NR4A2

Chr 2AD

nuclear receptor subfamily 4 group A member 2

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

NCBI Gene: 4929 ENSG00000153234 UniProt: P43354 OMIM: 601828

The protein functions as a transcriptional regulator essential for the differentiation and maintenance of midbrain dopaminergic neurons during development, controlling expression of genes critical for dopaminergic neuron function including dopamine transporter, vesicular monoamine transporter, tyrosine hydroxylase, and dopamine D2 receptor. Mutations cause autosomal dominant intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism. This gene is extremely intolerant to loss-of-function variation (pLI 1.0, LOEUF 0.13), reflecting its critical role in neurodevelopment.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.131 OMIM phenotype

Clinical Summary— NR4A2

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

52 unique Pathogenic / Likely Pathogenic· 151 VUS of 251 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

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

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?

LoF OE?0.00 (0.00–0.13)

0≤0.351.4

Missense OE?0.67 (0.60–0.74)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 0 / 22.4Missense obs/exp: 236 / 354.4Syn Z: 0.09

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongNR4A2-related developmental disorderLOFAD

This gene — mechanism propensity

0.2997th %ile

GOF

0.2398th %ile

LOF

0.83top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 58% of P/LP variants are LoF · LOEUF 0.13 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFNR4A2 haploinsufficiency is associated with intellectual disability and autism spectrum disorder.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 29770430 ↗

ClinVar Variant Classifications

251 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26

Likely Pathogenic26

VUS151

Likely Benign30

Benign7

Conflicting4

Pathogenic

Likely Pathogenic

151

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	20	6	0	0	26
Likely Pathogenic	10	16	0	0	26
VUS	5	116	22	8	151
Likely Benign	0	10	5	15	30
Benign	0	1	4	2	7
Conflicting	—				4
Total	35	149	31	25	244

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap NR4A2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →