FOXP4

Summary

FOXP4 (forkhead box P4, HGNC:20842) is a protein-coding gene on chromosome 6p21.1, encoding Forkhead box protein P4 (Q8IVH2). Transcriptional repressor that represses lung-specific expression.

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. Many members of the forkhead box gene family, including members of subfamily P, have roles in mammalian oncogenesis. This gene may play a role in the development of tumors of the kidney and larynx. Alternative splicing of this gene produces multiple transcript variants, some encoding different isoforms.

Source: NCBI Gene 116113 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 9
• Clinical variants (ClinVar): 179 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 2
• MANE Select transcript: NM_001012426

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20842
Approved symbol	FOXP4
Name	forkhead box P4
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ40908
Ensembl gene	ENSG00000137166
Ensembl biotype	protein_coding
OMIM	608924
Entrez	116113

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 20 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000307972, ENST00000373057, ENST00000373063, ENST00000409208, ENST00000451305, ENST00000670130, ENST00000704756, ENST00000704757, ENST00000704758, ENST00000892085, ENST00000892086, ENST00000937774, ENST00000937775, ENST00000937776, ENST00000937777, ENST00000937778, ENST00000937779, ENST00000937780, ENST00000937781, ENST00000937782, ENST00000937783, ENST00000937784, ENST00000937785, ENST00000958402

RefSeq mRNA: 6 — MANE Select: NM_001012426 NM_001012426, NM_001012427, NM_001405824, NM_001405825, NM_001405826, NM_138457

CCDS: CCDS34447, CCDS34448, CCDS4856, CCDS93916

Canonical transcript exons

ENST00000307972 — 17 exons

Exon	Start	End
ENSE00000849893	41585431	41585517
ENSE00000849896	41587793	41587897
ENSE00000849897	41588644	41588731
ENSE00000974138	41587009	41587156
ENSE00000974139	41589771	41589854
ENSE00000974143	41597176	41597242
ENSE00000974149	41597781	41597950
ENSE00000974151	41590271	41590347
ENSE00000974152	41594870	41594991
ENSE00001034702	41577986	41578081
ENSE00001120658	41584769	41584891
ENSE00001410670	41587299	41587512
ENSE00001416825	41589963	41590170
ENSE00001459438	41565745	41565964
ENSE00001831951	41598789	41602384
ENSE00002429365	41591221	41591322
ENSE00003911656	41546381	41546867

Expression profiles

Bgee: expression breadth ubiquitous, 235 present calls, max score 93.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.0774 / max 224.7544, expressed in 1800 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67749	13.2497	1738
67751	7.6918	1723
67748	1.3408	961
67755	0.7891	97
67750	0.5472	298
67757	0.3480	165
67756	0.0763	47
67759	0.0345	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
kidney epithelium	UBERON:0004819	93.22	gold quality
pylorus	UBERON:0001166	93.17	gold quality
body of stomach	UBERON:0001161	93.05	gold quality
cardia of stomach	UBERON:0001162	91.98	gold quality
stomach	UBERON:0000945	91.72	gold quality
cardiac muscle of right atrium	UBERON:0003379	91.39	gold quality
embryo	UBERON:0000922	91.30	gold quality
ganglionic eminence	UBERON:0004023	91.30	gold quality
fundus of stomach	UBERON:0001160	91.26	gold quality
popliteal artery	UBERON:0002250	91.06	gold quality
tibial artery	UBERON:0007610	91.03	gold quality
right coronary artery	UBERON:0001625	90.33	gold quality
left ventricle myocardium	UBERON:0006566	90.22	silver quality
aorta	UBERON:0000947	90.00	gold quality
left lobe of thyroid gland	UBERON:0001120	89.79	gold quality
right lobe of thyroid gland	UBERON:0001119	89.44	gold quality
body of uterus	UBERON:0009853	89.21	gold quality
thyroid gland	UBERON:0002046	89.15	gold quality
coronary artery	UBERON:0001621	88.98	gold quality
left coronary artery	UBERON:0001626	88.95	gold quality
body of pancreas	UBERON:0001150	88.77	gold quality
ascending aorta	UBERON:0001496	88.73	gold quality
thoracic aorta	UBERON:0001515	88.69	gold quality
mucosa of stomach	UBERON:0001199	88.60	gold quality
endocervix	UBERON:0000458	87.87	gold quality
prostate gland	UBERON:0002367	87.87	gold quality
descending thoracic aorta	UBERON:0002345	87.83	gold quality
right testis	UBERON:0004534	87.64	gold quality
nasal cavity epithelium	UBERON:0005384	87.48	silver quality
left testis	UBERON:0004533	87.41	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.10

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
CD8A
FOXP1	Repression
FOXP2	Repression
TSPOAP1

JASPAR motifs

Motif	Name	Family
MA2117.1	FOXP4	FOX

JASPAR matrix evidence (PMIDs): PMID:14701752

miRNA regulators (miRDB)

207 targeting FOXP4, 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-9-5P	100.00	72.28	2361
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4756-5P	99.84	64.98	1809

Literature-anchored findings (GeneRIF, showing 26)

• these data implicate specific members of the FOX family of TFs (FOXC1, C2, P1, P4, and O1A) not previously suggested in heart failure pathogenesis. (PMID:16952980)
• Contrary to the current view, T cell receptor-mediated signals are not responsible for the induction of FOXP3 in human thymocytes. (PMID:18322169)
• Our results provide further support for association of the C2orf43, FOXP4, GPRC6A and RFX6 genes with prostate cancer in Eastern Asian populations (PMID:22662242)
• Foxp4 is dispensable for T cell development, but necessary for normal T cell cytokine recall responses to antigen following pathogenic infection (PMID:22912696)
• These findings suggest that miR-338-3p regulates survival of hepatocellular carcinoma cells partially through the downregulation of FOXP4 (PMID:25755720)
• High FOXP4 expression is associated with non-small cell lung cancer. (PMID:25994569)
• FOXP4 and SHROOM1 genes are hypermethylated in the knee osteoarthritic cartilage. (PMID:26484395)
• association of the THADA, FOXP4, GPRC6A/RFX6 and 8q24 genes with prostate cancer in Asian populations. (PMID:26537068)
• rs4714476 at the 5’ near gene of FOXP4 potentially contributes to the susceptibility of prostate cancer in Chinese men (PMID:26642711)
• results indicated lncRNA MFI2 could promote proliferation and migration of osteosarcoma cells by regulating FOXP4 expression, which suggested critical roles of lncRNA MFI2 and FOXP4 in occurrence and development of human osteosarcoma (PMID:27513470)
• findings demonstrated a key role of circMYO9B/miR-4316/FOXP4 axis in regulating BC progression (PMID:29702064)
• our current study reveals the role of the circ-ZNF609/miR-138-5p/FOXP4 regulatory network in renal carcinoma and provides a new perspective for the pathogenesis of renal carcinoma. (PMID:30478938)
• paired box 5 (PAX5) transcriptionally activated FOXP4-AS1 and FOXP4 in prostate cancer. (PMID:31209207)
• Circular RNA circABCC4 as the ceRNA of miR-1182 facilitates prostate cancer progression by promoting FOXP4 expression. (PMID:31270953)
• MicroRNA-4651 represses hepatocellular carcinoma cell growth and facilitates apoptosis via targeting FOXP4. (PMID:32436934)
• Long noncoding RNA LINC00858 promotes the proliferation, migration and invasion of gastric cancer cells via the miR-363-3p/FOXP4 axis. (PMID:33015780)
• Heterozygous variants that disturb the transcriptional repressor activity of FOXP4 cause a developmental disorder with speech/language delays and multiple congenital abnormalities. (PMID:33110267)
• circ0000212 promotes cell proliferation of colorectal cancer by sponging miR491 and modulating FOXP4 expression. (PMID:33649850)
• The forkhead box transcription factor FoxP4 regulates thermogenic programs in adipocytes. (PMID:34384787)
• FOXP4 promotes laryngeal squamous cell carcinoma progression through directly targeting LEF1. (PMID:34590150)
• Downregulation of microRNA4235p suppresses TGFbeta1induced EMT by targeting FOXP4 in airway fibrosis. (PMID:35642665)
• FOXP4 inhibits squamous differentiation of atypical cells in cervical intraepithelial neoplasia via an ELF3-dependent pathway. (PMID:35838233)
• FOXP4 promotes proliferation of human spermatogonial stem cells. (PMID:36018067)
• Recurrent FOXP4 nonsense variant in two unrelated patients: Association with neurodevelopmental disease and congenital diaphragmatic hernia. (PMID:36301021)
• Polymorphisms of IFN signaling genes and FOXP4 influence the severity of COVID-19. (PMID:38429664)
• FOXP4-mediated induction of PTK7 activates the Wnt/beta-catenin pathway and promotes ovarian cancer development. (PMID:38740744)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	foxp4	ENSDARG00000076120
mus_musculus	Foxp4	ENSMUSG00000023991
rattus_norvegicus	Foxp4	ENSRNOG00000022804

Paralogs (4): FOXP2 (ENSG00000128573), FOXF2 (ENSG00000137273), FOXI1 (ENSG00000168269), FOXG1 (ENSG00000176165)

Protein

Protein identifiers

Forkhead box protein P4 — Q8IVH2 (reviewed: Q8IVH2)

Alternative names: Fork head-related protein-like A

All UniProt accessions (2): B7ZBM3, Q8IVH2

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor that represses lung-specific expression.

Subunit / interactions. Forms homodimers and heterodimers with FOXP1 and FOXP2. Dimerization is required for DNA-binding.

Subcellular location. Nucleus.

Domain organisation. The leucine zipper (ZIP) is required for dimerization and transcriptional repression.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8IVH2-1	1	yes
Q8IVH2-2	2
Q8IVH2-3	3

RefSeq proteins (6): NP_001012426, NP_001012427, NP_001392753, NP_001392754, NP_001392755, NP_612466 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001766	Fork_head_dom	Domain
IPR030456	TF_fork_head_CS_2	Conserved_site
IPR032354	FOXP-CC	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR047414	FH_FOXP4	Domain
IPR050998	FOXP	Family

Pfam: PF00250, PF16159

UniProt features (29 total): compositionally biased region 5, helix 4, region of interest 4, modified residue 3, cross-link 3, splice variant 3, strand 2, chain 1, domain 1, zinc finger region 1, sequence variant 1, DNA-binding region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6XAT	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IVH2-F1	59.91	0.18

Functional residue map

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

Post-translational modifications (6): 52, 86, 554, 175, 246, 378

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 165 (showing top): PEREZ_TP63_TARGETS, SP3_Q3, CAGCAGG_MIR370, FOSTER_TOLERANT_MACROPHAGE_UP, HEN1_01, BOYLAN_MULTIPLE_MYELOMA_C_CLUSTER_UP, PEREZ_TP53_AND_TP63_TARGETS, GOCC_TRANSCRIPTION_REGULATOR_COMPLEX, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, SREBP1_Q6, MEISSNER_BRAIN_HCP_WITH_H3K4ME3_AND_H3K27ME3, KOYAMA_SEMA3B_TARGETS_DN, GOBP_NEGATIVE_REGULATION_OF_TRANSCRIPTION_BY_RNA_POLYMERASE_II, CHEMNITZ_RESPONSE_TO_PROSTAGLANDIN_E2_DN, GOBP_NEGATIVE_REGULATION_OF_NUCLEOBASE_CONTAINING_COMPOUND_METABOLIC_PROCESS

GO Biological Process (3): regulation of transcription by RNA polymerase II (GO:0006357), negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (9): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), zinc ion binding (GO:0008270), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
transition metal ion binding	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
binding	1
DNA binding	1
cation binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1

Protein interactions and networks

STRING

1106 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FOXP4	HAND1	O96004	939
FOXP4	HAND2	P61296	765
FOXP4	FOXP2	O15409	662
FOXP4	A0A3B3IT14	A0A3B3IT14	657
FOXP4	FOXP1	Q9H334	655
FOXP4	ZNF609	O15014	538
FOXP4	CTBP1	Q13363	502
FOXP4	EZH2	Q15910	467
FOXP4	SRPX2	O60687	466
FOXP4	HDAC1	Q13547	452
FOXP4	CTBP2	P56545	436
FOXP4	MYC	P01106	428
FOXP4	TMEM141	Q96I45	401
FOXP4	FOXJ2	Q9P0K8	400
FOXP4	DPP9	Q86TI2	395

IntAct

82 interactions, top by confidence:

A	B	Type	Score
FOXP1	FOXP2	psi-mi:“MI:0914”(association)	0.910
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
FOXP4	FOXP2	psi-mi:“MI:0914”(association)	0.770
FOXP2	FOXP4	psi-mi:“MI:0914”(association)	0.770
FOXP2	FOXP4	psi-mi:“MI:0915”(physical association)	0.770
FOXP2	FOXP2	psi-mi:“MI:0914”(association)	0.740
NFIC	NFIB	psi-mi:“MI:2364”(proximity)	0.690
FOXP1	FOXP4	psi-mi:“MI:0915”(physical association)	0.600
FOXP1	FOXP4	psi-mi:“MI:0403”(colocalization)	0.600
FOXP3	FOXP2	psi-mi:“MI:0914”(association)	0.530
EDA	AP3B1	psi-mi:“MI:0914”(association)	0.530
TBR1	FOXP4	psi-mi:“MI:2364”(proximity)	0.510
TBR1	FOXP4	psi-mi:“MI:0403”(colocalization)	0.510
FOXP4	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXP1	MYL12B	psi-mi:“MI:0914”(association)	0.350
ASB3	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
MRPL12		psi-mi:“MI:0914”(association)	0.350
FOXP3	FOXP2	psi-mi:“MI:0914”(association)	0.350
FOXP2	DUSP14	psi-mi:“MI:0914”(association)	0.350
DHDDS	FOXP4	psi-mi:“MI:0914”(association)	0.350
SOX2	CBX4	psi-mi:“MI:0914”(association)	0.350
CEP192	WASL	psi-mi:“MI:0914”(association)	0.350
PRKY	METTL15	psi-mi:“MI:0914”(association)	0.350

BioGRID (136): FOXP4 (Affinity Capture-MS), XAGE2 (Two-hybrid), FOXP4 (Affinity Capture-MS), FOXP4 (Affinity Capture-MS), FOXP4 (Affinity Capture-MS), FOXP1 (Affinity Capture-MS), FOXP2 (Affinity Capture-MS), DDX39A (Affinity Capture-MS), UBA7 (Affinity Capture-MS), ZMYM3 (Affinity Capture-MS), NRAS (Affinity Capture-MS), NME1 (Affinity Capture-MS), PFKL (Affinity Capture-MS), FOXP4 (Affinity Capture-MS), FOXP4 (Affinity Capture-MS)

ESM2 similar proteins: A2A5E6, A5PK23, A6NKF2, A6PWV5, B0K011, E9Q6W4, O02786, O95402, P09086, P13297, P55198, Q00196, Q08DS3, Q0VDQ9, Q29013, Q2NKI2, Q2VL80, Q2VL82, Q2VL83, Q2VL85, Q2VL86, Q569K4, Q5XI28, Q62255, Q66K41, Q6AXX3, Q6PBT9, Q86V15, Q8BXJ8, Q8IVH2, Q8K4J6, Q8TAX0, Q8VD12, Q8VDL9, Q8WUU4, Q92766, Q969V6, Q96PM9, Q9BXA9, Q9BZE0

Diamond homologs: A4IFD2, F1QDF8, F1R8Z9, O00409, O13606, O15409, O42097, P0CF24, P23512, P32314, P32315, P33205, P33206, P35582, P35583, P55316, P55317, P56260, P58462, P58463, P84961, Q00939, Q01167, Q07342, Q16676, Q17381, Q1A1A1, Q1A1A2, Q1A1A3, Q1A1A4, Q1A1A5, Q1A1A6, Q28D67, Q28EM1, Q28G71, Q28HT3, Q2LE08, Q32NH9, Q33BP8, Q3BJS3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 84 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
Deactivation of the beta-catenin transactivating complex	6	27.4×	2e-05
TCF dependent signaling in response to WNT	7	16.2×	3e-05
Signaling by WNT	6	13.2×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
response to wounding	5	14.2×	9e-04
anatomical structure morphogenesis	6	10.7×	8e-04
gene expression	8	8.2×	6e-04
neuron differentiation	6	7.7×	3e-03
transcription by RNA polymerase II	8	7.2×	8e-04
nervous system development	8	4.7×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	126
Likely benign	10
Benign	5

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1472670	NM_001012426.2(FOXP4):c.1540G>A (p.Ala514Thr)	Pathogenic
1329592	NM_001012426.2(FOXP4):c.10G>T (p.Glu4Ter)	Likely pathogenic
3376844	NM_001012426.2(FOXP4):c.1615G>C (p.Asp539His)	Likely pathogenic

SpliceAI

3142 predictions. Top by Δscore:

Variant	Effect	Δscore
6:41565742:CAG:C	acceptor_loss	1.0000
6:41565743:A:C	acceptor_loss	1.0000
6:41565961:ACAG:A	donor_loss	1.0000
6:41565962:CAG:C	donor_loss	1.0000
6:41565963:AGGTA:A	donor_loss	1.0000
6:41565965:GT:G	donor_loss	1.0000
6:41565966:T:A	donor_loss	1.0000
6:41584765:GCA:G	acceptor_loss	1.0000
6:41584766:CAGGT:C	acceptor_loss	1.0000
6:41584768:G:GA	acceptor_loss	1.0000
6:41584768:GGT:G	acceptor_gain	1.0000
6:41584888:GCAG:G	donor_gain	1.0000
6:41584891:GGT:G	donor_loss	1.0000
6:41584892:G:GG	donor_gain	1.0000
6:41585425:CCCCA:C	acceptor_loss	1.0000
6:41585426:CCCA:C	acceptor_loss	1.0000
6:41585427:CCA:C	acceptor_loss	1.0000
6:41585428:CAGC:C	acceptor_loss	1.0000
6:41585429:A:AC	acceptor_loss	1.0000
6:41585429:A:AG	acceptor_gain	1.0000
6:41585430:G:GA	acceptor_gain	1.0000
6:41585430:G:T	acceptor_loss	1.0000
6:41585430:GC:G	acceptor_gain	1.0000
6:41585430:GCT:G	acceptor_gain	1.0000
6:41585430:GCTAC:G	acceptor_gain	1.0000
6:41585513:AAGAG:A	donor_gain	1.0000
6:41585515:GAG:G	donor_gain	1.0000
6:41585515:GAGGT:G	donor_loss	1.0000
6:41585516:AG:A	donor_gain	1.0000
6:41585516:AGGT:A	donor_loss	1.0000

AlphaMissense

4428 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:41587845:T:A	C309S	1.000
6:41587845:T:C	C309R	1.000
6:41587846:G:A	C309Y	1.000
6:41587846:G:C	C309S	1.000
6:41587846:G:T	C309F	1.000
6:41587847:C:G	C309W	1.000
6:41587851:T:A	W311R	1.000
6:41587851:T:C	W311R	1.000
6:41587852:G:C	W311S	1.000
6:41587853:G:C	W311C	1.000
6:41587853:G:T	W311C	1.000
6:41587860:T:C	C314R	1.000
6:41587861:G:A	C314Y	1.000
6:41587861:G:T	C314F	1.000
6:41587862:T:G	C314W	1.000
6:41587890:T:C	F324L	1.000
6:41587891:T:C	F324S	1.000
6:41587892:T:A	F324L	1.000
6:41587892:T:G	F324L	1.000
6:41588645:C:G	H327D	1.000
6:41588647:C:A	H327Q	1.000
6:41588647:C:G	H327Q	1.000
6:41588649:T:C	L328P	1.000
6:41588660:C:G	H332D	1.000
6:41588661:A:G	H332R	1.000
6:41588662:C:A	H332Q	1.000
6:41588662:C:G	H332Q	1.000
6:41588670:A:T	D335V	1.000
6:41588672:G:C	D336H	1.000
6:41588678:A:C	S338R	1.000

