RBFOX1

Chr 16

RNA binding fox-1 homolog 1

Also known as: 2BP1, A2BP1, FOX-1, FOX1, HRNBP1

NCBI Gene: 54715 ENSG00000078328 UniProt: Q9NWB1 OMIM: 605104

RBFOX1 encodes an RNA-binding protein that regulates tissue-specific alternative splicing by recognizing specific RNA sequences. Mutations cause autism spectrum disorder, intellectual disability, epilepsy, and other neurodevelopmental phenotypes with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.95, LOEUF 0.34), indicating that haploinsufficiency is likely not tolerated in the general population.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

The Fox-1 family of RNA-binding proteins is evolutionarily conserved, and regulates tissue-specific alternative splicing in metazoa. Fox-1 recognizes a (U)GCAUG stretch in regulated exons or in flanking introns. The protein binds to the C-terminus of ataxin-2 and may contribute to the restricted pathology of spinocerebellar ataxia type 2 (SCA2). Ataxin-2 is the product of the SCA2 gene which causes familial neurodegenerative diseases. Fox-1 and ataxin-2 are both localized in the trans-Golgi network. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.34

Clinical Summary— RBFOX1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

13 unique Pathogenic / Likely Pathogenic· 299 VUS of 588 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — RBFOX1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.34LOEUF

pLI 0.953

Z-score 4.12

OE 0.15 (0.07–0.34)

Highly constrained

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

Missense Constraint?

0.20Z-score

OE missense 0.97 (0.88–1.07)

271 obs / 280.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.15 (0.07–0.34)

0≤0.351.4

Missense OE?0.97 (0.88–1.07)

0≤0.61.4

Synonymous OE?1.39

0≤1.21.6

LoF obs/exp: 4 / 27.2Missense obs/exp: 271 / 280.2Syn Z: -3.41

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedRBFOX1-related neurodevelopmental disorderLOFAD

This gene — mechanism propensity

0.5575th %ile

GOF

0.2795th %ile

LOF

0.75top 10%

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

LOFprediction above median · LOEUF 0.34

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

ClinVar Variant Classifications

588 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic12

VUS299

Likely Benign244

Benign19

Conflicting6

Pathogenic

Likely Pathogenic

299

VUS

244

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	0	3	9	0	12
VUS	26	229	43	1	299
Likely Benign	0	18	111	115	244
Benign	0	1	9	9	19
Conflicting	—				6
Total	27	251	172	125	581

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

View in ClinVar →

35 pathogenic / likely-pathogenic (of 197) ClinVar copy-number / structural variants overlap RBFOX1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →