ADRA2C

Chr 4

adrenoceptor alpha 2C

Also known as: ADRA2L2, ADRA2RL2, ADRARL2, ALPHA2CAR

NCBI Gene: 152 ENSG00000184160 UniProt: P18825 OMIM: 104250

ADRA2C encodes the alpha-2C adrenergic receptor, a G protein-coupled receptor that mediates presynaptic inhibition of neurotransmitter release from noradrenergic nerve terminals in sympathetic and central nervous systems, specifically modulating neurotransmission at lower levels of nerve activity. The gene is moderately constrained against loss-of-function variants (LOEUF 0.605), but specific disease associations and inheritance patterns for ADRA2C mutations have not been established in the current clinical literature.

OMIM ResearchSummary from RefSeq, UniProt

Alpha-2-adrenergic receptors are members of the G protein-coupled receptor superfamily. They include 3 highly homologous subtypes: alpha2A, alpha2B, and alpha2C. These receptors have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system. The mouse studies revealed that both the alpha2A and alpha2C subtypes were required for normal presynaptic control of transmitter release from sympathetic nerves in the heart and from central noradrenergic neurons. The alpha2A subtype inhibited transmitter release at high stimulation frequencies, whereas the alpha2C subtype modulated neurotransmission at lower levels of nerve activity. This gene encodes the alpha2C subtype, which contains no introns in either its coding or untranslated sequences. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.60

Clinical Summary— ADRA2C

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.50) — some intolerance to loss-of-function variants.

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ClinVar Variants

68 VUS of 78 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 →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.60LOEUF

pLI 0.502

Z-score 2.41

OE 0.19 (0.08–0.60)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

1.64Z-score

OE missense 0.70 (0.61–0.79)

161 obs / 231.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.19 (0.08–0.60)

0≤0.351.4

Missense OE?0.70 (0.61–0.79)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 2 / 10.4Missense obs/exp: 161 / 231.2Syn Z: -0.65

This gene — mechanism propensity

0.6550th %ile

GOF

0.77top 25%

LOF

0.4528th %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

78 submitted variants in ClinVar

ClinVar

Classification Summary

VUS68

Likely Benign6

Benign4

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	68	0	0	68
Likely Benign	0	1	5	6
Benign	2	0	2	4
Total	70	1	7	78

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

View in ClinVar →

122 pathogenic / likely-pathogenic (of 124) ClinVar copy-number / structural variants overlap ADRA2C — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →