FBXL19

Chr 16

F-box and leucine rich repeat protein 19

Also known as: CXXC11, Fbl19, JHDM1C

NCBI Gene: 54620 ENSG00000099364 UniProt: Q6PCT2 OMIM: 609085

The protein functions as a substrate-recognition component of SCF-type E3 ubiquitin ligase complexes, mediating ubiquitination and degradation of multiple targets including RHOA, RAC1, RAC3, and IL1RL1, while also recruiting factors for chromatin regulation and gene expression during cell differentiation. Mutations cause autosomal dominant neurodevelopmental disorders with intellectual disability and developmental delay. This gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to be pathogenic.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the Skp1-Cullin-F-box family of E3 ubiquitin ligases. The encoded protein is reported to bind to the transmembrane receptor interleukin 1 receptor-like 1 and regulate its ubiquitination and degradation. This protein has been linked to the regulation of pulmonary inflammation and psoriasis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.10

Clinical Summary— FBXL19

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

71 VUS of 91 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.10LOEUF

pLI 1.000

Z-score 5.05

OE 0.00 (0.00–0.10)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.87Z-score

OE missense 0.46 (0.41–0.52)

189 obs / 409.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.10)

0≤0.351.4

Missense OE?0.46 (0.41–0.52)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 0 / 29.7Missense obs/exp: 189 / 409.3Syn Z: 0.03

This gene — mechanism propensity

0.2199th %ile

GOF

0.3491th %ile

LOF

0.83top 5%

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

LOFprediction above median · LOEUF 0.10

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

91 submitted variants in ClinVar

ClinVar

Classification Summary

VUS71

Likely Benign2

Benign3

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	3	68	0	71
Likely Benign	0	0	2	2
Benign	0	1	2	3
Total	3	69	4	76

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap FBXL19 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →