RBFOX2

Chr 22

RNA binding fox-1 homolog 2

Also known as: FOX2, Fox-2, HNRBP2, HRNBP2, RBM9, RTA, dJ106I20.3, fxh

NCBI Gene: 23543ENSG00000100320UniProt: O43251

This gene is one of several human genes similar to the C. elegans gene Fox-1. This gene encodes an RNA binding protein that is thought to be a key regulator of alternative exon splicing in the nervous system and other cell types. The protein binds to a conserved UGCAUG element found downstream of many alternatively spliced exons and promotes inclusion of the alternative exon in mature transcripts. The protein also interacts with the estrogen receptor 1 transcription factor and regulates estrogen receptor 1 transcriptional activity. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

162
ClinVar variants
21
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— RBFOX2
⚡
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
21 Pathogenic / Likely Pathogenic· 73 VUS of 162 total submissions

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.
0.19LOEUF
pLI 0.999
Z-score 4.40
OE 0.04 (0.01–0.19)
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.
2.58Z-score
OE missense 0.55 (0.48–0.63)
144 obs / 261.6 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.0.04 (0.01–0.19)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.55 (0.48–0.63)
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.1.03
0≤1.21.6
LoF obs/exp: 1 / 24.5Missense obs/exp: 144 / 261.6Syn Z: -0.28

ClinVar Variant Classifications

162 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18
Likely Pathogenic3
VUS73
Likely Benign38
Benign11
18
Pathogenic
3
Likely Pathogenic
73
VUS
38
Likely Benign
11
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
1
16
0
18
Likely Pathogenic
0
0
3
0
3
VUS
1
59
13
0
73
Likely Benign
0
10
7
21
38
Benign
0
2
4
5
11
Total2724326143

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

View in ClinVar →

Protein Context — Lollipop Plot

RBFOX2 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
FBXO7 Confers Mesenchymal Properties and Chemoresistance in Glioblastoma by Controlling Rbfox2-Mediated Alternative Splicing.
Li S et al.·Adv Sci (Weinh)
2023
RNA splicing factor RBFOX2 is a key factor in the progression of cancer and cardiomyopathy.
Shen J et al.·Clin Transl Med
2024Review
Dysregulation of RBFOX2 Is an Early Event in Cardiac Pathogenesis of Diabetes.
Nutter CA et al.·Cell Rep
2016
RBFOX1 and RBFOX2 are dispensable in iPSCs and iPSC-derived neurons and do not contribute to neural-specific paternal UBE3A silencing.
Chen PF et al.·Sci Rep
2016
RNA binding protein with multiple splicing (RBPMS) promotes contractile phenotype splicing in human embryonic stem cell-derived vascular smooth muscle cells.
Jacob AG et al.·Cardiovasc Res
2024
RBFOX2 confers tumor growth by PI3K/AKT and MAPK signaling in gastric cancer.
Xie S et al.·Eur J Cancer Prev
2023
Alternative Splicing of the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) Is Regulated by RBFOX2 in Lymphoid Malignancies.
Cooper AM et al.·Mol Cell Biol
2022
NF-YAl drives EMT in Claudin(low) tumours.
Londero M et al.·Cell Death Dis
2023
LncRNA ZFAS1 promotes laryngeal cancer progression through RBFOX2-mediated MENA alternative splicing.
Lu B et al.·Environ Toxicol
2023
Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.
Jia X et al.·Mol Psychiatry
2021Meta-analysis
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