SOX4

Summary

SOX4 (SRY-box transcription factor 4, HGNC:11200) is a protein-coding gene on chromosome 6p22.3, encoding Transcription factor SOX-4 (Q06945). Transcriptional activator that binds with high affinity to the T-cell enhancer motif 5’-AACAAAG-3’ motif.

This intronless gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins, such as syndecan binding protein (syntenin). The protein may function in the apoptosis pathway leading to cell death as well as to tumorigenesis and may mediate downstream effects of parathyroid hormone (PTH) and PTH-related protein (PTHrP) in bone development. The solution structure has been resolved for the HMG-box of a similar mouse protein.

Source: NCBI Gene 6659 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Coffin-Siris syndrome 10 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 14
• Clinical variants (ClinVar): 250 total — 8 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 85
• Transcription factor: yes — 27 downstream targets (CollecTRI)
• MANE Select transcript: NM_003107

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11200
Approved symbol	SOX4
Name	SRY-box transcription factor 4
Location	6p22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000124766
Ensembl biotype	protein_coding
OMIM	184430
Entrez	6659

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000244745

RefSeq mRNA: 1 — MANE Select: NM_003107 NM_003107

CCDS: CCDS4547

Canonical transcript exons

ENST00000244745 — 1 exons

Exon	Start	End
ENSE00000848186	21593751	21598619

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 157.9500 / max 10801.9646, expressed in 1749 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
66299	109.2325	1725
66317	32.7149	1586
66314	2.8659	952
66315	2.5958	906
66311	2.2300	872
66310	1.6820	743
66304	1.4083	751
66312	1.2355	610
66302	0.7598	339
66303	0.5884	377

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.57	gold quality
ganglionic eminence	UBERON:0004023	99.46	gold quality
embryo	UBERON:0000922	99.03	gold quality
ventricular zone	UBERON:0003053	97.78	gold quality
tendon of biceps brachii	UBERON:0008188	97.74	gold quality
corpus epididymis	UBERON:0004359	97.48	gold quality
type B pancreatic cell	CL:0000169	97.45	gold quality
visceral pleura	UBERON:0002401	97.36	gold quality
mammary duct	UBERON:0001765	97.30	gold quality
endometrium epithelium	UBERON:0004811	97.26	gold quality
epithelium of mammary gland	UBERON:0003244	97.22	gold quality
adult organism	UBERON:0007023	96.40	gold quality
caput epididymis	UBERON:0004358	95.94	gold quality
endometrium	UBERON:0001295	95.81	gold quality
tibia	UBERON:0000979	95.68	gold quality
thymus	UBERON:0002370	95.60	gold quality
stromal cell of endometrium	CL:0002255	95.51	gold quality
vena cava	UBERON:0004087	95.43	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	95.24	gold quality
germinal epithelium of ovary	UBERON:0001304	95.23	gold quality
olfactory bulb	UBERON:0002264	95.04	gold quality
cartilage tissue	UBERON:0002418	94.89	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.79	gold quality
nasal cavity epithelium	UBERON:0005384	94.78	gold quality
cauda epididymis	UBERON:0004360	94.53	gold quality
pleura	UBERON:0000977	94.50	gold quality
skin of hip	UBERON:0001554	94.34	gold quality
bronchial epithelial cell	CL:0002328	94.21	gold quality
cardia of stomach	UBERON:0001162	94.21	gold quality
renal medulla	UBERON:0000362	94.19	gold quality

Single-cell (SCXA)

Detected in 59 experiment(s), a significant marker in 47.

Experiment	Marker?	Max mean expression
E-CURD-7	yes	17643.80
E-HCAD-5	yes	8544.95
E-ENAD-21	yes	7855.32
E-MTAB-9435	yes	5421.71
E-MTAB-8221	yes	5211.99
E-HCAD-56	yes	5144.45
E-MTAB-10485	yes	4365.91
E-MTAB-11121	yes	3699.46
E-CURD-114	yes	3278.49
E-HCAD-31	yes	2746.19
E-MTAB-10432	yes	2681.25
E-CURD-122	yes	2228.19
E-MTAB-9154	yes	2117.22
E-MTAB-8884	yes	2110.13
E-MTAB-7008	yes	1467.78

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

27 targets.

Target	Regulation
AGO1	Unknown
AXIN2	Unknown
BAX	Activation
BBC3	Unknown
CALD1
CDH2	Activation
CDKN1A	Activation
CEL
DHX9	Unknown
DICER1	Unknown
DLL1	Activation
EGFR
FZD5
GCG	Activation
GCKR
HDAC8	Activation
IGLL1	Unknown
KMT2A	Unknown
MECOM	Activation
NCAM1	Activation
NKX3-1	Unknown
NOTCH1
PTCH1
SOX2	Activation
SOX4	Activation
TBXT
TNC	Activation

JASPAR motifs

Motif	Name	Family
MA0867.1	SOX4	SOX-related factors
MA0867.2	SOX4	SOX-related factors
MA0867.3	SOX4	SOX-related factors

JASPAR matrix evidence (PMIDs): PMID:12920151, PMID:17599239

Upstream regulators (CollecTRI, top): AR, CEBPA, ERG, FOSL2, JUND, KAT5, SOX4, SOX9, TP53

miRNA regulators (miRDB)

199 targeting SOX4, 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-3613-3P	100.00	76.36	7965
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-19A-3P	99.98	75.33	2762

Literature-anchored findings (GeneRIF, showing 40)

• Sox-4 is a positive regulator of Hep3B and HepG2 cells’ apoptosis induced by prostaglandin (PG)A(2) and delta(12)-PGJ(2). (PMID:12216117)
• Data suggest that the apoptotic activity of Sox4 can be dissociated from its transcriptional trans-activation and is mediated through its central pro-apoptotic CD domain. (PMID:15522200)
• The human transcription factor SOX4 was 5-fold up-regulated in bladder tumors compared with normal tissue based on whole-genome expression profiling of 166 clinical bladder tumor samples and 27 normal urothelium samples. (PMID:16585165)
• Stable transfection of SOX4 into nontransformed prostate cells enabled colony formation in soft agar, suggesting that, in the proper cellular context, SOX4 can be a transforming oncogene. (PMID:16618720)
• It shows that Ubc9 interacts with SOX4 and represses its transcriptional activity independent of its SUMO-1-conjugating activity. (PMID:16631117)
• indings suggest that Sox4 contributes to the malignant phenotype of adenoid cystic carcinoma cells by promoting cell survival (PMID:16636670)
• Sox4 expression in trangenic mice counteracts differentiation of radial glia and has to be downregulated before full maturation can occur. (PMID:17507571)
• mutation of SOX4 gene in the different tumor tissues with pathological stages and types of non-small cell lung cancer (NSCLC) (PMID:17922414)
• overexpression of SOX4 potentiates metastasis in hepatocellular carcinoma. (PMID:18504433)
• There was a trend toward better survival with increasing SOX4 expression in medulloblastoma. (PMID:18577562)
• SOX4 affects developmental signaling pathways and these changes may influence cancer progression via regulation of gene networks involved in microRNA processing, transcriptional regulation, growth factor signaling, and tumor metastasis. (PMID:19147588)
• In lung cancer, SOX4 is overexpressed due to gene amplification and provide evidence of oncogenic properties of SOX4. (PMID:19153074)
• high SOX4 transcript levels correlated with recurrence of colorectal cancer (PMID:19156145)
• SOX4, a new DNA damage sensor, is required for the activation of p53 tumor suppressor in response to DNA damage. (PMID:19234109)
• A direct link between miR-129 and the two putative targets GALNT1 and SOX4 in bladder cancer. (PMID:19487295)
• Results imply that the aberrant expression of SOX4 is caused by epigenetic repression of miR-129-2 in endometrial cancer. (PMID:19887623)
• induction of SOX4 gene expression might be responsible for the CD56 expression in human myeloma cells (PMID:20049565)
• SOX4 has been implicated in pancreas development and the regulation of insulin secretion and risk of type 2 diabetes. (PMID:20080751)
• up-regulation of SOX4 was inversely associated with the epigenetic silencing of miR-129-2 in gastric cancer, and restoration of miR-129-2 down-regulated SOX4 expression. (PMID:20331975)
• SOX4 contributes to hepatocarcinogenesis by inhibiting p53-mediated apoptosis. (PMID:20400479)
• SOX4 and TGFBI expression is elevated in GBM tissues compared with normal brain tissues at both the RNA and protein levels (PMID:20419098)
• SOX4 is closely associated with early recurrence of hepatocellular carcinoma after curative resection, and its overexpression may contribute to early recurrence. (PMID:20423819)
• Sox4 regulates melanoma cell migration and invasion in an NF-kappaB p50-dependent manner and may serve as a prognostic marker and potential therapeutic target for human melanoma. (PMID:20952589)
• Sox4 acts as an agonist of Wnt signaling in cancer cells. (PMID:21165564)
• SOX4 gene may have a role in bladder cancer tumorigenesis. (PMID:21680105)
• our data demonstrate that the Sox4 C-terminal domain regulates polyubiquitin-independent proteasomal degradation of Sox4 that can be modulated by interaction with syntenin (PMID:21986941)
• findings identify a functional role for SOX genes in SCLC, particularly for SOX4 and several novel targets defined in this study (PMID:22084397)
• Junction plakoglobin (JUP) interacts with SOX4 in both the cytosol and the nucleus and the interaction between SOX4 and plakoglobin is significantly increased when prostate and breast cancer cells are stimulated with WNT3A. (PMID:22098624)
• The SOX4-plakoglobin complex affected the expression of Wnt pathway target genes and SOX4 downstream targets, such as AXIN2, DICER1, and DHX9. (PMID:22098624)
• may serve as a positive regulator of beta-catenin signaling through alteration in TCF4 expression during morular differentiation of endometrial carcinoma cells, leading to inhibition of cell proliferation (PMID:22231735)
• Our data indicate for the first time that the over-expression of SOX4 in primary gallbladder carcinoma was significantly correlated with favorable clinicopathologic features (PMID:22510499)
• demonstrate that SPARC expression suppressed irradiation induced SOX-4 mediated DNA repair (PMID:22542805)
• Sox4 and CREB cooperate and contribute to increased proliferation of hematopoietic progenitor cells. (PMID:22627767)
• Knockdown of Sox4 induces a major change in the expression pattern of miRNAs in melanoma cells, mainly due to reduced expression of Dicer. (PMID:22689055)
• Our findings define an important function for SOX4 in the progression of breast cancer by orchestrating EMT, and they implicate this gene product as a marker of poor prognosis in this disease. (PMID:22787120)
• SOX4 gene expression was strongly up-regulated in human Ph+ pre-BALL cells by tyrosine kinase inhibitor treatment.High levels of SOX4 expression in ALL cells at the time of diagnosis predicted poor outcome in a pediatric clinical trial (COG P9906). (PMID:23152540)
• we disclose a miR-129-2(miR-335)/SOX4/Semaphorin-Plexin regulatory axis in the tumorigenesis of pancreatic cancer. (PMID:23251334)
• overexpression of nuclear SOX4 was a clear prognostic marker for GC (P=0.004). Overexpression of nuclear SOX4 can be used as a marker to predict the outcome of patients with GC. (PMID:23285187)
• TGF-b-mediated increased expression of SOX4 is required for the induction of a mesenchymal phenotype during EMT in human mammary epithelial cells (PMID:23301048)
• study demonstrates the role and clinical relevance of miR-138 in ovarian cancer cell invasion and metastasis, providing a potential therapeutic strategy for suppression of ovarian cancer metastasis by targeting SOX4 and HIF-1alpha pathways (PMID:23389731)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	sox4a	ENSDARG00000004588
danio_rerio	sox4b	ENSDARG00000098834
mus_musculus	Sox4	ENSMUSG00000076431
rattus_norvegicus	Sox4	ENSRNOG00000065643
drosophila_melanogaster	Sox14	FBGN0005612
drosophila_melanogaster	Sox21a	FBGN0036411
drosophila_melanogaster	Sox102F	FBGN0039938
caenorhabditis_elegans		WBGENE00001182

Paralogs (20): SOX8 (ENSG00000005513), SOX30 (ENSG00000039600), SOX10 (ENSG00000100146), SOX6 (ENSG00000110693), SOX21 (ENSG00000125285), SOX9 (ENSG00000125398), SOX15 (ENSG00000129194), SOX5 (ENSG00000134532), SOX3 (ENSG00000134595), SOX13 (ENSG00000143842), SOX17 (ENSG00000164736), SOX14 (ENSG00000168875), SOX7 (ENSG00000171056), SOX11 (ENSG00000176887), SOX12 (ENSG00000177732), CFAP65 (ENSG00000181378), SOX2 (ENSG00000181449), SOX1 (ENSG00000182968), SRY (ENSG00000184895), SOX18 (ENSG00000203883)

Protein

Protein identifiers

Transcription factor SOX-4 — Q06945 (reviewed: Q06945)

All UniProt accessions (1): Q06945

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional activator that binds with high affinity to the T-cell enhancer motif 5’-AACAAAG-3’ motif. Required for IL17A-producing Vgamma2-positive gamma-delta T-cell maturation and development, via binding to regulator loci of RORC to modulate expression. Involved in skeletal myoblast differentiation by promoting gene expression of CALD1.

Subunit / interactions. Interacts with UBE2I. Interacts with HDAC1; interaction inhibits the transcriptional activator activity.

Subcellular location. Nucleus.

Tissue specificity. Testis, brain, and heart.

Post-translational modifications. Acetylation at Lys-95 by KAT5 promotes the transcription activator activity and is required during myoblast differentiation. Acetylation by KAT5 abolishes the interaction between SOX4 and HDAC1 and switches SOX4 into a transcriptional activator.

Disease relevance. Intellectual developmental disorder with speech delay and dysmorphic facies (IDDSDF) [MIM:618506] An autosomal dominant disorder characterized by mild to severe intellectual disability, global developmental delay, mild but distinct facial dysmorphism, fifth finger clinodactyly, and small stature. Hypotonia, ventricular septal defect, and spastic quadriparesis may also be present. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.

RefSeq proteins (1): NP_003098* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009071	HMG_box_dom	Domain
IPR017386	SOX-12/11/4	Family
IPR036910	HMG_box_dom_sf	Homologous_superfamily
IPR050140	SRY-related_HMG-box_TF-like	Family

Pfam: PF00505

UniProt features (25 total): compositionally biased region 10, sequence variant 4, region of interest 4, mutagenesis site 2, chain 1, DNA-binding region 1, modified residue 1, sequence conflict 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q06945-F1	55.71	0.19

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 (1): 95

Mutagenesis-validated functional residues (2):

Position	Phenotype
45	does not affect acetylation by kat5.
95	abolished acetylation by kat5.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-3769402	Deactivation of the beta-catenin transactivating complex
R-HSA-162582	Signal Transduction
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT

MSigDB gene sets: 899 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_SPINAL_CORD_DEVELOPMENT, AHRARNT_01, GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, MODULE_52, GOBP_EPITHELIUM_DEVELOPMENT, KOBAYASHI_EGFR_SIGNALING_24HR_UP, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_VENTRICULAR_SEPTUM_MORPHOGENESIS, CCAWYNNGAAR_UNKNOWN

GO Biological Process (39): negative regulation of transcription by RNA polymerase II (GO:0000122), pro-B cell differentiation (GO:0002328), mitral valve morphogenesis (GO:0003183), cardiac right ventricle morphogenesis (GO:0003215), atrial septum primum morphogenesis (GO:0003289), noradrenergic neuron differentiation (GO:0003357), regulation of DNA-templated transcription (GO:0006355), nervous system development (GO:0007399), brain development (GO:0007420), heart development (GO:0007507), positive regulation of cell population proliferation (GO:0008284), gene expression (GO:0010467), glial cell proliferation (GO:0014009), spinal cord development (GO:0021510), glial cell development (GO:0021782), neuron differentiation (GO:0030182), T cell differentiation (GO:0030217), endocrine pancreas development (GO:0031018), positive regulation of insulin secretion (GO:0032024), somatic stem cell population maintenance (GO:0035019), ascending aorta morphogenesis (GO:0035910), glucose homeostasis (GO:0042593), positive regulation of apoptotic process (GO:0043065), regulation of DNA damage response, signal transduction by p53 class mediator (GO:0043516), positive regulation of gamma-delta T cell differentiation (GO:0045588), negative regulation of myoblast differentiation (GO:0045662), positive regulation of myoblast differentiation (GO:0045663), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), sympathetic nervous system development (GO:0048485), camera-type eye morphogenesis (GO:0048593), protein stabilization (GO:0050821), ventricular septum morphogenesis (GO:0060412), mesenchyme development (GO:0060485), neuroepithelial cell differentiation (GO:0060563), kidney morphogenesis (GO:0060993), hematopoietic stem cell homeostasis (GO:0061484), cellular response to glucose stimulus (GO:0071333), positive regulation of canonical Wnt signaling pathway (GO:0090263)

GO Molecular Function (9): transcription cis-regulatory region binding (GO:0000976), 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 activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), miRNA binding (GO:0035198), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), mitochondrion (GO:0005739)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
TCF dependent signaling in response to WNT	1
Signal Transduction	1
Signaling by WNT	1

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 transcription by RNA polymerase II	2
central nervous system development	2
animal organ development	2
cell population proliferation	2
anatomical structure development	2
intracellular membrane-bounded organelle	2
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
lymphoid progenitor cell differentiation	1
mitral valve development	1
atrioventricular valve morphogenesis	1
cardiac ventricle morphogenesis	1
septum primum development	1
atrial septum morphogenesis	1
neuron differentiation	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
system development	1
head development	1
circulatory system development	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
macromolecule biosynthetic process	1
gliogenesis	1
glial cell differentiation	1
cell development	1
cell differentiation	1
generation of neurons	1
lymphocyte differentiation	1
T cell activation	1
pancreas development	1
endocrine system development	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
stem cell population maintenance	1

Protein interactions and networks

STRING

2730 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SOX4	POU5F1	P31359	914
SOX4	EZH2	Q15910	871
SOX4	SDCBP	O00560	803
SOX4	CTNNB1	P35222	753
SOX4	IL5RA	Q01344	707
SOX4	STAT3	P40763	704
SOX4	MYC	P01106	678
SOX4	GATA3	P23771	655
SOX4	UBE2I	P50550	645
SOX4	LEF1	Q9UJU2	640
SOX4	HMGB4	Q8WW32	633
SOX4	SNAI2	O43623	628
SOX4	ASCL1	P50553	610
SOX4	HNF4A	P41235	602
SOX4	SMAD4	Q13485	598

IntAct

31 interactions, top by confidence:

