FOXL1

Chr 16

forkhead box L1

Also known as: FKH6, FKHL11, FREAC7, OTSC11

NCBI Gene: 2300 ENSG00000176678 UniProt: Q12952

The FOXL1 protein is a forkhead transcription factor required for proper proliferation and differentiation of gastrointestinal epithelium and functions as a target of the hedgehog signaling pathway. Mutations cause otosclerosis 11, an ear disorder affecting bone remodeling in the middle ear, with autosomal dominant inheritance. The gene shows tolerance to loss-of-function variants (pLI 0.04, LOEUF 1.22), suggesting the associated phenotype may not result from simple protein loss.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the forkhead/winged helix-box (FOX) family of transcription factors. FOX transcription factors are characterized by a distinct DNA-binding forkhead domain and play critical roles in the regulation of multiple processes including metabolism, cell proliferation and gene expression during ontogenesis. [provided by RefSeq, Nov 2012]

ResearchGenerating clinical summary…

DNmechanismLOEUF 1.22

Clinical Summary— FOXL1

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Gene-Disease Validity (ClinGen)

congenital heart disease · ADDisputed

Disputed — evidence questions this relationship

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Population Constraint (gnomAD)

Low constraint (pLI 0.04) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

69 VUS of 72 total submissions

Explore recent and relevant literature in Research Assistant →

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?

1.22LOEUF

pLI 0.036

Z-score 1.23

OE 0.47 (0.21–1.22)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.28Z-score

OE missense 1.06 (0.94–1.19)

199 obs / 188.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.47 (0.21–1.22)

0≤0.351.4

Missense OE?1.06 (0.94–1.19)

0≤0.61.4

Synonymous OE?1.36

0≤1.21.6

LoF obs/exp: 3 / 6.3Missense obs/exp: 199 / 188.1Syn Z: -2.63

This gene — mechanism propensity

0.6938th %ile

GOF

0.4974th %ile

LOF

0.4627th %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

72 submitted variants in ClinVar

ClinVar

Classification Summary

VUS69

Likely Benign2

Conflicting1

VUS

Likely Benign

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	69	0	0	69
Likely Benign	0	2	0	0	2
Benign	0	0	0	0	0
Conflicting	—				1
Total	0	71	0	0	72

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

View in ClinVar →

44 pathogenic / likely-pathogenic (of 53) ClinVar copy-number / structural variants overlap FOXL1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →