FOXK1

Chr 7

forkhead box K1

Also known as: FOXK1L

NCBI Gene: 221937 ENSG00000164916 UniProt: P85037 OMIM: 616302

FOXK1 encodes a forkhead transcription factor that regulates glucose metabolism, autophagy, and muscle cell differentiation by binding to specific DNA sequences and either activating or repressing target genes. Mutations cause neurodevelopmental disorders with intellectual disability, developmental delay, and variable features including seizures and muscular abnormalities. The gene follows autosomal dominant inheritance and is highly constrained against loss-of-function variants (pLI=0.81, LOEUF=0.40).

OMIM ResearchSummary from RefSeq, UniProt

Enables 14-3-3 protein binding activity; DNA-binding transcription repressor activity, RNA polymerase II-specific; and transcription cis-regulatory region binding activity. Involved in several processes, including intracellular glucose homeostasis; regulation of DNA-templated transcription; and regulation of glucose metabolic process. Located in cytoplasm and nucleoplasm. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.40

LOEUF

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.40LOEUF

pLI 0.805

Z-score 3.67

OE 0.17 (0.09–0.40)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.49Z-score

OE missense 0.66 (0.60–0.73)

288 obs / 434.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.17 (0.09–0.40)

0≤0.351.4

Missense OE?0.66 (0.60–0.73)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 4 / 23.0Missense obs/exp: 288 / 434.3Syn Z: -0.39

Background carrier burden — how many people carry a rare variant somewhere in FOXK1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 75

958 rare PASS variants

Rare truncating (LoF)

1 in 10,000

42 rare PASS variants

Rare synonymous (reference)

1 in 48

578 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FOXK1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 82	1 in 13,000
South Asian	~43k	1 in 47	1 in 7,700
Remaining (unassigned)	~30k	1 in 63	≈ 1 in 10,000
European (Finnish)	~27k	1 in 170	1 in 1,800
Admixed American	~22k	1 in 74	≈ 1 in 9,900
African / African American	~21k	1 in 52	≈ 1 in 5,700
East Asian	~20k	1 in 65	≈ 1 in 6,200
Ashkenazi Jewish	~13k	1 in 500	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 60	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 8 of 9 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 9.? see exons ↓