NR2F1

Chr 5AD

nuclear receptor subfamily 2 group F member 1

Also known as: BBOAS, BBSOAS, COUP-TFI, COUPTF1, EAR-3, EAR3, ERBAL3, SVP44

NCBI Gene: 7025ENSG00000175745UniProt: P10589

The protein encoded by this gene is a nuclear hormone receptor and transcriptional regulator. The encoded protein acts as a homodimer and binds to 5'-AGGTCA-3' repeats. Defects in this gene are a cause of Bosch-Boonstra optic atrophy syndrome (BBOAS). [provided by RefSeq, Apr 2014]

Primary Disease Associations & Inheritance

Bosch-Boonstra-Schaaf optic atrophy syndromeMIM #615722
AD
486
ClinVar variants
146
Pathogenic / LP
0.99
pLI score· haploinsufficient
0
Active trials
Clinical Summary— NR2F1
🧬
Gene-Disease Validity (ClinGen)
Bosch-Boonstra-Schaaf optic atrophy 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
146 Pathogenic / Likely Pathogenic· 165 VUS of 486 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.
0.19LOEUF
pLI 0.995
Z-score 3.66
OE 0.00 (0.00–0.19)
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.
4.17Z-score
OE missense 0.25 (0.21–0.31)
63 obs / 247.3 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 (0.00–0.19)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.25 (0.21–0.31)
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.0.92
0≤1.21.6
LoF obs/exp: 0 / 15.6Missense obs/exp: 63 / 247.3Syn Z: 0.63

ClinVar Variant Classifications

486 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic77
Likely Pathogenic69
VUS165
Likely Benign141
Benign9
Conflicting25
77
Pathogenic
69
Likely Pathogenic
165
VUS
141
Likely Benign
9
Benign
25
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
16
19
42
0
77
Likely Pathogenic
11
45
13
0
69
VUS
2
135
21
7
165
Likely Benign
0
6
26
109
141
Benign
0
3
4
2
9
Conflicting
—25
Total29208106118486

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

View in ClinVar →

Protein Context — Lollipop Plot

NR2F1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

NR2F1-related Bosch-Boonstra-Schaaf optic atrophy syndrome

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

Bosch-Boonstra-Schaaf optic atrophy syndrome

MIM #615722

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — NR2F1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy.
Khalil BD et al.·J Exp Med
2022
Exosome-delivered NR2F1-AS1 and NR2F1 drive phenotypic transition from dormancy to proliferation in treatment-resistant prostate cancer via stabilizing hormonal receptors.
Chen W et al.·J Nanobiotechnology
2024
The emerging role of NR2F1-AS1 in the tumorigenesis and progression of human cancer.
Luo D et al.·Pathol Res Pract
2022Review
The Parkinson's-disease-associated mutation LRRK2-G2019S alters dopaminergic differentiation dynamics via NR2F1.
Walter J et al.·Cell Rep
2021
NR2F1 and mTORC1 provide the bridge between melanoma dormancy and therapeutic resistance.
Mamidi N et al.·J Clin Invest
2025
Long non-coding RNA NR2F1-AS1: an increasingly significant LncRNA in human cancers.
Yao Q et al.·J Physiol Biochem
2025Review
Intestinal fibrosis in aganglionic segment of Hirschsprung's disease revealed by single-cell RNA sequencing.
He S et al.·Clin Transl Med
2023
MacroH2A impedes metastatic growth by enforcing a discrete dormancy program in disseminated cancer cells.
Sun D et al.·Sci Adv
2022
A pathogenic NR2F1 gene variant disrupts transcriptional activity and causes severe neurodevelopmental delay in Bosch-Boonstra-Schaaf syndrome.
Liu J et al.·Hereditas
2025Case report
The top 10 most frequently involved genes in hereditary optic neuropathies in 2186 probands.
Rocatcher A et al.·Brain
2023
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