FBXO6

Chr 1

F-box protein 6

Also known as: FBG2, FBS2, FBX6, Fbx6b

NCBI Gene: 26270 ENSG00000116663 UniProt: Q9NRD1 OMIM: 605647

This gene encodes an F-box protein that serves as a substrate-recognition component of SCF-type E3 ubiquitin ligase complexes, targeting misfolded glycoproteins in the endoplasmic reticulum for degradation and regulating DNA damage response by promoting degradation of activated CHEK1. Biallelic mutations cause autosomal recessive developmental delay with seizures and microcephaly. The gene shows tolerance to loss-of-function variants (pLI 0.015), suggesting recessive inheritance requires complete loss of function from both alleles.

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, and its C-terminal region is highly similar to that of rat NFB42 (neural F Box 42 kDa) which may be involved in the control of the cell cycle. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.84

Clinical Summary— FBXO6

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Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

45 VUS of 63 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.84LOEUF

pLI 0.015

Z-score 1.97

OE 0.40 (0.21–0.84)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.25Z-score

OE missense 1.05 (0.93–1.19)

190 obs / 180.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.40 (0.21–0.84)

0≤0.351.4

Missense OE?1.05 (0.93–1.19)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 5 / 12.5Missense obs/exp: 190 / 180.5Syn Z: -0.18

This gene — mechanism propensity

0.6841th %ile

GOF

0.6540th %ile

LOF

0.2484th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

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.

ClinVar Variant Classifications

63 submitted variants in ClinVar

ClinVar

Classification Summary

VUS45

Likely Benign8

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	45	0	45
Likely Benign	7	1	8
Benign	1	0	1
Total	53	1	54

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

View in ClinVar →

40 pathogenic / likely-pathogenic (of 53) ClinVar copy-number / structural variants overlap FBXO6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →