FOXP4

Chr 6

forkhead box P4

Also known as: hFKHLA

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.

ResearchSummary from RefSeq, UniProt, Mechanism
LOFmechanismLOEUF 0.31
Clinical SummaryFOXP4
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.
📋
ClinVar Variants
10 unique Pathogenic / Likely Pathogenic· 128 VUS of 188 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.31LOEUF
pLI 0.982
Z-score 4.64
OE 0.15 (0.070.31)
Highly constrained

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

Missense Constraint
1.95Z-score
OE missense 0.73 (0.670.80)
304 obs / 415.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.15 (0.070.31)
00.351.4
Missense OE0.73 (0.670.80)
00.61.4
Synonymous OE1.06
01.21.6
LoF obs/exp: 5 / 34.4Missense obs/exp: 304 / 415.7Syn Z: -0.65
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
moderateFOXP4-related developmental disorderOTHERAD
DN
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

188 submitted variants in ClinVar

Classification Summary

Pathogenic8
Likely Pathogenic2
VUS128
Likely Benign12
Benign5
8
Pathogenic
2
Likely Pathogenic
128
VUS
12
Likely Benign
5
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
7
0
8
Likely Pathogenic
1
1
0
0
2
VUS
12
107
8
1
128
Likely Benign
0
5
1
6
12
Benign
0
1
0
4
5
Total131151611155

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

View in ClinVar →

Protein Context — Lollipop Plot

FOXP4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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