ARID1A

Chr 1

AT-rich interaction domain 1A

Also known as: B120, BAF250, BAF250a, BM029, C1orf4, CSS2, ELD, MRD14

NCBI Gene: 8289 ENSG00000117713 UniProt: O14497

The protein functions as a component of SWI/SNF chromatin remodeling complexes that alter DNA-histone contacts in an ATP-dependent manner, with specific roles in neural progenitor-specific (npBAF) and neuron-specific (nBAF) complexes essential for neural stem cell self-renewal and neuronal differentiation. Loss-of-function mutations cause Coffin-Siris syndrome 2, a neurodevelopmental disorder inherited in an autosomal dominant pattern. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the disease mechanism.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the SWI/SNF family, whose members 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. It possesses at least two conserved domains that could be important for its function. First, it has a DNA-binding domain that can specifically bind an AT-rich DNA sequence known to be recognized by a SNF/SWI complex at the beta-globin locus. Second, the C-terminus of the protein can stimulate glucocorticoid receptor-dependent transcriptional activation. It is thought that the protein encoded by this gene confers specificity to the SNF/SWI complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtCoffin-Siris syndrome 2

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Coffin-Siris syndrome · AD · ClinGen 2021

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

538

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.07

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — ARID1A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.07LOEUF

pLI 1.000

Z-score 8.55

OE 0.02 (0.01–0.07)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.66Z-score

OE missense 0.70 (0.66–0.74)

823 obs / 1176.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.07)

0≤0.351.4

Missense OE?0.70 (0.66–0.74)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 2 / 89.0Missense obs/exp: 823 / 1176.0Syn Z: -1.27

Background carrier burden — how many people carry a rare variant somewhere in ARID1A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 34

2,770 rare PASS variants

Rare truncating (LoF)

1 in 2,200

93 rare PASS variants

Rare synonymous (reference)

1 in 35

1,457 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ARID1A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 37	1 in 3,200
South Asian	~43k	1 in 26	1 in 820
Remaining (unassigned)	~30k	1 in 25	1 in 2,200
European (Finnish)	~27k	1 in 68	1 in 1,300
Admixed American	~22k	1 in 30	1 in 300
African / African American	~21k	1 in 25	≈ 1 in 5,500
East Asian	~20k	1 in 26	1 in 1,700
Ashkenazi Jewish	~13k	1 in 62	1 in 900
Middle Eastern	~2,884	1 in 37	≈ 1 in 720

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 19 of 20 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 20.? see exons ↓