FBXL2

Chr 3

F-box and leucine rich repeat protein 2

Also known as: FBL2, FBL3

NCBI Gene: 25827 ENSG00000153558 UniProt: Q9UKC9 OMIM: 605652

The protein functions as a calcium-activated substrate recognition component of the SCF ubiquitin ligase complex, targeting specific proteins including cyclins and inflammatory regulators for degradation to control cell cycle progression, autophagy, and inflammation. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, refractory seizures, and progressive brain atrophy. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.52), consistent with its role in essential cellular processes.

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 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 Fbls class and, in addition to an F-box, contains 12 tandem leucine-rich repeats. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.52

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.52LOEUF

pLI 0.008

Z-score 3.67

OE 0.31 (0.19–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.46Z-score

OE missense 0.55 (0.48–0.64)

132 obs / 239.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.31 (0.19–0.52)

0≤0.351.4

Missense OE?0.55 (0.48–0.64)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 10 / 32.6Missense obs/exp: 132 / 239.0Syn Z: 0.82

Background carrier burden — how many people carry a rare variant somewhere in FBXL2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 270

379 rare PASS variants

Rare truncating (LoF)

1 in 2,700

84 rare PASS variants

Rare synonymous (reference)

1 in 300

198 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FBXL2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 340	1 in 3,300
South Asian	~43k	1 in 340	1 in 1,400
Remaining (unassigned)	~30k	1 in 140	1 in 3,800
European (Finnish)	~27k	1 in 360	1 in 3,000
Admixed American	~22k	1 in 180	1 in 3,100
African / African American	~21k	1 in 320	1 in 1,900
East Asian	~20k	1 in 290	1 in 2,800
Ashkenazi Jewish	~13k	1 in 1,000	≈ 1 in 12,000
Middle Eastern	~2,884	1 in 360	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 12 of 15 coding exons well covered in gnomAD exomes; exons 1, 2, 3 marginal. Genomes: all 15.? see exons ↓