FOXP1

Chr 3AD

forkhead box P1

Also known as: 12CC4, HSPC215, MFH, QRF1, hFKH1B

NCBI Gene: 27086ENSG00000114861UniProt: Q9H334OMIM: 605515

FOXP1 encodes a forkhead box transcription factor that regulates tissue- and cell type-specific gene transcription during development and contains DNA-binding and protein-protein binding domains. Heterozygous loss-of-function mutations cause autosomal dominant intellectual developmental disorder with language impairment with or without autistic features. The gene is highly intolerant to loss-of-function variants, indicating haploinsufficiency as the underlying disease mechanism.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismADLOEUF 0.171 OMIM phenotype
Clinical Summary— FOXP1
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Gene-Disease Validity (ClinGen)
intellectual disability-severe speech delay-mild dysmorphism syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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
106 unique Pathogenic / Likely Pathogenic· 184 VUS of 500 total submissions
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — FOXP1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.17LOEUF
pLI 1.000
Z-score 5.75
OE 0.07 (0.03–0.17)
Highly constrained

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

Missense Constraint
2.28Z-score
OE missense 0.67 (0.60–0.74)
247 obs / 370.2 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.07 (0.03–0.17)
0≤0.351.4
Missense OE0.67 (0.60–0.74)
0≤0.61.4
Synonymous OE1.18
0≤1.21.6
LoF obs/exp: 3 / 44.3Missense obs/exp: 247 / 370.2Syn Z: -1.69
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveFOXP1-related intellectual developmental disorder with language impairment and autistic featuresLOFAD
DN
0.4587th %ile
GOF
0.3986th %ile
LOF
0.77top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 74% of P/LP variants are LoF · LOEUF 0.17
DN1 literature citation

Literature Evidence

DNInterestingly, the three novel variants retained the ability to interact with wild-type FOXP1, suggesting these variants could exert a dominant-negative effect by interfering with the normal FOXP1 protein.PMID:26647308
LOFTo address this question, we investigated Foxp1 +/- mice reflecting FOXP1 haploinsufficiency.PMID:31611379

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

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic68
Likely Pathogenic38
VUS184
Likely Benign171
Benign10
Conflicting8
68
Pathogenic
38
Likely Pathogenic
184
VUS
171
Likely Benign
10
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
55
2
10
1
68
Likely Pathogenic
23
12
3
0
38
VUS
6
144
34
0
184
Likely Benign
2
12
65
92
171
Benign
0
1
6
3
10
Conflicting
—8
Total8617111896479

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

View in ClinVar →

Protein Context — Lollipop Plot

FOXP1 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Examining Genetic Variants Associated with FOXP1 Syndrome through Molecular Dynamics of Its DNA-Binding Domain and Self-Organizing Maps.
Motta S et al.·J Chem Inf Model
2026
Conserved sleep disturbances in FOXP1 syndrome originate from developmental dysregulation of peptidergic signaling.
Coll-Tané M et al.·J Clin Invest
2026
FOXP1 deficiency exacerbates cellular senescence in PM2.5-induced renal injury.
Chen H et al.·Ecotoxicol Environ Saf
2026
Retraction Notice to: circ-SHKBP1 Regulates the Angiogenesis of U87 Glioma-Exposed Endothelial Cells through miR-544a/FOXP1 and miR-379/FOXP2 Pathways.
He Q et al.·Mol Ther Nucleic Acids
2026Open Access
Endothelial Foxp1 overexpression inhibits endothelial-to-mesenchymal transition via suppressing Notch pathway activation to attenuate valvular calcification in chronic kidney disease.
Wang X et al.·Biochem Pharmacol
2026
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients