FOXP1

Chr 3AD

forkhead box P1

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

NCBI Gene: 27086ENSG00000114861UniProt: Q9H334OMIM: 605515

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. Forkhead box P1 protein contains both DNA-binding- and protein-protein binding-domains. This gene may act as a tumor suppressor as it is lost in several tumor types and maps to a chromosomal region (3p14.1) reported to contain a tumor suppressor gene(s). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

GeneReviewsOMIMResearchGenerating clinical summary…
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
204 unique Pathogenic / Likely Pathogenic· 364 VUS of 1105 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 OE?0.07 (0.03–0.17)
0≤0.351.4
Missense OE?0.67 (0.60–0.74)
0≤0.61.4
Synonymous OE?1.18
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

This gene — mechanism propensity

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 · 78% of P/LP variants are LoF · LOEUF 0.17 · ClinGen HI: Sufficient evidence for dosage pathogenicity
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.1
LOFTo address this question, we investigated Foxp1 +/- mice reflecting FOXP1 haploinsufficiency.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

  1. 1.PMID 26647308 ↗
  2. 2.PMID 31611379 ↗

ClinVar Variant Classifications

1105 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic127
Likely Pathogenic77
VUS364
Likely Benign399
Benign63
Conflicting53
127
Pathogenic
77
Likely Pathogenic
364
VUS
399
Likely Benign
63
Benign
53
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
113
8
5
1
127
Likely Pathogenic
46
26
5
0
77
VUS
9
299
51
5
364
Likely Benign
3
51
153
192
399
Benign
0
7
49
7
63
Conflicting
—53
Total1713912632051,083

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap FOXP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

FOXP1 · protein map & ClinVar variants

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

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