dbSNP variants (sampled 300 via entrez): RS1000052567 (6:41548275 G>A,T), RS1000122350 (6:41547124 C>G), RS1000145342 (6:41586663 G>A), RS1000161301 (6:41570118 G>A,C,T), RS1000216507 (6:41564294 C>T), RS1000289149 (6:41581755 A>C,T), RS1000396411 (6:41576063 C>A,T), RS1000415670 (6:41547192 G>A), RS1000425286 (6:41548654 G>A), RS1000585092 (6:41565218 G>C), RS1000642996 (6:41552452 T>G), RS1000699108 (6:41577144 A>G), RS1000708064 (6:41602347 G>A), RS1000743238 (6:41550760 A>G), RS1000762914 (6:41552642 G>A)

Disease associations

OMIM: gene MIM:608924 | disease phenotypes: MIM:614429

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Strong	Autosomal dominant
neurodevelopmental disorder	Moderate	Autosomal dominant

Mondo (6): ventricular septal defect (MONDO:0002070), hearing loss disorder (MONDO:0005365), sensorineural hearing loss disorder (MONDO:0020678), lung adenocarcinoma (MONDO:0005061), neurodevelopmental disorder (MONDO:0700092), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (2): NON RARE IN EUROPE: Ventricular septal defect (Orphanet:1480), NON RARE IN EUROPE: Adenocarcinoma of the lung (Orphanet:415268)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0001629	Ventricular septal defect
HP:0000407	Sensorineural hearing impairment

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000750_11	Prostate cancer	8.000000e-08
GCST003605_6	EGFR mutation-positive lung adenocarcinoma	4.000000e-09
GCST007576_267	Chronotype	1.000000e-08
GCST008834_2	Non-small cell lung cancer	1.000000e-10
GCST008860_21	Prostate cancer	5.000000e-08
GCST009391_16	Metabolite levels	2.000000e-06
GCST010397_90	Gut microbiota (bacterial taxa, rank normal transformation method)	7.000000e-09
GCST90002385_558	High light scatter reticulocyte count	1.000000e-09
GCST90002386_101	High light scatter reticulocyte percentage of red cells	2.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0007874	gut microbiome measurement
EFO:0007986	reticulocyte count

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D006345	Heart Septal Defects, Ventricular	C14.240.400.560.540; C14.280.400.560.540; C16.131.240.400.560.540
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	3
Valproic Acid	affects expression, decreases expression	3
FR900359	increases phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
bisphenol A	increases methylation	1
lead acetate	increases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, decreases methylation	1
afimoxifene	decreases expression, decreases reaction	1
cupric chloride	increases expression	1
coumarin	increases phosphorylation	1
phenanthrene	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
licochalcone B	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Caffeine	affects phosphorylation	1
Diethylhexyl Phthalate	decreases methylation, increases abundance	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	decreases expression	1
Estrogens	decreases expression, decreases reaction	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Gold Compounds	increases expression	1
Antirheumatic Agents	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02914652	PHASE4	COMPLETED	The Cardiopulmonary Effect of Inhaled Beta-2-agonists on Adult Patients Born With Ventricular Septum Defects.
NCT05688670	PHASE4	COMPLETED	Regional Anesthesia Following Pediatric Cardiac Surgery
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00113698	PHASE3	TERMINATED	Angiotensin Converting Enzyme Inhibition in Children With Mitral Regurgitation
NCT05253209	PHASE3	TERMINATED	A Study Evaluating the Efficacy and Safety of IV L-Citrulline for the Prevention of Clinical Sequelae of Acute Lung Injury Induced by Cardiopulmonary Bypass in Pediatric Patients Undergoing Surgery for Congenital Heart Defects
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00199771	PHASE2	COMPLETED	Hypertonic Saline Dextran in Pediatric Cardiac Surgery
NCT00556361	PHASE2	COMPLETED	Use of Ketamine Prior to Cardiopulmonary Bypass in Children
NCT00848393	PHASE2	COMPLETED	Measures to Lower the Stress Response in Pediatric Cardiac Surgery
NCT04017975	PHASE2	ACTIVE_NOT_RECRUITING	Optical Tissue Identification for Myocardial Architecture
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism