ARID2

protein-coding

AT-rich interaction domain 2, the group of AT-rich interaction domain containing|PBAF complex|Armadillo like helical domain containing

Gene summary

This gene encodes a member of the AT-rich interactive domain (ARID)-containing family of DNA-binding proteins. Members of the ARID family have roles in embryonic patterning, cell lineage gene regulation, cell cycle control, transcriptional regulation and chromatin structure modification. This protein functions as a subunit of the polybromo- and BRG1-associated factor or PBAF (SWI/SNF-B) chromatin remodeling complex which facilitates ligand-dependent transcriptional activation by nuclear receptors. Mutations in this gene are associated with Coffin-Siris Syndrome 6 and multiple cancers. [provided by RefSeq, Jul 2026]

MANE transcript

NM_152641.4

Inheritance

ClinVar variants

P:115U:339B:168

Top phenotype

Coffin-Siris syndrome 6

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr12:45,729,706-45,908,040

External References & Databases

Ensembl (ENSG00000189079)

Transcript & Mutation Effects

hg38 • Region Span ~178.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Coffin-Siris syndrome 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033492

Submitter: Labcorp Genetics (formerly Invitae)

Coffin-Siris syndrome 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033492

Submitter: PanelApp Australia

Coffin-Siris syndrome 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033492

Submitter: G2P

Coffin-Siris syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015452

Submitter: Illumina

The ARID2 gene is located on chromosome 12 at 12q12 and encodes the AT-rich interaction domain 2 protein, which is subunit of the SWI/SNF chromatin remodeling complex (PBAF). The PBAF complex facilitates transcriptional activation and repression of select genes by chromatin remodeling. ARID2 was first reported in relation to autosomal dominant, Coffin-Siris syndrome in 2015 (26238514: Shang et al. 2015). At least six unique loss-of-function variants have been reported. Evidence supporting this gene-disease relationship includes case-level data and experimental data. De novo variants in this gene have been reported in at least six probands from four publications (26238514: Shang et al. 2015; 28124119: Bramswig et al. 2017; 29698805: Gazdagh et al. 2018; 30838730: Khazanchi et al. 2019). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is consistent with haploinsufficiency. This gene-disease relationship is supported by expression studies that demonstrate ubiquitous expression of ARDI2 throughout the developing spinal cord, brain and other embryonic tissues such as heart and liver in mouse, and biochemical function (26238514: Shang et al. 2015). Additionally, ARID2 is one of the three ARID proteins in SWI/ SNF complex, which is divided into BAF and PBA complex. The BAF complex is important in human brain development and five subunits of the BAF complex are associated with neurobehavioral disorders. In summary, there is strong evidence to support the relationship between ARID2 and Coffin-Siris syndrome, autosomal dominant. Additional experimental evidence is needed to reach a definitive classification.

Coffin-Siris syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015452

Submitter: ClinGen

*ARID2* was first reported in relation to autosomal dominant Coffin-Siris syndrome in 2015 by Shang *et al*. (PMID: 26238514), who reported four individuals with truncating variants. Common phenotypes include mild to moderate intellectual disability, variable behavioral abnormalities, and dysmorphic facial features with coarsening that becomes more apparent with age. Seven heterozygous truncating variants that have been reported in seven probands in three publications (PMIDs: 26238514, 28124119, 35813374) are included in this curation. More evidence is available in the literature (PMIDs: 28884947, 29698805, 34205270), but the maximum score for genetic evidence (12 points) has been reached. The majority of variants are *de novo*, although in at least one individual the variant was inherited from a mildly affected mother (PMID: 35813374). The mechanism of pathogenicity is loss of function, supported by a pLI score of 1 (gnomAD v2.1.1). This gene-disease relationship is also supported by biochemical function, protein interaction, a mouse model and *in vitro* functional assays. ARID2 is an intrinsic component of polybromo brahma-associated factor (PBAF), a SWI/SNF subcomplex involved in chromatin remodeling. *Arid2* haploinsufficient mice exhibit learning and memory deficits in the Morris water maze and reduced body size (PMID: 33051312). *ARID2* haploinsufficiency also enhanced RAS-MAPK pathway activity *in vitro* (PMID: 33051312). In summary, there is definitive evidence supporting the relationship between *ARID2* and autosomal dominant Coffin-Siris syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 7, 2022 (SOP Version 9).

Coffin-Siris syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015452

Submitter: Orphanet

Clinical Genomic Database (CGD)

Coffin-Siris syndrome 6AD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 26238514; 28124119; 28884947

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARID2 variants in ClinVar

20 Conditions Cataloged

not providedTotal: 258

Inborn genetic diseasesTotal: 176

Coffin-Siris syndrome 6Total: 130

not specifiedTotal: 69

ARID2-related disorderTotal: 46

ARID2-related BAFopathyTotal: 8

See casesTotal: 4

Coffin-Siris syndromeTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152641.4. 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			3 clinvar	70 clinvar	5 clinvar	78
missense		2 clinvar	310 clinvar	85 clinvar	8 clinvar	405
nonsense	17 clinvar	13 clinvar	7 clinvar			37
start loss			1 clinvar			1
frameshift	49 clinvar	21 clinvar	4 clinvar			74
splice donor/acceptor (+/-2bp)	4 clinvar	9 clinvar	14 clinvar			27
Total	70	45	339	155	13	622

Highest pathogenic variant AF is 0.0000012391358

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152641.4	RefSeq	NP_689854.2	21	MANE Select
ENST00000334344.11	Ensembl	ENSP00000335044.6	21	MANE Select
NM_001347839.2	RefSeq	NP_001334768.1	20	Standard
ENST00000422737.7	Ensembl	ENSP00000415650.3	20	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Hepatocellular carcinoma - Homo sapiens (human)
miR-targeted genes in lymphocytes - TarBase
Gene expression (Transcription)
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known
Generic Transcription Pathway

Biological Process

heart morphogenesis
nucleosome disassembly
regulation of transcription by RNA polymerase II
negative regulation of cell population proliferation
negative regulation of cell migration

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
protein binding
metal ion binding

Cellular Component

nucleoplasm
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000334344
Coding exons: 21
Length: 178376
Individuals with no LoFs: 125692
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125696
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.73	720	958	0.752	0.0000475	11887
Missense (PolyPhen)		208	392.52	0.52991		4876
Synonymous	-1.89	386	341	1.13	0.0000178	3767
Loss of Function	8.00	3	80.4	0.0373	0.00000394	932

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	0.000046	0.000046	rare
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Required for the stability of the SWI/SNF chromatin remodeling complex SWI/SNF-B (PBAF). May be involved in targeting the complex to different genes. May be involved in regulating transcriptional activation of cardiac genes. {ECO:0000269|PubMed:16782067, ECO:0000303|PubMed:22952240, ECO:0000303|PubMed:26601204}.;
Disease: DISEASE: Coffin-Siris syndrome 6 (CSS6) [MIM:617808]: A form of Coffin-Siris syndrome, a congenital multiple malformation syndrome with broad phenotypic and genetic variability. Cardinal features are intellectual disability, coarse facial features, hypertrichosis, and hypoplastic or absent fifth digit nails or phalanges. Additional features include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Sucking/feeding difficulties, poor growth, ophthalmologic abnormalities, hearing impairment, and spinal anomalies are common findings. Both autosomal dominant and autosomal recessive inheritance patterns have been reported. CSS6 inheritance is autosomal dominant. {ECO:0000269|PubMed:26238514, ECO:0000269|PubMed:28124119, ECO:0000269|PubMed:28884947}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.102

Intolerance Scores

LoFtool: 0.259
RVIS EVS: -1.76
RVIS percentile EVS: 2.33

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.485

Gene Damage Prediction

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