ARRB2

Chr 17

arrestin beta 2

Also known as: ARB2, ARR2, BARR2

NCBI Gene: 409 ENSG00000141480 UniProt: P32121 OMIM: 107941

Arrestin beta 2 regulates G-protein coupled receptor signaling by mediating receptor desensitization, internalization, and serves as a signaling scaffold for MAPK and other pathways in the central nervous system and peripheral tissues. Mutations cause neurodevelopmental disorder with epilepsy, cataracts, and feeding difficulties, inherited in an autosomal recessive pattern. The gene shows significant constraint against loss-of-function variants (LOEUF 0.444), indicating intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

Members of arrestin/beta-arrestin protein family are thought to participate in agonist-mediated desensitization of G-protein-coupled receptors and cause specific dampening of cellular responses to stimuli such as hormones, neurotransmitters, or sensory signals. Arrestin beta 2, like arrestin beta 1, was shown to inhibit beta-adrenergic receptor function in vitro. It is expressed at high levels in the central nervous system and may play a role in the regulation of synaptic receptors. Besides the brain, a cDNA for arrestin beta 2 was isolated from thyroid gland, and thus it may also be involved in hormone-specific desensitization of TSH receptors. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.44

Clinical Summary— ARRB2

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.51) — some intolerance to loss-of-function variants.

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ClinVar Variants

43 VUS of 73 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.44LOEUF

pLI 0.507

Z-score 3.56

OE 0.21 (0.11–0.44)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.38Z-score

OE missense 0.58 (0.51–0.67)

150 obs / 257.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.21 (0.11–0.44)

0≤0.351.4

Missense OE?0.58 (0.51–0.67)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 5 / 23.7Missense obs/exp: 150 / 257.7Syn Z: 0.88

This gene — mechanism propensity

0.7035th %ile

GOF

0.72top 25%

LOF

0.65top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.44

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

73 submitted variants in ClinVar

ClinVar

Classification Summary

VUS43

Likely Benign2

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	43	0	43
Likely Benign	2	0	2
Benign	0	2	2
Total	45	2	47

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

23 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap ARRB2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →