FOXJ3

Chr 1

forkhead box J3

NCBI Gene: 22887 ENSG00000198815 UniProt: Q9UPW0 OMIM: 616035

This protein functions as a transcriptional activator that regulates MEF2C and plays important roles in skeletal muscle fiber identity, muscle regeneration, and spermatogenesis. Mutations cause autosomal dominant neurodevelopmental disorders with intellectual disability, developmental delays, and various congenital anomalies. The gene is highly constrained against loss-of-function mutations, indicating intolerance to protein-disrupting variants.

OMIM ResearchSummary from RefSeq, UniProt

Enables DNA-binding transcription activator activity, RNA polymerase II-specific and sequence-specific double-stranded DNA binding activity. Involved in positive regulation of transcription by RNA polymerase II. Predicted to be located in chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.27

Clinical Summary— FOXJ3

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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

86 VUS of 109 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.27LOEUF

pLI 0.996

Z-score 4.76

OE 0.12 (0.06–0.27)

Highly constrained

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

Missense Constraint?

1.31Z-score

OE missense 0.80 (0.72–0.88)

271 obs / 339.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.12 (0.06–0.27)

0≤0.351.4

Missense OE?0.80 (0.72–0.88)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 4 / 33.9Missense obs/exp: 271 / 339.0Syn Z: -1.02

This gene — mechanism propensity

0.2997th %ile

GOF

0.2895th %ile

LOF

0.83top 5%

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

LOFprediction above median · LOEUF 0.27

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

109 submitted variants in ClinVar

ClinVar

Classification Summary

VUS86

Conflicting1

VUS

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	86	0	0	86
Likely Benign	0	0	0	0	0
Benign	0	0	0	0	0
Conflicting	—				1
Total	0	86	0	0	87

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap FOXJ3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →