FBXL3

Chr 13AR

F-box and leucine rich repeat protein 3

Also known as: FBL3, FBL3A, FBXL3A, IDDSFAS

NCBI Gene: 26224ENSG00000005812UniProt: Q9UKT7OMIM: 605653

The protein functions as a substrate-recognition component of the SCF(FBXL3) E3 ubiquitin ligase complex that regulates circadian rhythm by mediating ubiquitination and degradation of CRY1 and CRY2 proteins in the nucleus. Mutations cause sleep-wake cycle disorders with disrupted circadian rhythms, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants (pLI 0.98, LOEUF 0.29), indicating that complete loss of protein function is likely incompatible with normal development.

OMIMResearchSummary from RefSeq, UniProt
LOFmechanismARLOEUF 0.291 OMIM phenotype
Clinical Summary— FBXL3
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
77 unique Pathogenic / Likely Pathogenic· 35 VUS of 125 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.29LOEUF
pLI 0.981
Z-score 3.53
OE 0.06 (0.02–0.29)
Highly constrained

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

Missense Constraint
2.83Z-score
OE missense 0.48 (0.41–0.56)
111 obs / 232.6 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.06 (0.02–0.29)
0≤0.351.4
Missense OE0.48 (0.41–0.56)
0≤0.61.4
Synonymous OE1.03
0≤1.21.6
LoF obs/exp: 1 / 16.5Missense obs/exp: 111 / 232.6Syn Z: -0.18
DN
0.3196th %ile
GOF
0.4381th %ile
LOF
0.68top 25%

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

LOFprediction above median · LOEUF 0.29

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

125 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic77
VUS35
Likely Benign5
Benign4
77
Pathogenic
35
VUS
5
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
1
73
0
77
Likely Pathogenic
0
0
0
0
0
VUS
0
29
6
0
35
Likely Benign
0
0
2
3
5
Benign
0
0
3
1
4
Total330844121

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

View in ClinVar →

Protein Context — Lollipop Plot

FBXL3 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients