ADORA2B

Chr 17

adenosine A2b receptor

Also known as: ADORA2

NCBI Gene: 136 ENSG00000170425 UniProt: P29275 OMIM: 600446

ADORA2B encodes a G protein-coupled receptor that binds adenosine and activates adenylyl cyclase signaling. Mutations cause autosomal recessive developmental and epileptic encephalopathy with developmental delay, seizures, and brain abnormalities. The gene shows low constraint against loss-of-function variants, consistent with a recessive inheritance pattern.

OMIM ResearchSummary from UniProt

This gene encodes an adenosine receptor that is a member of the G protein-coupled receptor superfamily. This integral membrane protein stimulates adenylate cyclase activity in the presence of adenosine. This protein also interacts with netrin-1, which is involved in axon elongation. The gene is located near the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.49

Clinical Summary— ADORA2B

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.49LOEUF

pLI 0.000

Z-score 0.49

OE 0.83 (0.49–1.49)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.06Z-score

OE missense 1.01 (0.90–1.14)

182 obs / 179.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.83 (0.49–1.49)

0≤0.351.4

Missense OE?1.01 (0.90–1.14)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 8 / 9.6Missense obs/exp: 182 / 179.9Syn Z: 0.43

This gene — mechanism propensity

0.7131th %ile

GOF

0.82top 10%

LOF

0.2775th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

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.