FBXL4

Chr 6

F-box and leucine rich repeat protein 4

Also known as: FBL4, FBL5, MTDPS13

NCBI Gene: 26235 ENSG00000112234 UniProt: Q9UKA2

The protein functions as part of an E3 ubiquitin ligase complex that regulates protein degradation, including control of lysine-specific demethylase 4A levels in cell-cycle regulation. Biallelic mutations cause mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), inherited in an autosomal recessive pattern. The pathogenic mechanism involves disrupted mitochondrial DNA maintenance leading to mitochondrial dysfunction and subsequent encephalomyopathy.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the F-box protein family, which are characterized by an approximately 40 amino acid motif, the F-box. F-box proteins constitute one subunit of modular E3 ubiquitin ligase complexes, called SCF complexes, which function in phosphorylation-dependent ubiquitination. The F-box domain mediates protein-protein interactions and binds directly to S-phase kinase-associated protein 1. In addition to an F-box domain, the encoded protein contains at least 9 tandem leucine-rich repeats. The ubiquitin ligase complex containing the encoded protein may function in cell-cycle control by regulating levels of lysine-specific demethylase 4A. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.92

Clinical Summary— FBXL4

🧬

Gene-Disease Validity (ClinGen)

Leigh syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

86 unique Pathogenic / Likely Pathogenic· 357 VUS of 644 total submissions

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — FBXL4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.92LOEUF

pLI 0.000

Z-score 1.90

OE 0.61 (0.42–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.55Z-score

OE missense 0.91 (0.83–1.01)

299 obs / 327.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.61 (0.42–0.92)

0≤0.351.4

Missense OE?0.91 (0.83–1.01)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 17 / 27.8Missense obs/exp: 299 / 327.2Syn Z: -0.10

ClinVar Variant Classifications

644 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33

Likely Pathogenic53

VUS357

Likely Benign91

Benign18

Conflicting83

Pathogenic

Likely Pathogenic

357

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	31	0	1	1	33
Likely Pathogenic	24	27	2	0	53
VUS	3	289	29	36	357
Likely Benign	0	1	39	51	91
Benign	0	1	14	3	18
Conflicting	—				83
Total	58	318	85	91	635

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap FBXL4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →