FBXO2

Chr 1

F-box protein 2

Also known as: FBG1, FBX2, Fbs1, NFB42, OCP1

NCBI Gene: 26232 ENSG00000116661 UniProt: Q9UK22 OMIM: 607112

This gene encodes FBXO2, a substrate recognition component of SCF E3 ubiquitin ligase complexes that targets misfolded glycoproteins in the endoplasmic reticulum-associated degradation pathway for proteasomal destruction. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, refractory seizures, and progressive microcephaly. The gene shows very low constraint against loss-of-function variants, consistent with a recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. This protein is highly similar to the rat NFB42 (neural F Box 42 kDa) protein which is enriched in the nervous system and may play a role in maintaining neurons in a postmitotic state. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 1.00

Clinical Summary— FBXO2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.00LOEUF

pLI 0.000

Z-score 1.58

OE 0.55 (0.32–1.00)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.09Z-score

OE missense 0.98 (0.86–1.12)

164 obs / 167.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.55 (0.32–1.00)

0≤0.351.4

Missense OE?0.98 (0.86–1.12)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 8 / 14.5Missense obs/exp: 164 / 167.3Syn Z: 0.34

This gene — mechanism propensity

0.5966th %ile

GOF

0.73top 25%

LOF

0.2483th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.