A	B	Type	Score
SOX4	TP53	psi-mi:“MI:0915”(physical association)	0.590
TP53	SOX4	psi-mi:“MI:0915”(physical association)	0.590
CREBBP	SOX4	psi-mi:“MI:0915”(physical association)	0.400
EP300	SOX4	psi-mi:“MI:0915”(physical association)	0.400
SOX4	ACTBL2	psi-mi:“MI:0915”(physical association)	0.400
SOX4	GATA3	psi-mi:“MI:0915”(physical association)	0.400
SOX4	UBE2M	psi-mi:“MI:0914”(association)	0.350
MYO1B	ZMPSTE24	psi-mi:“MI:0914”(association)	0.350
SOX4	SEC16A	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	SOX4	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	SOX4	psi-mi:“MI:2364”(proximity)	0.270
SOX4	SMARCA4	psi-mi:“MI:2364”(proximity)	0.270
SMARCA4	SOX4	psi-mi:“MI:2364”(proximity)	0.270
SOX4	PTPN11	psi-mi:“MI:2364”(proximity)	0.270
SPAG9	SOX4	psi-mi:“MI:0915”(physical association)	0.000
MCM4	SOX4	psi-mi:“MI:0915”(physical association)	0.000
MCM2	SOX4	psi-mi:“MI:0915”(physical association)	0.000
MCM6	SOX4	psi-mi:“MI:0915”(physical association)	0.000
EPS15L1	SOX4	psi-mi:“MI:0915”(physical association)	0.000
USP15	SOX4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (85): TAF5 (Affinity Capture-MS), TNNI3 (Two-hybrid), SCNN1G (Two-hybrid), MINPP1 (Two-hybrid), IGF1 (Two-hybrid), PLD3 (Two-hybrid), CAPN15 (Two-hybrid), FOXH1 (Two-hybrid), RGSL1 (Two-hybrid), LMNB2 (Two-hybrid), CTR9 (Two-hybrid), ITIH1 (Two-hybrid), APOC3 (Two-hybrid), EDF1 (Two-hybrid), NANOGNB (Two-hybrid)

ESM2 similar proteins: A1Z6W3, A7X8B3, A7X8B7, A7X8C4, B0WAQ0, O97960, P06401, P08155, P09631, P0C1G9, P15619, P23949, P25172, P35716, P40650, P41894, P47974, P48435, P57073, P57074, P78415, P81067, P84550, P84551, Q04886, Q05A36, Q06831, Q06945, Q0V9X5, Q14774, Q15464, Q292U2, Q292U5, Q297V5, Q2VWA4, Q5IS79, Q5U5Q3, Q66JF1, Q6PD21, Q6QT55

Diamond homologs: A0A0G2JTZ2, A2TED3, A5D8R3, B1H349, B3DLD3, B3DM43, F1M8W4, O42342, O42601, P0C1G9, P35710, P35711, P35712, P35713, P35716, P36389, P36390, P36393, P36394, P36396, P40645, P40646, P40647, P40649, P40650, P40656, P40657, P43680, P47792, P48433, P48435, Q03255, Q03257, Q04891, Q05738, Q06831, Q06945, Q20201, Q23045, Q27949

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
CEBPA	down-regulates	SOX4	“transcriptional regulation”
SOX4	down-regulates	Differentiation
SOX4	“up-regulates activity”	CTNNB1	binding
SOX4	“up-regulates quantity”	DICER1	“transcriptional regulation”
SOX4	up-regulates	Proliferation
miRNA-214-5p	“down-regulates quantity by destabilization”	SOX4	“post transcriptional regulation”
IL5RA	“up-regulates activity”	SOX4	binding
SDCBP	“up-regulates activity”	SOX4	binding
FOXC1	“up-regulates quantity by expression”	SOX4	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	12
Uncertain significance	173
Likely benign	33
Benign	7

Top pathogenic / likely-pathogenic (20)

Variant ID	HGVS	Classification
1686223	NM_003107.3(SOX4):c.975C>G (p.Tyr325Ter)	Pathogenic
1691155	NM_003107.3(SOX4):c.289T>G (p.Trp97Gly)	Pathogenic
2443795	NM_003107.3(SOX4):c.1333G>T (p.Glu445Ter)	Pathogenic
2443796	NM_003107.3(SOX4):c.130_133delinsCGCT (p.Gly44_Lys45delinsArgTer)	Pathogenic
3254650	NM_003107.3(SOX4):c.386_390del (p.Arg129fs)	Pathogenic
3340821	NM_003107.3(SOX4):c.291G>C (p.Trp97Cys)	Pathogenic
4074737	NM_003107.3(SOX4):c.1274C>A (p.Ser425Ter)	Pathogenic
4795244	NM_003107.3(SOX4):c.468_469del (p.Asp156fs)	Pathogenic
2580163	NM_003107.3(SOX4):c.281G>A (p.Gly94Asp)	Likely pathogenic
2664011	NM_003107.3(SOX4):c.373_378del (p.Asp125_Tyr126del)	Likely pathogenic
3067564	NM_003107.3(SOX4):c.998C>A (p.Ser333Ter)	Likely pathogenic
3254652	NM_003107.3(SOX4):c.335C>A (p.Ala112Glu)	Likely pathogenic
3347110	NM_003107.3(SOX4):c.744_745delinsA (p.Leu250fs)	Likely pathogenic
3391688	NM_003107.3(SOX4):c.280G>A (p.Gly94Ser)	Likely pathogenic
3392529	NM_003107.3(SOX4):c.200T>C (p.Met67Thr)	Likely pathogenic
3629480	NM_003107.3(SOX4):c.185C>T (p.Pro62Leu)	Likely pathogenic
3774374	NM_003107.3(SOX4):c.185C>G (p.Pro62Arg)	Likely pathogenic
4279018	NM_003107.3(SOX4):c.251T>G (p.Met84Arg)	Likely pathogenic
4813418	NM_003107.3(SOX4):c.332dup (p.Ala112fs)	Likely pathogenic
548142	NM_003107.3(SOX4):c.198C>A (p.Phe66Leu)	Likely pathogenic

SpliceAI

62 predictions. Top by Δscore:

Variant	Effect	Δscore
6:21594038:GGA:G	acceptor_gain	0.8000
6:21594033:TTGTA:T	acceptor_loss	0.7600
6:21594034:TGTAG:T	acceptor_loss	0.7600
6:21594035:GTAGG:G	acceptor_loss	0.7600
6:21594036:TA:T	acceptor_loss	0.7600
6:21594037:A:AC	acceptor_loss	0.7600
6:21594029:T:A	acceptor_loss	0.7400
6:21594038:GGAGA:G	acceptor_gain	0.7300
6:21594024:T:A	acceptor_loss	0.7200
6:21594032:ATTGT:A	acceptor_loss	0.7200
6:21594935:TG:T	donor_gain	0.6900
6:21594037:A:AG	acceptor_gain	0.6700
6:21594038:G:GG	acceptor_gain	0.6700
6:21595709:C:CA	acceptor_gain	0.6500
6:21595710:G:A	acceptor_gain	0.6500
6:21594036:TAGG:T	acceptor_gain	0.6300
6:21594037:AGGA:A	acceptor_gain	0.6300
6:21594038:GGAG:G	acceptor_gain	0.6300
6:21594032:A:AG	acceptor_gain	0.6100
6:21594037:AG:A	acceptor_gain	0.6100
6:21594038:GG:G	acceptor_gain	0.6100
6:21594025:GCTTT:G	acceptor_loss	0.6000
6:21594026:CTTT:C	acceptor_loss	0.5800
6:21594030:GCATT:G	acceptor_loss	0.5800
6:21598072:A:G	acceptor_gain	0.5800
6:21596448:T:A	acceptor_gain	0.5700
6:21594936:GA:G	donor_gain	0.5200
6:21594937:AA:A	donor_gain	0.5200
6:21594032:ATT:A	acceptor_gain	0.4900
6:21594033:T:G	acceptor_gain	0.4900

AlphaMissense

3041 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:21594685:T:A	W51R	1.000
6:21594685:T:C	W51R	1.000
6:21594687:G:C	W51C	1.000
6:21594687:G:T	W51C	1.000
6:21594688:T:A	C52S	1.000
6:21594688:T:C	C52R	1.000
6:21594689:G:A	C52Y	1.000
6:21594689:G:C	C52S	1.000
6:21594690:C:G	C52W	1.000
6:21594703:G:T	G57W	1.000
6:21594706:C:G	H58D	1.000
6:21594710:T:A	I59N	1.000
6:21594710:T:C	I59T	1.000
6:21594710:T:G	I59S	1.000
6:21594712:A:G	K60E	1.000
6:21594713:A:T	K60M	1.000
6:21594714:G:C	K60N	1.000
6:21594714:G:T	K60N	1.000
6:21594715:C:G	R61G	1.000
6:21594716:G:A	R61Q	1.000
6:21594716:G:T	R61L	1.000
6:21594718:C:A	P62T	1.000
6:21594718:C:G	P62A	1.000
6:21594718:C:T	P62S	1.000
6:21594719:C:A	P62H	1.000
6:21594719:C:G	P62R	1.000
6:21594719:C:T	P62L	1.000
6:21594722:T:A	M63K	1.000
6:21594722:T:C	M63T	1.000
6:21594722:T:G	M63R	1.000

dbSNP variants (sampled 300 via entrez): RS1000016194 (6:21596098 G>A,C,T), RS1000391858 (6:21594217 T>C), RS1000573405 (6:21598431 G>A), RS1000620262 (6:21594515 G>A,T), RS1000686943 (6:21593631 T>C), RS1001222943 (6:21598227 A>G,T), RS1001569510 (6:21597901 G>A,T), RS1001800156 (6:21595251 C>A,G,T), RS1002886917 (6:21596091 T>C), RS1003252136 (6:21592529 C>T), RS1003814845 (6:21596675 A>AGG), RS1003968598 (6:21596678 C>T), RS1004467409 (6:21596706 G>T), RS1004513030 (6:21598703 T>G), RS1004564341 (6:21592238 G>A)

Disease associations

OMIM: gene MIM:184430 | disease phenotypes: MIM:618506, MIM:135900, MIM:609943, MIM:614562

GenCC curated gene-disease

Disease	Classification	Inheritance
Coffin-Siris syndrome 10	Strong	Autosomal dominant
Coffin-Siris syndrome	Supportive	Autosomal dominant
atrial fibrillation	Limited	Autosomal dominant

Mondo (7): Coffin-Siris syndrome 10 (MONDO:0032791), intellectual disability (MONDO:0001071), disorder of sexual differentiation (MONDO:0002145), neurodevelopmental disorder (MONDO:0700092), Coffin-Siris syndrome 1 (MONDO:0007617), atrial fibrillation (MONDO:0004981), Coffin-Siris syndrome (MONDO:0015452)

Orphanet (3): Difference of sex development (Orphanet:90771), Coffin-Siris syndrome (Orphanet:1465), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

85 total (30 of 85 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000085	Horseshoe kidney
HP:0000119	Abnormality of the genitourinary system
HP:0000154	Wide mouth
HP:0000179	Thick lower lip vermilion
HP:0000219	Thin upper lip vermilion
HP:0000243	Trigonocephaly
HP:0000252	Microcephaly
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000289	Broad philtrum
HP:0000294	Low anterior hairline
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000545	Myopia
HP:0000574	Thick eyebrow
HP:0000684	Delayed eruption of teeth
HP:0000696	Delayed eruption of permanent teeth
HP:0000708	Atypical behavior
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST000960_16	Cardiac hypertrophy	4.000000e-06
GCST001050_5	Bone mineral density	4.000000e-06
GCST001784_13	Pulmonary function (smoking interaction)	2.000000e-07
GCST001784_35	Pulmonary function (smoking interaction)	2.000000e-07
GCST003436_3	Endometrial cancer	2.000000e-08
GCST006464_8	Endometrial cancer	4.000000e-16
GCST006465_15	Endometrial cancer (endometrioid histology)	6.000000e-13
GCST009391_1002	Metabolite levels	8.000000e-06
GCST009391_2122	Metabolite levels	3.000000e-06
GCST90011898_138	Alanine aminotransferase levels	2.000000e-11
GCST90011899_19	Aspartate aminotransferase levels	4.000000e-10
GCST90013663_58	Alanine aminotransferase levels	1.000000e-12
GCST90013664_88	Aspartate aminotransferase levels	1.000000e-10
GCST90027899_4	Eosinophilic esophagitis	3.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0002503	cardiac hypertrophy
EFO:0003892	pulmonary function measurement
EFO:0004713	FEV/FVC ratio
EFO:0010358	lysophosphatidylcholine 16:1 measurement
EFO:0010382	phosphatidylcholine 36:4 measurement
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D001281	Atrial Fibrillation	C14.280.067.198; C23.550.073.198
D012734	Disorders of Sex Development	C12.050.351.875.253; C12.200.706.316; C12.800.316; C16.131.939.316; C19.391.119
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C536436	Coffin-Siris syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, affects expression, increases expression, increases methylation, affects reaction (+1 more)	7
Benzo(a)pyrene	decreases methylation, increases expression	5
sodium arsenite	decreases expression	4
Estradiol	decreases expression, increases expression, affects cotreatment	4
Tetrachlorodibenzodioxin	decreases expression, increases reaction, affects expression, affects binding, increases expression	4
bisphenol A	affects expression, decreases expression	3
Ethinyl Estradiol	affects expression, decreases expression	3
Progesterone	affects cotreatment, decreases expression	3
Cyclosporine	decreases expression, increases expression	3
trichostatin A	affects cotreatment, decreases expression	2
entinostat	decreases expression, affects cotreatment	2
Tretinoin	decreases expression, increases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
Genistein	decreases expression	2
bisphenol F	decreases expression	1
dicrotophos	decreases expression	1
testosterone enanthate	affects expression	1
methyleugenol	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
deoxynivalenol	increases expression	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
potassium chromate(VI)	decreases expression	1
ferrous chloride	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
hydroquinone	decreases expression	1
beta-methylcholine	affects expression	1
celastrol	decreases expression	1
6-methyl-1,3,8-trichlorodibenzofuran	affects binding, decreases expression, increases reaction	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00032591	PHASE4	COMPLETED	The Home INR Study
NCT00127712	PHASE4	COMPLETED	Prevention of Atrial Fibrillation Following Noncardiac Thoracic Surgery
NCT00157781	PHASE4	COMPLETED	LEAF - Low Energy In Atrial Fibrillation
NCT00170313	PHASE4	TERMINATED	CORE: Study to Evaluate the Conducted AF-Response-Algorithm in Patients Suffering From Heart Failure and Atrial Fibrillation
NCT00189319	PHASE4	COMPLETED	To Evaluate the Impact of Oral Flecainide on Quality of Life in Patients With Paroxysmal Atrial Fibrillation
NCT00196144	PHASE4	COMPLETED	FFS - Far Field Sensing Test Study in Cardiac Dual Chamber Pacemakers
NCT00196157	PHASE4	UNKNOWN	Line Versus Spot Ablation in Persistent Atrial Fibrillation
NCT00196183	PHASE4	COMPLETED	Trigger- vs. Substrate-Ablation for Paroxysmal Atrial Fibrillation
NCT00196209	PHASE4	UNKNOWN	Cardioversion vs. Catheter Ablation for Persistent Atrial Fibrillation
NCT00227344	PHASE4	TERMINATED	CACAF2 Study: Catheter Ablation for Cure of Atrial Fibrillation
NCT00232219	PHASE4	COMPLETED	Use of Fish Oils to Reduce Recurrence of Atrial Fibrillation Following DC Cardioversion
NCT00232232	PHASE4	COMPLETED	Use of Fish Oils to Prevent Atrial Mechanical Stunning and Atrial Remodeling Due to Atrial Arrhythmia
NCT00232245	PHASE4	COMPLETED	Use of Fish Oils to Reduce the Frequency and Duration of Episodes of Atrial Fibrillation in Patients With Paroxysmal Atrial Fibrillation.
NCT00239226	PHASE4	COMPLETED	Electrophysiologically Guided PAcing Site Selection Study
NCT00247780	PHASE4	COMPLETED	Cavotricuspid Isthmusblock and Circumferential Pulmonary Vein Isolation in Patients With Atrial Fibrillation
NCT00256152	PHASE4	COMPLETED	Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial
NCT00262119	PHASE4	COMPLETED	MINERVA: MINimizE Right Ventricular Pacing to Prevent Atrial Fibrillation and Heart Failure
NCT00287209	PHASE4	COMPLETED	Reduction of Atrial Fibrillation Study in Patients Undergoing Coronary Artery Bypass Grafting. (RASCABG 1 Study)
NCT00289042	PHASE4	COMPLETED	Assessment of Cardioversion Using Transesophageal Echocardiography II (ACUTE II)
NCT00313443	PHASE4	COMPLETED	Concentrations of Amiodarone in Fat Tissue During Chronic Treatment
NCT00340314	PHASE4	COMPLETED	A Trial of Circumferential Pulmonary Vein Ablation (CPVA) Versus Antiarrhythmic Drug Therapy in for Paroxysmal Atrial Fibrillation (AF)
NCT00343499	PHASE4	TERMINATED	The Use of DIOVAN to Reduce Post-Cardioversion Recurrence of Atrial Fibrillation Trial (the DRAFT Trial)
NCT00408473	PHASE4	TERMINATED	Comparative Study of Flecainide CR and Placebo in the Early Treatment of Atrial Fibrillation.
NCT00420017	PHASE4	COMPLETED	Prevention of Atrial Fibrillation Following Esophagectomy
NCT00438113	PHASE4	COMPLETED	Atrial Substrate Modification With Aggressive Blood Pressure Lowering to Prevent AF
NCT00446966	PHASE4	COMPLETED	Fish Oil for Reduction of Atrial Fibrillation After Cardiac Surgery
NCT00449410	PHASE4	COMPLETED	Silent Cerebrovascular Lesion and Cognitive Decline Prevention by Cholesterol Lowering in Elderly AF Patients
NCT00466973	PHASE4	WITHDRAWN	Atrial Fibrillation Ablation Device Comparison Study
NCT00511173	PHASE4	COMPLETED	Comparison of Warfarin Dosing Using Decision Model Versus Pharmacogenetic Algorithm
NCT00512915	PHASE4	COMPLETED	Avoid FFS - Use of the Atrial Pacemaker Lead 1699 With Very Short Tip Ring Spacing to Avoid Far Field Sensing
NCT00552084	PHASE4	COMPLETED	Evaluating the Effectiveness of Fish Oil Supplements at Reducing the Recurrence of Atrial Fibrillation
NCT00559988	PHASE4	TERMINATED	Combined Use of BIOTRONIK Home Monitoring and Predefined Anticoagulation to Reduce Stroke Risk
NCT00579098	PHASE4	COMPLETED	The Use of Statins Following a Left Atrial Catheter Ablation Procedure to Prevent Atrial Fibrillation
NCT00586287	PHASE4	COMPLETED	Study to Find Out the Appropriate Initial Dose of the Anticoagulant Drug Phenprocoumon
NCT00597077	PHASE4	COMPLETED	Atrial Fibrillation and Congestive Heart Failure Trial
NCT00603317	PHASE4	COMPLETED	Pharmacodynamic Drug Interaction Between Warfarin and Amoxicillin-clavulanic Acid
NCT00605748	PHASE4	UNKNOWN	Pulmonary Vein (PV) -Isolation: Arrhythmogenic Vein(s) Versus All Veins
NCT00643188	PHASE4	COMPLETED	Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and AF
NCT00678340	PHASE4	COMPLETED	Randomized Trial of Two Ablation Catheters in Paroxysmal Atrial Fibrillation
NCT00680927	PHASE4	COMPLETED	Reveal® XT Performance Trial (XPECT)