NR2F2

Chr 15AD

nuclear receptor subfamily 2 group F member 2

Also known as: ARP-1, ARP1, CHTD4, COUPTF2, COUPTFB, COUPTFII, NF-E3, SRXX5

NCBI Gene: 7026ENSG00000185551UniProt: P24468

This gene encodes a member of the steroid thyroid hormone superfamily of nuclear receptors. The encoded protein is a ligand inducible transcription factor that is involved in the regulation of many different genes. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

Primary Disease Associations & Inheritance

46XX sex reversal 5MIM #618901
AD
Congenital heart defects, multiple types, 4MIM #615779
AD
UniProt46,XX sex reversal 5
230
ClinVar variants
88
Pathogenic / LP
0.99
pLI score· haploinsufficient
0
Active trials
Clinical Summary— NR2F2
🧬
Gene-Disease Validity (ClinGen)
NR2F2 related multiple congenital anomalies/dysmorphic syndrome · 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 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
88 Pathogenic / Likely Pathogenic· 78 VUS of 230 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.22LOEUF
pLI 0.990
Z-score 3.44
OE 0.00 (0.00–0.22)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
3.60Z-score
OE missense 0.34 (0.28–0.41)
79 obs / 233.7 exp
Constrained

Highly missense-constrained (top ~0.1%)

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 (0.00–0.22)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.34 (0.28–0.41)
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.1.30
0≤1.21.6
LoF obs/exp: 0 / 13.8Missense obs/exp: 79 / 233.7Syn Z: -2.38

ClinVar Variant Classifications

230 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic69
Likely Pathogenic19
VUS78
Likely Benign50
Benign12
Conflicting2
69
Pathogenic
19
Likely Pathogenic
78
VUS
50
Likely Benign
12
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
3
57
0
69
Likely Pathogenic
5
6
8
0
19
VUS
1
71
6
0
78
Likely Benign
0
2
8
40
50
Benign
0
0
11
1
12
Conflicting
—2
Total15829041230

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

View in ClinVar →

Protein Context — Lollipop Plot

NR2F2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

NR2F2-related congenital heart defects and 46XX sex reversal

definitive
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

46XX sex reversal 5

MIM #618901

Molecular basis of disorder known

Autosomal dominant

Congenital heart defects, multiple types, 4

MIM #615779

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — NR2F2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Psychedelic control of neuroimmune interactions governing fear.
Chung EN et al.·Nature
2025
Genome-Wide Methylation Analysis Reveals a KCNK3-Prominent Causal Cascade on Hypertension.
Huang D et al.·Circ Res
2024
Heterozygous rare variants in NR2F2 cause a recognizable multiple congenital anomaly syndrome with developmental delays.
Ganapathi M et al.·Eur J Hum Genet
2023
Inflammation and DKK1-induced AKT activation contribute to endothelial dysfunction following NR2F2 loss.
Dougherty EJ et al.·Am J Physiol Lung Cell Mol Physiol
2023
Evidence for NR2F2/COUP-TFII involvement in human testis development.
Wankanit S et al.·Sci Rep
2024Case report
Enhancer-mediated NR2F2 recruitment activates BGN to promote tumor growth and shape tumor microenvironment in papillary thyroid cancer.
Tao M et al.·Theranostics
2026
Diagnosis and management of non-CAH 46,XX disorders/differences in sex development.
Yavas Abalı Z et al.·Front Endocrinol (Lausanne)
2024Review
NR2F2 Regulates Cell Proliferation and Immunomodulation in Whartons' Jelly Stem Cells.
Ma L et al.·Genes (Basel)
2022
Congenital diaphragmatic hernias: from genes to mechanisms to therapies.
Kardon G et al.·Dis Model Mech
2017Review
Long non-coding RNA NR2F2-AS1 regulates human osteosarcoma growth and metastasis through miR-425-5p-mediated HMGB2.
Ye J et al.·Int J Clin Oncol
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools