DRD3

Chr 3AD

dopamine receptor D3

Also known as: D3DR, ETM1, FET1

NCBI Gene: 1814 ENSG00000151577 UniProt: P35462 OMIM: 126451

The DRD3 protein encodes a dopamine receptor primarily expressed in limbic brain areas that inhibits adenylyl cyclase via G protein coupling and regulates cognitive, emotional, and endocrine functions. Mutations cause autosomal dominant hereditary essential tremor type 1, with genetic variants also associated with increased susceptibility to schizophrenia. This gene shows low constraint against loss-of-function variants (pLI 0.002), suggesting that complete loss of function may be tolerated.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes the D3 subtype of the five (D1-D5) dopamine receptors. The activity of the D3 subtype receptor is mediated by G proteins which inhibit adenylyl cyclase. This receptor is localized to the limbic areas of the brain, which are associated with cognitive, emotional, and endocrine functions. Genetic variation in this gene may be associated with susceptibility to hereditary essential tremor 1. Alternative splicing of this gene results in transcript variants encoding different isoforms, although some variants may be subject to nonsense-mediated decay (NMD). [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.812 OMIM phenotypes

Clinical Summary— DRD3

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

44 VUS of 72 total submissions

💊

Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — DRD3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.002

Z-score 2.13

OE 0.43 (0.24–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.47Z-score

OE missense 0.73 (0.64–0.83)

169 obs / 232.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.24–0.81)

0≤0.351.4

Missense OE?0.73 (0.64–0.83)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 7 / 16.3Missense obs/exp: 169 / 232.0Syn Z: -0.09

This gene — mechanism propensity

0.80top 10%

GOF

0.82top 10%

LOF

0.2580th %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 · 1 literature citation

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.

Literature Evidence

GOFThe gain-of-function produced by the Gly-9 variant may explain why drugs active against tremor in Parkinson's disease (PD) are usually not effective in the treatment of ET and suggests that DRD3 partial agonists or antagonists should be considered as novel therapeutic options for patients with ET.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 16809426 ↗

ClinVar Variant Classifications

72 submitted variants in ClinVar

ClinVar

Classification Summary

VUS44

Likely Benign16

Benign7

Conflicting2

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	42	1	0	44
Likely Benign	0	3	4	9	16
Benign	0	0	3	4	7
Conflicting	—				2
Total	1	45	8	13	69

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap DRD3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →