ADRA2A

Chr 10AD

adrenoceptor alpha 2A

Also known as: ADRA2, ADRA2R, ADRAR, ALPHA2AAR, FPLD8

NCBI Gene: 150 ENSG00000150594 UniProt: P08913 OMIM: 104210

The ADRA2A protein is a G protein-coupled receptor for catecholamines that inhibits adenylyl cyclase and regulates neurotransmitter release from sympathetic and central nervous system terminals, controlling blood pressure, lipolysis, and insulin release. Mutations cause familial partial lipodystrophy type 8 with autosomal dominant inheritance. The gene shows low constraint to loss-of-function variation (pLI 0.0008, LOEUF 1.23), suggesting that complete loss of function may be tolerated.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Alpha-2-adrenergic receptors are members of the G protein-coupled receptor superfamily. The alpha-2-adrenergic receptors are a type of adrenergic receptors (for adrenaline or epinephrine), which inhibit adenylate cyclase. These receptors include 3 highly homologous subtypes: alpha2A, alpha2B, and alpha2C. They are involved in regulating the release of neurotransmitter molecules from sympathetic nerves and from adrenergic neurons in the central nervous system. The sympathetic nervous system regulates cardiovascular function by activating adrenergic receptors in the heart, blood vessels and kidney. Studies in mouse revealed that both the alpha2A and alpha2C receptor subtypes were required for presynaptic transmitter release from the sympathetic nervous system in the heart and from central noradrenergic neurons. The alpha-2-adrenergic receptors are also involved in catecholamine signaling by extracellular regulated protein kinase 1 and 2 (ERK1/2) pathways. A clear association between the alpha-2-adrenergic receptor and disease has not been yet established. [provided by RefSeq, Sep 2019]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.231 OMIM phenotype

Clinical Summary— ADRA2A

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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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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 64 VUS of 76 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ADRA2A

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.23LOEUF

pLI 0.001

Z-score 1.08

OE 0.62 (0.34–1.23)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.80Z-score

OE missense 0.68 (0.60–0.77)

172 obs / 252.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.62 (0.34–1.23)

0≤0.351.4

Missense OE?0.68 (0.60–0.77)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 6 / 9.6Missense obs/exp: 172 / 252.5Syn Z: 1.27

This gene — mechanism propensity

0.7326th %ile

GOF

0.80top 10%

LOF

0.3452th %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.

ClinVar Variant Classifications

76 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS64

Likely Benign8

Benign3

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	1
Likely Pathogenic	0	0	0	0
VUS	64	0	0	64
Likely Benign	4	2	2	8
Benign	0	0	3	3
Total	69	2	5	76

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

View in ClinVar →

25 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap ADRA2A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →