FOXD4

Chr 9

forkhead box D4

Also known as: FKHL9, FOXD4A, FREAC-5, FREAC5

NCBI Gene: 2298 ENSG00000170122 UniProt: Q12950 OMIM: 601092

FOXD4 encodes a forkhead transcription factor that regulates metabolism, cell proliferation, and gene expression during development. Mutations cause a complex phenotype characterized by dilated cardiomyopathy, obsessive-compulsive disorders, and suicidality with autosomal dominant inheritance. The gene is not highly constrained against loss-of-function variants, suggesting tolerance to protein-truncating mutations.

OMIM ResearchSummary from RefSeq

This gene encodes a member of the forkhead/winged helix-box (FOX) family of transcription factors. FOX transcription factors play critical roles in the regulation of multiple processes including metabolism, cell proliferation and gene expression during ontogenesis. Mutations in this gene are associated with a complex phenotype consisting of dilated cardiomyopathy, obsessive-compulsive disorders, and suicidality. [provided by RefSeq, Mar 2012]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.90

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.90LOEUF

pLI 0.000

Z-score -0.63

OE 1.29 (0.71–1.90)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-4.07Z-score

OE missense 1.74 (1.60–1.88)

418 obs / 240.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.29 (0.71–1.90)

0≤0.351.4

Missense OE?1.74 (1.60–1.88)

0≤0.61.4

Synonymous OE?1.59

0≤1.21.6

LoF obs/exp: 7 / 5.4Missense obs/exp: 418 / 240.4Syn Z: -4.84

Background carrier burden — how many people carry a rare variant somewhere in FOXD4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 60

735 rare PASS variants

Rare truncating (LoF)

1 in 1,000

65 rare PASS variants

Rare synonymous (reference)

1 in 140

302 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FOXD4. 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 90	1 in 680
South Asian	~43k	1 in 52	1 in 780
Remaining (unassigned)	~30k	1 in 38	1 in 920
European (Finnish)	~27k	1 in 190	≈ 1 in 27,000
Admixed American	~22k	1 in 62	1 in 810
African / African American	~21k	1 in 43	1 in 650
East Asian	~20k	1 in 66	1 in 2,500
Ashkenazi Jewish	~13k	1 in 260	1 in 810
Middle Eastern	~2,779	1 in 65	≈ 1 in 1,100

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): All 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