (2022)
c.427C>G
p.Pro143Ala
missense_variant
De novo
Simplex
28714951
Lim ET , et al. (2017)
c.3032T>C
p.Met1011Thr
missense_variant
Unknown
22426308
Tsurusaki Y , et al. (2012)
c.3469C>G
p.Arg1157Gly
missense_variant
De novo
22426308
Tsurusaki Y , et al. (2012)
c.4764C>T
p.Val1588=
synonymous_variant
De novo
Simplex
35982159
Zhou X et al. (2022)
c.4912-2A>C
p.?
splice_site_variant
Unknown
40756852
Suzanne M Musgrave et al. (2024)
c.1675G>A
p.Glu559Lys
missense_variant
De novo
Unknown
33619735
Brunet T et al. (2021)
c.2282G>A
p.Gly761Asp
missense_variant
Unknown
Not maternal
32686290
Li D et al. (2020)
c.3236C>T
p.Ser1079Leu
missense_variant
De novo
Multiplex
35982159
Zhou X et al. (2022)
c.4543G>A
p.Glu1515Lys
missense_variant
De novo
Simplex
28990276
Zhao JJ , et al. (2017)
c.1537C>T
p.Arg513Trp
missense_variant
De novo
Simplex
33644862
Hiraide T et al. (2021)
c.1636_1638del
p.Lys546del
inframe_deletion
De novo
22426308
Tsurusaki Y , et al. (2012)
c.4309C>T
p.Arg1437Trp
missense_variant
De novo
Multiplex
36973392
Miyake N et al. (2023)
c.2933G>A
p.Arg978Gln
missense_variant
De novo
Simplex
35887114
Levchenko O et al. (2022)
c.2681C>T
p.Thr894Met
missense_variant
Unknown
Unknown
35887114
Levchenko O et al. (2022)
c.2936G>A
p.Arg979Gln
missense_variant
Unknown
Simplex
37541188
Sanchis-Juan A et al. (2023)
c.1199C>T
p.Ala400Val
missense_variant
De novo
Multiplex
37506195
Cirnigliaro M et al. (2023)
c.4213C>T
p.Arg1405Trp
missense_variant
De novo
Unknown
39610113
Sawako Furukawa et al. (2025)
c.4171-1754_4171-1753del
splice_site_variant
Familial
Paternal
31452935
Feliciano P et al. (2019)
c.3411_3412insAACGGCCCGTTGGCATCGAGCCGCCGGCGCGCGGTTTCGAGCAC
p.Leu1138AsnfsTer17
frameshift_variant
De novo
Simplex
37595579
Lowther C et al. (2023)
Common Variants
No common variants reported.
Current Score
Scoring History
3rd Party Scoring
SFARI Gene score
High Confidence
Score Delta: Score remained at
criteria met
See SFARI Gene'scoring criteria
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.
4/1/2022
Decreased from
to
1/1/2021
Decreased from
to
Description
Two de novo missense variants in the SMARCA4 gene were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014; both of these variants were later determined to be postzygotic mosaic mutations (PZMs) in Lim et al., 2017. A third non-synonymous PZM in SMARCA4 was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (3/571 observed vs. 11/84,448 expected; hypergeometric P-value of 4.9E-05). Furthermore, Lim et al., 2017 demonstrated that overexpression of two SMARCA4 mutants in mouse neuroblastoma (N2A) cells resulted in significantly lower expression of GRIN2B compared to wild-type SMARCA4. Mutations in the SMARCA4 gene are also associated with Coffin-Siris syndrome 4 (CSS4; OMIM 614609) (PMIDs 22426308, 23637025, 25168959).
Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
[Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing2021]
7/1/2020
Decreased from
to
Description
Two de novo missense variants in the SMARCA4 gene were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014; both of these variants were later determined to be postzygotic mosaic mutations (PZMs) in Lim et al., 2017. A third non-synonymous PZM in SMARCA4 was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (3/571 observed vs. 11/84,448 expected; hypergeometric P-value of 4.9E-05). Furthermore, Lim et al., 2017 demonstrated that overexpression of two SMARCA4 mutants in mouse neuroblastoma (N2A) cells resulted in significantly lower expression of GRIN2B compared to wild-type SMARCA4. Mutations in the SMARCA4 gene are also associated with Coffin-Siris syndrome 4 (CSS4; OMIM 614609) (PMIDs 22426308, 23637025, 25168959).
Reports Added
[The variability of SMARCA4-related Coffin-Siris syndrome: Do nonsense candidate variants add to milder phenotypes?2020]
10/1/2019
Decreased from
to
New Scoring Scheme
Description
Two de novo missense variants in the SMARCA4 gene were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014; both of these variants were later determined to be postzygotic mosaic mutations (PZMs) in Lim et al., 2017. A third non-synonymous PZM in SMARCA4 was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (3/571 observed vs. 11/84,448 expected; hypergeometric P-value of 4.9E-05). Furthermore, Lim et al., 2017 demonstrated that overexpression of two SMARCA4 mutants in mouse neuroblastoma (N2A) cells resulted in significantly lower expression of GRIN2B compared to wild-type SMARCA4. Mutations in the SMARCA4 gene are also associated with Coffin-Siris syndrome 4 (CSS4; OMIM 614609) (PMIDs 22426308, 23637025, 25168959).
Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019]
[New Scoring Scheme]
7/1/2017
Increased from
to
Description
Two de novo missense variants in the SMARCA4 gene were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014; both of these variants were later determined to be postzygotic mosaic mutations (PZMs) in Lim et al., 2017. A third non-synonymous PZM in SMARCA4 was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (3/571 observed vs. 11/84,448 expected; hypergeometric P-value of 4.9E-05). Furthermore, Lim et al., 2017 demonstrated that overexpression of two SMARCA4 mutants in mouse neuroblastoma (N2A) cells resulted in significantly lower expression of GRIN2B compared to wild-type SMARCA4. Mutations in the SMARCA4 gene are also associated with Coffin-Siris syndrome 4 (CSS4; OMIM 614609) (PMIDs 22426308, 23637025, 25168959).
Krishnan Probability Score
Score
0.57176725654226
Ranking
751/25841
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:
with the ability to view networks of associated ASD risk genes, can be found at
asd.princeton.edu.
Original Source
ExAC Score
Score
0.99999999761183
Ranking
112/18225
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
Iossifov Probability Score
Score
0.88
Ranking
167/239
scored genes
[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists
239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This
probability metric combines the evidence from de novo likely-gene- disrupting and missense
mutations and assesses it against the background mutation rate in unaffected individuals from the
University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/).
The list of probability scores can be found here:
www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/-
/DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score
Score
0.56792349975214
Ranking
612/18665
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
0.41135906664072
Ranking
1332/20870
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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