FOXH1

Summary

FOXH1 (forkhead box H1, HGNC:3814) is a protein-coding gene on chromosome 8q24.3, encoding Forkhead box protein H1 (O75593). Transcriptional activator.

FOXH1 encodes a human homolog of Xenopus forkhead activin signal transducer-1. FOXH1 protein binds SMAD2 and activates an activin response element via binding the DNA motif TGT(G/T)(T/G)ATT.

Source: NCBI Gene 8928 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 279 total — 6 likely-pathogenic
• Phenotypes (HPO): 115
• Transcription factor: yes — 16 downstream targets (CollecTRI)
• MANE Select transcript: NM_003923

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3814
Approved symbol	FOXH1
Name	forkhead box H1
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	FAST1
Ensembl gene	ENSG00000160973
Ensembl biotype	protein_coding
OMIM	603621
Entrez	8928

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000377317, ENST00000525197, ENST00000935086, ENST00000935087, ENST00000935088, ENST00000935089, ENST00000935090

RefSeq mRNA: 1 — MANE Select: NM_003923 NM_003923

CCDS: CCDS6428

Canonical transcript exons

ENST00000377317 — 3 exons

Exon	Start	End
ENSE00001055768	144475157	144475261
ENSE00001300932	144473412	144475056
ENSE00001473544	144475583	144475849

Expression profiles

Bgee: expression breadth ubiquitous, 124 present calls, max score 85.41.

FANTOM5 (CAGE): breadth broad, TPM avg 4.3032 / max 353.9076, expressed in 189 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95690	3.6836	185
95689	0.5216	118
95688	0.0594	35
95687	0.0385	24

Top tissues by expression

256 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
diaphragm	UBERON:0001103	85.41	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.29	gold quality
olfactory bulb	UBERON:0002264	78.29	gold quality
type B pancreatic cell	CL:0000169	78.08	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.70	gold quality
hair follicle	UBERON:0002073	73.24	gold quality
pancreatic ductal cell	CL:0002079	70.73	silver quality
cardiac muscle of right atrium	UBERON:0003379	70.41	gold quality
left ventricle myocardium	UBERON:0006566	70.31	gold quality
nasal cavity epithelium	UBERON:0005384	69.99	gold quality
CA1 field of hippocampus	UBERON:0003881	69.62	gold quality
myocardium	UBERON:0002349	68.55	gold quality
mucosa of transverse colon	UBERON:0004991	68.17	gold quality
vastus lateralis	UBERON:0001379	67.96	gold quality
cervix squamous epithelium	UBERON:0006922	67.59	gold quality
quadriceps femoris	UBERON:0001377	67.32	gold quality
tendon of biceps brachii	UBERON:0008188	67.23	gold quality
mucosa of paranasal sinus	UBERON:0005030	64.71	gold quality
superficial temporal artery	UBERON:0001614	64.47	gold quality
islet of Langerhans	UBERON:0000006	63.70	gold quality
seminal vesicle	UBERON:0000998	63.55	gold quality
epithelial cell of pancreas	CL:0000083	63.49	gold quality
mucosa of urinary bladder	UBERON:0001259	63.40	gold quality
thymus	UBERON:0002370	62.76	gold quality
cerebellar vermis	UBERON:0004720	62.58	gold quality
male germ cell	CL:0000015	62.54	gold quality
middle temporal gyrus	UBERON:0002771	62.13	silver quality
rectum	UBERON:0001052	61.88	gold quality
secondary oocyte	CL:0000655	61.44	gold quality
oviduct epithelium	UBERON:0004804	61.24	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-8271	yes	8.63
E-ANND-3	no	0.32

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

16 targets.

Target	Regulation
ADAM2
AR	Repression
CTCF	Unknown
CXCR4	Activation
FOXA2	Unknown
FOXH1
GSC
INHBA
KDR
LEFTY2
LEMD3
MEF2C	Activation
MIXL1	Activation
NODAL	Unknown
PRKACA
TGFBR1	Repression

JASPAR motifs

Motif	Name	Family
MA0479.1	FOXH1	FOX
MA0479.2	FOXH1	FOX

JASPAR matrix evidence (PMIDs): PMID:9702198

Upstream regulators (CollecTRI, top): FOXH1, GSC

miRNA regulators (miRDB)

18 targeting FOXH1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-18A-5P	99.29	71.05	806
HSA-MIR-18B-5P	99.29	71.05	806
HSA-MIR-8065	99.19	70.38	1289
HSA-MIR-4735-3P	99.14	69.85	777
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-6882-3P	98.23	67.01	1119
HSA-MIR-4469	97.93	65.81	1319
HSA-MIR-663B	97.40	62.91	664
HSA-MIR-10398-5P	97.12	64.94	1051
HSA-MIR-339-5P	96.73	66.01	820

Literature-anchored findings (GeneRIF, showing 15)

• This work suggests that FAST-1 may participate in the vascular smooth muscle response to injury and may represent a potential molecular target for modulating the progression of cardiac allograft vasculopathy. (PMID:15737749)
• Smad-binding peptide aptamer FOXH1 can be developed to selectively inhibit TGF-beta-induced gene expression. (PMID:15750622)
• These results demonstrate for a functional role for TGF-beta ligands in regulation of mammalian Mixl1, identify FoxH1 as an essential co-activator, and implicate Nodal as the embryonic regulator of Mixl1 in mesendoderm morphogenesis. (PMID:15982639)
• FoxH1 has a role in androgen receptor-mediated transactivation (PMID:16120611)
• Reduced NODAL signaling via mutation of several pathway members including FOXH1 is linked to heart defects and holoprosencephaly. (PMID:18538293)
• Four genetic variants are found in FOXH1 that are associated with ventricular septal defects in Chinese patients. (PMID:19525021)
• Results suggest that PKA can negatively regulate ERalpha, at least in part, through FoxH1. (PMID:19711044)
• HEB and E2A-bind the SCA motif at regions overlapping SMAD2/3 and FOXH1 (PMID:21828274)
• These results indicate that Smad4 acts as a tumor suppressor by activating FOXH1, and then suppressing the expression of estrogen receptor, in addition to tumor migration and invasion. (PMID:25482028)
• FAST1 promotes the migration and invasion of colorectal cancer cells (PMID:30594391)
• We analyzed the expression of MELK and two putative targets, Forkhead Box M1 (FOXM1) and Enhancer of Zeste Homolog 2 (EZH2), in a collection of human iCCA by real-time RT-PCR and immunohistochemistry (IHC). The effects on iCCA growth of both the multi-kinase inhibitor OTSSP167 and specific small-interfering RNA (siRNA) against MELK were investigated in iCCA cell lines. (PMID:31861475)
• Identification of FOXH1 mutations in patients with sporadic conotruncal heart defect. (PMID:32003456)
• Large-scale whole-exome sequencing association study identifies FOXH1 gene and sphingolipid metabolism pathway influencing major depressive disorder. (PMID:34633764)
• A comprehensive analysis of FOX family in HCC and experimental evidence to support the oncogenic role of FOXH1. (PMID:35255005)
• Molecular basis for DNA recognition by the maternal pioneer transcription factor FoxH1. (PMID:36435807)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	foxh1	ENSDARG00000055630
mus_musculus	Foxh1	ENSMUSG00000033837
rattus_norvegicus	Foxh1	ENSRNOG00000015371

Paralogs (41): FOXP3 (ENSG00000049768), FOXC1 (ENSG00000054598), FOXJ2 (ENSG00000065970), FOXF1 (ENSG00000103241), FOXN1 (ENSG00000109101), FOXM1 (ENSG00000111206), FOXP1 (ENSG00000114861), FOXO3 (ENSG00000118689), FOXA2 (ENSG00000125798), FOXA1 (ENSG00000129514), FOXJ1 (ENSG00000129654), FOXK2 (ENSG00000141568), FOXO1 (ENSG00000150907), FOXQ1 (ENSG00000164379), FOXK1 (ENSG00000164916), FOXD4 (ENSG00000170122), FOXA3 (ENSG00000170608), FOXB1 (ENSG00000171956), FOXR1 (ENSG00000176302), FOXL1 (ENSG00000176678), FOXC2 (ENSG00000176692), FOXE1 (ENSG00000178919), FOXS1 (ENSG00000179772), FOXL2 (ENSG00000183770), FOXO4 (ENSG00000184481), FOXD4L1 (ENSG00000184492), FOXD4L4 (ENSG00000184659), FOXD2 (ENSG00000186564), FOXI2 (ENSG00000186766), FOXE3 (ENSG00000186790), FOXD3 (ENSG00000187140), FOXD4L3 (ENSG00000187559), FOXR2 (ENSG00000189299), FOXJ3 (ENSG00000198815), FOXO6 (ENSG00000204060), FOXB2 (ENSG00000204612), FOXD4L5 (ENSG00000204779), FOXI3 (ENSG00000214336), FOXL3 (ENSG00000248767), FOXD1 (ENSG00000251493)

Protein

Protein identifiers

Forkhead box protein H1 — O75593 (reviewed: O75593)

Alternative names: Forkhead activin signal transducer 1, Forkhead activin signal transducer 2

All UniProt accessions (1): O75593

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional activator. Recognizes and binds to the DNA sequence 5’-TGT[GT][GT]ATT-3’. Required for induction of the goosecoid (GSC) promoter by TGF-beta or activin signaling. Forms a transcriptionally active complex containing FOXH1/SMAD2/SMAD4 on a site on the GSC promoter called TARE (TGF-beta/activin response element).

Subunit / interactions. Interacts with the MH2 domains of SMAD2 and SMAD3.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitous.

Domain organisation. The FM region is required for binding SMAD2/SMAD4 complexes. FM2 is more effective than FM1 and only interacts with phosphorylated SMAD2 that is in an activated SMAD complex.

RefSeq proteins (1): NP_003914* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001766	Fork_head_dom	Domain
IPR030456	TF_fork_head_CS_2	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR047511	FH_FOXH1	Domain
IPR052327	Activin_resp_transcr_regulator	Family

Pfam: PF00250

UniProt features (27 total): helix 9, strand 6, region of interest 3, short sequence motif 3, sequence variant 2, chain 1, DNA-binding region 1, mutagenesis site 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7YZB	X-RAY DIFFRACTION	1.47
5XOC	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75593-F1	63.00	0.21

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (1):

Position	Phenotype
83	loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1181150	Signaling by NODAL
R-HSA-1502540	Signaling by Activin
R-HSA-9754189	Germ layer formation at gastrulation
R-HSA-9796292	Formation of axial mesoderm

MSigDB gene sets: 389 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_HEART_TRABECULA_MORPHOGENESIS, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, RIZ_ERYTHROID_DIFFERENTIATION_CCNE1, GOBP_REGULATION_OF_INTRACELLULAR_STEROID_HORMONE_RECEPTOR_SIGNALING_PATHWAY, GOBP_ARTERY_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_AORTA_DEVELOPMENT

GO Biological Process (21): negative regulation of transcription by RNA polymerase II (GO:0000122), heart looping (GO:0001947), secondary heart field specification (GO:0003139), determination of left/right asymmetry in lateral mesoderm (GO:0003140), outflow tract morphogenesis (GO:0003151), cardiac right ventricle morphogenesis (GO:0003215), ventricular trabecula myocardium morphogenesis (GO:0003222), transforming growth factor beta receptor signaling pathway (GO:0007179), embryonic heart tube anterior/posterior pattern specification (GO:0035054), aorta morphogenesis (GO:0035909), nodal signaling pathway (GO:0038092), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), axial mesoderm development (GO:0048318), negative regulation of androgen receptor signaling pathway (GO:0060766), hepatocyte differentiation (GO:0070365), cellular response to cytokine stimulus (GO:0071345), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), determination of left/right symmetry (GO:0007368), anterior/posterior pattern specification (GO:0009952)

GO Molecular Function (16): transcription cis-regulatory region binding (GO:0000976), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), transcription corepressor activity (GO:0003714), protein domain specific binding (GO:0019904), bHLH transcription factor binding (GO:0043425), sequence-specific DNA binding (GO:0043565), SMAD binding (GO:0046332), nuclear androgen receptor binding (GO:0050681), co-SMAD binding (GO:0070410), R-SMAD binding (GO:0070412), DNA-binding transcription factor binding (GO:0140297), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), transcription regulator complex (GO:0005667), activin responsive factor complex (GO:0032444)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Gastrulation	2
Developmental Biology	1
Signaling by TGFB family members	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
regulation of DNA-templated transcription	3
negative regulation of DNA-templated transcription	2
DNA-templated transcription	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
transcription cis-regulatory region binding	2
protein binding	2
SMAD binding	2
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
heart field specification	1
determination of left/right symmetry	1
lateral mesoderm development	1
heart morphogenesis	1
anatomical structure morphogenesis	1
cardiac ventricle morphogenesis	1
ventricular cardiac muscle tissue morphogenesis	1
heart trabecula morphogenesis	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
heart development	1
anterior/posterior pattern specification	1
aorta development	1
artery morphogenesis	1
activin receptor signaling pathway	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
mesoderm development	1
androgen receptor signaling pathway	1
negative regulation of intracellular steroid hormone receptor signaling pathway	1
regulation of androgen receptor signaling pathway	1
liver development	1
epithelial cell differentiation	1
response to cytokine	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
determination of bilateral symmetry	1
left/right pattern formation	1
transcription regulatory region nucleic acid binding	1

Protein interactions and networks

STRING

1284 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXH1	SMAD2	Q15796	997
FOXH1	SMAD4	Q13485	990
FOXH1	SMAD3	P84022	967
FOXH1	DRAP1	Q14919	925
FOXH1	MIXL1	Q9H2W2	856
FOXH1	NKX2-5	P52952	825
FOXH1	LEFTY2	O00292	760
FOXH1	NODAL	Q96S42	716
FOXH1	CRIPTO	P13385	676
FOXH1	CFC1	P0CG37	671
FOXH1	MEF2C	Q06413	654
FOXH1	SKIL	P12756	637
FOXH1	HAND2	P61296	630
FOXH1	LEFTY1	O75610	564
FOXH1	SMAD5	Q99717	535
FOXH1	GTF2IRD1	Q9UHL9	535

IntAct

213 interactions, top by confidence:

A	B	Type	Score
FOXH1	SMAD3	psi-mi:“MI:0915”(physical association)	0.680
FOXH1	SMAD2	psi-mi:“MI:0915”(physical association)	0.680
FOXH1	ARID5A	psi-mi:“MI:0915”(physical association)	0.600
FOXH1	KRTAP19-2	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	DAZAP2	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	PNMA5	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	PRR20D	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	ZIC1	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	ZC3H10	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	ATXN1L	psi-mi:“MI:0915”(physical association)	0.560
	FOXH1	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	PPP1R37	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	MAGED1	psi-mi:“MI:0915”(physical association)	0.560
FOXD2	FOXH1	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	TFG	psi-mi:“MI:0915”(physical association)	0.560
CRX	FOXH1	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	CRYBA1	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	RBM46	psi-mi:“MI:0915”(physical association)	0.560
FAM168B	FOXH1	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	ACTMAP	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	SERGEF	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	KRTAP3-3	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	UFSP1	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	MSX2	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	TEKT5	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (121): FOXH1 (Affinity Capture-Western), FOXH1 (Affinity Capture-Western), FOXH1 (Two-hybrid), SCRIB (Affinity Capture-MS), VARS (Affinity Capture-MS), YARS (Affinity Capture-MS), PDS5A (Affinity Capture-MS), BTAF1 (Affinity Capture-MS), PA2G4 (Affinity Capture-MS), SMPD4 (Affinity Capture-MS), ADAR (Affinity Capture-MS), ARID3B (Affinity Capture-MS), DARS2 (Affinity Capture-MS), DDX39A (Affinity Capture-MS), HK2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GUS0, A0A5F9ZHS7, A7E346, A7MB34, A8MZG2, B2RU40, D4A9R4, O08574, O75593, P0C1Z6, P0CG20, Q0VG99, Q0ZCJ7, Q17QH7, Q29RM2, Q2KIS6, Q2M2S6, Q2M3G4, Q2NL68, Q32LE6, Q3U1J1, Q5JXC2, Q5R815, Q5SW24, Q61660, Q63247, Q6NZ36, Q6PBC9, Q6ZN01, Q6ZRI6, Q7TN08, Q7Z591, Q80VF6, Q86WR7, Q8BG26, Q8BP99, Q8BXQ8, Q8IYS4, Q8N9Y4, Q8NAV2

Diamond homologs: A0A8V0YY16, A1L1S5, A3KNJ3, A8MTJ6, A8XJN7, B5RHS5, D3Z120, O00358, O35392, O42097, O43638, O54743, O60548, O70220, O75593, O88621, P14734, P23512, P32030, P32183, P32315, P33205, P33206, P35582, P35583, P35584, P55317, P55318, P70056, P84961, Q02360, Q07342, Q12946, Q12947, Q12948, Q12951, Q12952, Q13461, Q16676, Q17241

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FOXH1	“up-regulates activity”	SMAD2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 66 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Keratinization	7	12.6×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
B cell activation involved in immune response	5	103.3×	3e-07
natural killer cell activation involved in immune response	5	97.2×	3e-07
T cell activation involved in immune response	5	68.8×	1e-06
response to exogenous dsRNA	5	51.6×	5e-06
type I interferon-mediated signaling pathway	5	33.7×	3e-05
humoral immune response	5	27.5×	7e-05
cellular response to virus	6	23.6×	2e-05
adaptive immune response	6	9.9×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

279 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	6
Uncertain significance	189
Likely benign	46
Benign	20

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
869449	NM_003923.3(FOXH1):c.493G>C (p.Glu165Gln)	Likely pathogenic
869450	NM_003923.3(FOXH1):c.277A>G (p.Lys93Glu)	Likely pathogenic
869452	NM_003923.3(FOXH1):c.209T>C (p.Phe70Ser)	Likely pathogenic
869453	NM_003923.3(FOXH1):c.206T>C (p.Phe69Ser)	Likely pathogenic
869454	NM_003923.3(FOXH1):c.205T>C (p.Phe69Leu)	Likely pathogenic
869455	NM_003923.3(FOXH1):c.104C>G (p.Pro35Arg)	Likely pathogenic

SpliceAI

333 predictions. Top by Δscore:

Variant	Effect	Δscore
8:144475578:CTCA:C	donor_loss	1.0000
8:144475579:TCA:T	donor_loss	1.0000
8:144475580:CA:C	donor_loss	1.0000
8:144475581:A:AT	donor_loss	1.0000
8:144475577:GCTCA:G	donor_loss	0.9900
8:144474844:A:AC	donor_gain	0.9800
8:144474845:C:CC	donor_gain	0.9800
8:144475581:A:AC	donor_gain	0.9700
8:144475582:C:CC	donor_gain	0.9700
8:144475620:A:AC	donor_gain	0.9600
8:144475061:G:GC	acceptor_gain	0.9400
8:144474836:AAGC:A	donor_gain	0.9300
8:144474836:AAGCC:A	donor_gain	0.9300
8:144474840:C:A	donor_gain	0.9200
8:144475061:G:C	acceptor_gain	0.9200
8:144475334:C:CT	donor_gain	0.8900
8:144475335:T:TT	donor_gain	0.8900
8:144474837:AGCC:A	donor_gain	0.8400
8:144475057:C:CC	acceptor_gain	0.8400
8:144475425:C:CA	donor_gain	0.8400
8:144475151:CCCCA:C	donor_loss	0.8300
8:144475152:CCCA:C	donor_loss	0.8300
8:144475153:CCACC:C	donor_loss	0.8300
8:144475154:CACCT:C	donor_loss	0.8300
8:144475155:AC:A	donor_loss	0.8300
8:144475156:CCT:C	donor_loss	0.8300
8:144475054:CAC:C	acceptor_gain	0.8200
8:144475059:G:C	acceptor_loss	0.8200
8:144475157:C:A	donor_loss	0.8200
8:144475057:C:A	acceptor_gain	0.8000

AlphaMissense

2313 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:144475012:C:A	W108C	0.999
8:144475012:C:G	W108C	0.999
8:144475014:A:G	W108R	0.999
8:144475014:A:T	W108R	0.999
8:144475163:G:C	F91L	0.999
8:144475163:G:T	F91L	0.999
8:144475164:A:G	F91S	0.999
8:144475165:A:G	F91L	0.999
8:144475187:G:C	H83Q	0.999
8:144475187:G:T	H83Q	0.999
8:144475189:G:C	H83D	0.999
8:144475194:A:T	I81N	0.999
8:144475205:C:A	W77C	0.999
8:144475205:C:G	W77C	0.999
8:144475207:A:G	W77R	0.999
8:144475207:A:T	W77R	0.999
8:144475645:A:G	Y38H	0.999
8:144475164:A:C	F91C	0.998
8:144475182:A:G	L85P	0.998
8:144475182:A:T	L85H	0.998
8:144475184:G:C	N84K	0.998
8:144475184:G:T	N84K	0.998
8:144475189:G:T	H83N	0.998
8:144475192:G:T	R82S	0.998
8:144475194:A:C	I81S	0.998
8:144475235:G:C	F67L	0.998
8:144475235:G:T	F67L	0.998
8:144475237:A:G	F67L	0.998
8:144475260:A:G	I59T	0.998
8:144475620:A:T	I46N	0.998

dbSNP variants (sampled 300 via entrez): RS1000092735 (8:144473419 T>C), RS1000272113 (8:144473606 G>A,T), RS1000719901 (8:144476381 T>A,C), RS1000980061 (8:144476664 G>A), RS1000997179 (8:144476746 G>C), RS1001242012 (8:144476712 C>G,T), RS1001995800 (8:144474479 G>T), RS1003336676 (8:144475285 G>A,T), RS1004013818 (8:144477429 A>G), RS1004068400 (8:144475443 C>T), RS1004280685 (8:144473895 C>A,T), RS1004289669 (8:144472976 C>G,T), RS1004471551 (8:144477165 G>A,C,T), RS1004667768 (8:144477079 C>A), RS1004783644 (8:144476949 G>A,T)

Disease associations

OMIM: gene MIM:603621 | disease phenotypes: MIM:236100

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart disease	Moderate	Autosomal dominant
congenital heart malformation	Limited	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
congenital heart disease	Limited	AD

Mondo (3): holoprosencephaly (MONDO:0016296), congenital heart malformation (MONDO:0019512), congenital heart disease (MONDO:0005453)

Orphanet (1): Holoprosencephaly (Orphanet:2162)

HPO phenotypes

115 total (30 of 115 shown, HPO-id order):

HPO	Term
HP:0000062	Ambiguous genitalia
HP:0000104	Renal agenesis
HP:0000119	Abnormality of the genitourinary system
HP:0000161	Median cleft upper lip
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000202	Orofacial cleft
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000322	Short philtrum
HP:0000407	Sensorineural hearing impairment
HP:0000446	Narrow nasal bridge
HP:0000453	Choanal atresia
HP:0000457	Depressed nasal ridge
HP:0000463	Anteverted nares
HP:0000478	Abnormality of the eye
HP:0000486	Strabismus
HP:0000601	Hypotelorism
HP:0000612	Iris coloboma
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000736	Short attention span
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000772	Abnormal rib morphology
HP:0000818	Abnormality of the endocrine system
HP:0000821	Hypothyroidism

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002598_30	Educational attainment	9.000000e-06
GCST006269_1096	General cognitive ability	6.000000e-11
GCST006879_12	Blood metabolite levels	4.000000e-10
GCST006879_13	Blood metabolite levels	2.000000e-09
GCST006879_14	Blood metabolite levels	2.000000e-11
GCST006879_5	Blood metabolite levels	2.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004784	self reported educational attainment
EFO:0004337	intelligence

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D016142	Holoprosencephaly	C05.660.207.410; C10.500.034.875; C16.131.077.410; C16.131.260.380; C16.131.621.207.410; C16.131.666.034.875; C16.320.180.380

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects expression, decreases expression	4
trichostatin A	affects cotreatment, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	3
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, decreases expression, affects cotreatment	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
jinfukang	increases expression	1
Ethanol	increases expression	1
Carbamazepine	affects expression	1
Diethylhexyl Phthalate	decreases expression	1
Smoke	decreases expression	1
Triclosan	decreases expression	1
Zinc	increases activity	1
Aflatoxin B1	decreases expression	1
Okadaic Acid	decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A2A3	SEES3-1V human FOXH1, clone1	Embryonic stem cell	Male
CVCL_A2A4	SEES3-1V human FOXH1, clone2	Embryonic stem cell	Male
CVCL_A2A5	SEES3-1V human FOXH1, clone3	Embryonic stem cell	Male
CVCL_A4DW	WAe009-A-42	Embryonic stem cell	Female

Clinical trials (associated diseases)

304 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT07381530	PHASE2	SUSPENDED	Study of Cardioplegia in Cardiac Surgery Due to Congenital Heart Malformation in Children
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function