FBXL6

Chr 8

F-box and leucine rich repeat protein 6

Also known as: FBL6, FBL6A, PP14630

NCBI Gene: 26233 ENSG00000182325 UniProt: Q8N531 OMIM: 609076

The protein serves as a substrate-recognition component of the SCF E3 ubiquitin ligase complex, which targets specific proteins for degradation through the ubiquitin-proteasome pathway. Mutations cause autosomal recessive developmental delay with intellectual disability, seizures, and movement disorders. The gene shows moderate constraint against loss-of-function variants, suggesting some tolerance to haploinsufficiency.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of a family of proteins that are characterized by an F-box motif. The encoded protein also contains leucine-rich repeats. F-box-containing proteins comprise one of the subunits of the SCF (SKP1-cullin-F-box) complex, which functions in phosphorylation-dependent ubiquitination. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.10

Clinical Summary— FBXL6

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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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ClinVar Variants

108 VUS of 147 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.10LOEUF

pLI 0.000

Z-score 1.19

OE 0.73 (0.49–1.10)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.08Z-score

OE missense 1.18 (1.08–1.29)

329 obs / 278.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.73 (0.49–1.10)

0≤0.351.4

Missense OE?1.18 (1.08–1.29)

0≤0.61.4

Synonymous OE?1.42

0≤1.21.6

LoF obs/exp: 16 / 22.0Missense obs/exp: 329 / 278.4Syn Z: -3.70

This gene — mechanism propensity

0.6162th %ile

GOF

0.5562th %ile

LOF

0.4038th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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

147 submitted variants in ClinVar

ClinVar

Classification Summary

VUS108

Likely Benign10

108

VUS

Likely 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	108	0	108
Likely Benign	7	3	10
Benign	0	0	0
Total	115	3	118

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

View in ClinVar →

56 pathogenic / likely-pathogenic (of 71) ClinVar copy-number / structural variants overlap FBXL6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →