SMARCA5

protein-coding

SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 5, the group of Chromatin accessibility complex|B-WICH chromatin-remodelling complex subunits|Myb/SANT domain containing

Gene summary

The protein encoded by this gene is a member of the SWI/SNF family of proteins. 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 protein encoded by this gene is a component of the chromatin remodeling and spacing factor RSF, a facilitator of the transcription of class II genes by RNA polymerase II. The encoded protein is similar in sequence to the Drosophila ISWI chromatin remodeling protein. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003601.4

Inheritance

ClinVar variants

P:8U:136B:10

Top phenotype

neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr4:143,513,702-143,557,486

External References & Databases

Ensembl (ENSG00000153147)

Transcript & Mutation Effects

hg38 • Region Span ~43.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*SMARCA5* encodes the ATPase motor of the ISWI chromatin remodeler. *SMARCA5* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2021 (Li et al., PMID: 33980485). Affected individuals exhibit mild developmental delay, intellectual disability (in 50%), failure to thrive, postnatal microcephaly, short stature, mild dysmorphic facial features and mild skeletal and limb abnormalities (PMID: 33980485). Other less frequent features may include hypotonia, behavioral abnormalities, and seizures. Nine variants (7 missense and 2 in-frame deletions) reported in 10 probands in one publication (PMID: 33980485) are included in this curation. Most reported variants occur *de novo*. One variant is recurrent (p.Ile434_Leu435del), and several variants are located within or around the helicase domains. The mechanism of pathogenicity appears to be partial loss of function, based on the study of a missense variant and an in-frame variant in a Drosophila model (PMID: 33980485). This gene-disease relationship is also supported by experimental evidence, including a non-mammalian model system, biochemical function and protein interactions. Neuro-specific knockdown of *Iswi*, the *SMARCA5* ortholog in Drosophila, led to smaller brain size, structural deficits of the mushroom body, and impaired motor function (PMID: 33980485). Another member of the ISWI complex, BPTF, has been shown to interact with SMARCA5 (PMID: 22729083) and is involved in a neurodevelopmental disorder with overlapping features. In summary, there is moderate evidence supporting the relationship between *SMARCA5* and autosomal dominant complex neurodevelopmental disorder. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 18, 2025 (SOP Version 11).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SMARCA5 variants in ClinVar

16 Conditions Cataloged

not providedTotal: 66

Inborn genetic diseasesTotal: 63

SMARCA5-related disorderTotal: 12

Neurodevelopmental disorderTotal: 4

not specifiedTotal: 4

SMARCA5-associated neurodevelopmental disorderTotal: 3

Short statureTotal: 2

Delayed CNS myelinationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003601.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	5 clinvar	2 clinvar	9
missense	1 clinvar	5 clinvar	118 clinvar	3 clinvar		127
nonsense			5 clinvar			5
start loss			1 clinvar			1
frameshift	1 clinvar		3 clinvar			4
splice donor/acceptor (+/-2bp)		1 clinvar	7 clinvar			8
Total	2	6	136	8	2	154

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003601.4	RefSeq	NP_003592.3	24	MANE Select
ENST00000283131.4	Ensembl	ENSP00000283131.3	24	MANE Select
ENST00000885350.1	Ensembl	ENSP00000555409.1	23	Standard
ENST00000885350.2	Ensembl	ENSP00000555409.1	23	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
smarca5	Danio rerio	Structure: head Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

smarca5

Danio rerio

Structure: head

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

B-WICH complex positively regulates rRNA expression
Positive epigenetic regulation of rRNA expression
DNA Repair
NoRC negatively regulates rRNA expression
Negative epigenetic regulation of rRNA expression

Biological Process

chromatin silencing at rDNA
nucleosome assembly
chromatin remodeling
DNA-templated transcription, initiation
regulation of transcription by RNA polymerase II

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
helicase activity
protein binding
ATP binding

Cellular Component

condensed chromosome
fibrillar center
nucleus
nucleoplasm
chromatin silencing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000283131
Coding exons: 24
Length: 44024
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125738
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.42	198	558	0.355	0.0000288	6958
Missense (PolyPhen)		20	154.5	0.12945		1928
Synonymous	1.18	163	183	0.889	0.00000913	1868
Loss of Function	7.28	1	63.7	0.0157	0.00000368	760

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Helicase that possesses intrinsic ATP-dependent nucleosome-remodeling activity. Complexes containing SMARCA5 are capable of forming ordered nucleosome arrays on chromatin; this may require intact histone H4 tails. Also required for replication of pericentric heterochromatin in S-phase specifically in conjunction with BAZ1A. Probably plays a role in repression of polI dependent transcription of the rDNA locus, through the recruitment of the SIN3/HDAC1 corepressor complex to the rDNA promoter. Essential component of the WICH complex, a chromatin remodeling complex that mobilizes nucleosomes and reconfigures irregular chromatin to a regular nucleosomal array structure. The WICH complex regulates the transcription of various genes, has a role in RNA polymerase I and RNA polymerase III transcription, mediates the histone H2AX phosphorylation at 'Tyr-142', and is involved in the maintenance of chromatin structures during DNA replication processes. Essential component of the NoRC (nucleolar remodeling complex) complex, a complex that mediates silencing of a fraction of rDNA by recruiting histone-modifying enzymes and DNA methyltransferases, leading to heterochromatin formation and transcriptional silencing. {ECO:0000269|PubMed:10880450, ECO:0000269|PubMed:11980720, ECO:0000269|PubMed:12198550, ECO:0000269|PubMed:12434153, ECO:0000269|PubMed:12972596, ECO:0000269|PubMed:15543136, ECO:0000269|PubMed:16603771}.;

Recessive Scores

pRec: 0.360

Intolerance Scores

LoFtool: 0.0516
RVIS EVS: -0.98
RVIS percentile EVS: 8.75

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.952

Gene Damage Prediction

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