FOXP4

Chr 6

forkhead box P4

Also known as: hFKHLA

NCBI Gene: 116113 ENSG00000137166 UniProt: Q8IVH2 OMIM: 608924

This transcription factor regulates tissue- and cell-specific gene expression during development and adulthood. Loss-of-function mutations cause neurodevelopmental disorders with an autosomal dominant inheritance pattern, as evidenced by the gene's extreme intolerance to loss-of-function variants (pLI = 0.98). The high constraint against variation (LOEUF = 0.31) indicates that haploinsufficiency is the likely pathogenic mechanism.

OMIM ResearchSummary from RefSeq, UniProt, Mechanism

This gene belongs to subfamily P of the forkhead box (FOX) transcription factor family. Forkhead box transcription factors play important roles in the regulation of tissue- and cell type-specific gene transcription during both development and adulthood. Many members of the forkhead box gene family, including members of subfamily P, have roles in mammalian oncogenesis. This gene may play a role in the development of tumors of the kidney and larynx. Alternative splicing of this gene produces multiple transcript variants, some encoding different isoforms. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.31

Clinical Summary— FOXP4

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 127 VUS of 180 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.31LOEUF

pLI 0.982

Z-score 4.64

OE 0.15 (0.07–0.31)

Highly constrained

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

Missense Constraint?

1.95Z-score

OE missense 0.73 (0.67–0.80)

304 obs / 415.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.15 (0.07–0.31)

0≤0.351.4

Missense OE?0.73 (0.67–0.80)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 5 / 34.4Missense obs/exp: 304 / 415.7Syn Z: -0.65

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateFOXP4-related developmental disorderOTHERAD

This gene — mechanism propensity

0.3694th %ile

GOF

0.3788th %ile

LOF

0.80top 5%

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

LOFprediction above median · LOEUF 0.31

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

180 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic2

VUS127

Likely Benign12

Benign5

Pathogenic

Likely Pathogenic

127

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	1	1	0	0	2
VUS	13	107	6	1	127
Likely Benign	0	5	1	6	12
Benign	0	1	0	4	5
Total	14	115	7	11	147

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 9) ClinVar copy-number / structural variants overlap FOXP4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →