NR4A2

Chr 2AD

nuclear receptor subfamily 4 group A member 2

Also known as: HZF-3, IDLDP, NOT, NURR1, RNR1, TINUR

NCBI Gene: 4929ENSG00000153234UniProt: P43354

This gene encodes a member of the steroid-thyroid hormone-retinoid receptor superfamily. The encoded protein may act as a transcription factor. Mutations in this gene have been associated with disorders related to dopaminergic dysfunction, including Parkinson disease, schizophernia, and manic depression. Misregulation of this gene may be associated with rheumatoid arthritis. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonismMIM #619911
AD
259
ClinVar variants
69
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— NR4A2
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
69 Pathogenic / Likely Pathogenic· 153 VUS of 259 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.13LOEUF
pLI 1.000
Z-score 4.39
OE 0.00 (0.00–0.13)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.24Z-score
OE missense 0.67 (0.60–0.74)
236 obs / 354.4 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.13)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.67 (0.60–0.74)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 0 / 22.4Missense obs/exp: 236 / 354.4Syn Z: 0.09

ClinVar Variant Classifications

259 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic41
Likely Pathogenic28
VUS153
Likely Benign27
Benign7
Conflicting3
41
Pathogenic
28
Likely Pathogenic
153
VUS
27
Likely Benign
7
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
16
5
20
0
41
Likely Pathogenic
7
15
6
0
28
VUS
5
109
31
8
153
Likely Benign
0
9
5
13
27
Benign
0
1
4
2
7
Conflicting
—3
Total281396623259

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

View in ClinVar →

Protein Context — Lollipop Plot

NR4A2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

NR4A2-related developmental disorder

strong
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism

MIM #619911

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
NR4A transcription factors limit CAR T cell function in solid tumours.
Chen J et al.·Nature
2019
Rewiring endogenous genes in CAR T cells for tumour-restricted payload delivery.
Chen AXY et al.·Nature
2025
Identification of prostate cancer bone metastasis related genes and potential therapy targets by bioinformatics and in vitro experiments.
Jiang H et al.·J Cell Mol Med
2024
Regulation of NR4A2 Gene Expression and Its Importance in Neurodegenerative and Psychiatric Diseases.
Ruiz-Sánchez E et al.·Int J Mol Sci
2025Review
Expanding the Clinical Spectrum of NR4A2-Related Disorder: A Systematic Literature Review and Case Series.
Borden C et al.·Am J Med Genet A
2025Case report
NR4A2 as a Novel Target Gene for Developmental and Epileptic Encephalopathy: A Systematic Review of Related Disorders and Therapeutic Strategies.
Gabaldon-Albero A et al.·Int J Mol Sci
2024Review
Prdm12 governs an epigenetic checkpoint linking neuroimmune cross-talk to CD8(+) T cell exhaustion-suppressed antitumor immunity.
Liu G et al.·Sci Adv
2025
Whole-genome sequencing identifies novel genes for autism in Chinese trios.
Chang S et al.·Sci China Life Sci
2024
Parkinsonism in children: Clinical classification and etiological spectrum.
Leuzzi V et al.·Parkinsonism Relat Disord
2021Review
The roles of orphan nuclear receptor 4 group A1 and A2 in fibrosis.
Gao L et al.·Int Immunopharmacol
2024Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) Induces a Warburg-like Effect and Promotes Phospholipids Synthesis in the Mouse Heart.
Ashraf S et al.·Physiol Genomics
2026Functional
Generating graftable dopaminergic neurons by NR4A2 activation and exploring associated lncRNA signatures.
Malekmohammad L et al.·Life Sci
2026
Structure-activity landscape of Nurr1 (NR4A2) modulators: medicinal chemistry strategies for neurodegenerative disease intervention.
Jaidka S et al.·RSC Med Chem
2026
NR4A2 induces perineural invasion in head and neck squamous cell carcinoma and pancreatic ductal adenocarcinoma via CXCL5/CXCR2 signaling axis.
Chaudhary S et al.·Cancer Lett
2026
The multiple mechanisms of NR4A2 in neurological disorders and advances in targeted therapy research.
Duan K et al.·Neurobiol Dis
2026Functional
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools