SOX6

Summary

SOX6 (SRY-box transcription factor 6, HGNC:16421) is a protein-coding gene on chromosome 11p15.2, encoding Transcription factor SOX-6 (P35712). Transcription factor that plays a key role in several developmental processes, including neurogenesis, chondrocytes differentiation and cartilage formation.

This gene encodes a member of the D subfamily of sex determining region y-related transcription factors that are characterized by a conserved DNA-binding domain termed the high mobility group box and by their ability to bind the minor groove of DNA. The encoded protein is a transcriptional activator that is required for normal development of the central nervous system, chondrogenesis and maintenance of cardiac and skeletal muscle cells. The encoded protein interacts with other family members to cooperatively activate gene expression. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 55553 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 108
• Clinical variants (ClinVar): 276 total — 15 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 39
• Transcription factor: yes — 26 downstream targets (CollecTRI)
• MANE Select transcript: NM_001367873

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16421
Approved symbol	SOX6
Name	SRY-box transcription factor 6
Location	11p15.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000110693
Ensembl biotype	protein_coding
OMIM	607257
Entrez	55553

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 25 protein_coding, 7 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000316399, ENST00000396356, ENST00000524520, ENST00000524650, ENST00000525259, ENST00000525835, ENST00000526673, ENST00000527619, ENST00000527840, ENST00000528252, ENST00000528429, ENST00000529469, ENST00000530378, ENST00000531297, ENST00000533411, ENST00000533658, ENST00000533870, ENST00000655819, ENST00000683767, ENST00000887060, ENST00000887061, ENST00000887062, ENST00000887063, ENST00000887064, ENST00000887065, ENST00000887066, ENST00000887067, ENST00000887068, ENST00000887069, ENST00000887070, ENST00000887071, ENST00000887072, ENST00000887073, ENST00000887074

RefSeq mRNA: 6 — MANE Select: NM_001367873 NM_001145811, NM_001145819, NM_001367872, NM_001367873, NM_017508, NM_033326

CCDS: CCDS53604, CCDS7821, CCDS91447

Canonical transcript exons

ENST00000683767 — 16 exons

Exon	Start	End
ENSE00000988311	16095996	16096118
ENSE00000988314	16046514	16046701
ENSE00000997615	16186783	16186955
ENSE00001105543	16049755	16049938
ENSE00001105560	15986204	15986420
ENSE00001151478	16111803	16111923
ENSE00001596131	16183886	16183954
ENSE00001644501	15966449	15973112
ENSE00003526525	16055752	16055901
ENSE00003550610	16318446	16318653
ENSE00003590678	16234582	16234671
ENSE00003604339	16014942	16015050
ENSE00003605869	15988997	15989230
ENSE00003669078	16341012	16341252
ENSE00003690433	16097609	16097688
ENSE00003917676	16356094	16356546

Expression profiles

Bgee: expression breadth ubiquitous, 235 present calls, max score 95.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.7548 / max 376.1772, expressed in 1154 samples.

FANTOM5 promoters (27 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118807	1.3537	493
118822	1.1724	615
118809	0.6036	301
118804	0.5622	297
118802	0.5608	244
118808	0.4522	248
118781	0.4268	150
118783	0.4161	144
118791	0.2558	22
118785	0.2496	103

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelial cell of pancreas	CL:0000083	95.15	gold quality
tibia	UBERON:0000979	93.04	gold quality
kidney epithelium	UBERON:0004819	92.97	gold quality
deltoid	UBERON:0001476	92.41	gold quality
sperm	CL:0000019	92.29	silver quality
sural nerve	UBERON:0015488	92.21	gold quality
ileal mucosa	UBERON:0000331	91.97	gold quality
tibialis anterior	UBERON:0001385	91.96	gold quality
pancreatic ductal cell	CL:0002079	91.63	silver quality
ventricular zone	UBERON:0003053	91.62	gold quality
jejunal mucosa	UBERON:0000399	91.29	gold quality
calcaneal tendon	UBERON:0003701	91.12	gold quality
pigmented layer of retina	UBERON:0001782	90.63	gold quality
trabecular bone tissue	UBERON:0002483	89.94	gold quality
parietal pleura	UBERON:0002400	88.47	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	88.34	gold quality
germinal epithelium of ovary	UBERON:0001304	88.02	gold quality
quadriceps femoris	UBERON:0001377	87.41	gold quality
skeletal muscle tissue	UBERON:0001134	87.23	gold quality
bone marrow cell	CL:0002092	87.16	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	86.62	gold quality
vastus lateralis	UBERON:0001379	86.51	gold quality
oviduct epithelium	UBERON:0004804	86.51	gold quality
biceps brachii	UBERON:0001507	86.31	gold quality
colonic epithelium	UBERON:0000397	85.91	gold quality
esophagus squamous epithelium	UBERON:0006920	85.46	gold quality
buccal mucosa cell	CL:0002336	84.13	gold quality
tendon	UBERON:0000043	84.10	gold quality
left testis	UBERON:0004533	83.91	gold quality
jejunum	UBERON:0002115	83.78	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	4669.49
E-MTAB-9435	yes	499.61
E-HCAD-25	yes	29.34
E-ANND-3	yes	7.69
E-GEOD-93593	yes	4.15

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

26 targets.

Target	Regulation
ACAN	Activation
BCL2L1	Activation
CCNA2	Repression
CCND1	Repression
CDK4	Repression
CDKN1A	Activation
CEBPA	Activation
COL2A1	Activation
COMP	Activation
CTBP2	Repression
CTNNB1	Repression
FGF3	Unknown
HBE1	Unknown
HBG1	Repression
HBG2	Repression
INS	Unknown
MATN1	Unknown
MEST	Activation
MYH7	Repression
PPARG	Activation
PTHLH	Activation
RUNX2	Activation
SOCS3	Activation
SPTA1
SUPT7L
TP53	Activation

Upstream regulators (CollecTRI, top): CEBPB, MKX, PRDM1, RUNX1, SNAI2, SOX10, STAT3, TFAP2A, WWTR1, YAP1

miRNA regulators (miRDB)

273 targeting SOX6, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-548P	99.98	72.25	3784

Literature-anchored findings (GeneRIF, showing 40)

• SOX6 may be a potential diagnostic marker for gliomas. (PMID:15696967)
• SOX6 may be a useful marker for the diagnosis of tumors arising from immature bipotential cells that may differentiate into neuronal and glial cells. (PMID:15696972)
• co-expression of SOX6 with SUMO2 results in the appearance of SOX6 in a punctate nuclear pattern that colocalized with promyelocytic leukemia protein, which was partially abolished by mutations in SOX6 sumoylation sites (PMID:16442531)
• Thus, we successfully identified the Sox6 promoter and its core enhancer and characterized the interactions with regulatory transcription factors. (PMID:17433257)
• Results suggest that DAX-1 and SOX6 proteins interact, have overlapped expression in the testis, and act antagonistically during pre-mRNA splicing. (PMID:19384854)
• Although Sox6 is not required for specification of medial ganglionic eminence (MGE)-derived cortical interneurons, Sox6 gene is necessary for the normal positioning and maturation of these cells. (PMID:19709629)
• SOX6 was previously found to be essential to both cartilage formation/chondrogenesis and obesity-related insulin resistance, suggesting the gene’s dual role in both bone and fat (PMID:19714249)
• transcriptional silencing of gamma-globin genes by BCL11A involves long-range interactions and cooperation with SOX6 (PMID:20395365)
• The SOX6 is a novel tumor-suppressor gene in ESCC development and is a potential prognostic marker in esophageal squamous cell carcinoma. (PMID:21084391)
• Results support the SOX6 gene as an important gene for bone mineral density variation. (PMID:21104366)
• identified SOX5 and SOX6 as the first two SHOX-interacting proteins and have shown that this interaction regulates aggrecan expression, an essential factor in chondrogenesis and skeletal development. (PMID:21262861)
• Sox6 enhances erythroid differentiation in human erythroid progenitors. (PMID:21263153)
• Genetic variants in the SOX6 gene are associated with bone mineral density in both Caucasian and Chinese populations (PMID:21625884)
• SOX trio gene and protein decreased with advancement of osteoarthritis in human articular cartilage. (PMID:21728837)
• L-Sox5 and Sox6 proteins enhance chondrogenic miR-140 microRNA expression by strengthening dimeric Sox9 activity (PMID:22547066)
• Findings provide evidence for the first time that SOX6 expression was decreased in hepatocellular carcinoma. (PMID:23731550)
• results suggest that miR-208 represents a potential onco-miR and participates in ESCC carcinogenesis by suppressing SOX6 expression (PMID:25023649)
• SCF-mediated gamma-globin gene expression in adult human erythroid cells is associated with KLF1, BCL11A and SOX6 down-regulation. (PMID:25457384)
• The highly conserved high-mobility group (HMG) domain of SOX6 is required for SOX6-mediated p53 stabilization and tumor inhibitory activity. (PMID:26119940)
• SOX6 rs16933090 affects coronary calcium score obtained at CT angiography, but plays minor role in the development of subclinical atherosclerosis in subjects with type 2 diabetes. (PMID:26868133)
• SOX6 is a novel regulator of adipogenesis synergizing with epigenetic mechanisms. (PMID:26893351)
• the SOX6 gene is potentially targeted by five MicroRNAs that are up-regulated only in Hereditary persistence of fetal hemoglobin deletion type-2, compared to Sicilian-deltabeta-thalassemia and controls. (PMID:27591578)
• Our observations revealed that SOX6 is a tumor suppressor in ovarian cancer cells, and SOX6 exerts an inhibitory effect on the proliferation, invasion, and tumor cell-induced angiogenesis of ovarian cancer cells, whereas nerin-1 plays an opposite role and its expression is inversely correlated with SOX6. (PMID:28475012)
• Low SOX6 expression is associated with Glioma. (PMID:28687615)
• miR-96 could promote cell proliferation, migration, and invasion in HCC by targeting SOX6 (PMID:28892647)
• Differential proteomic analysis on human erythroid K562 cells overexpressing Sox6. Sox6-overexpression induces dysregulation of 64 proteins, involved in cytoskeleton remodeling and in protein synthesis, folding and trafficking, key processes for erythroid maturation. (PMID:29074889)
• This is the first report on gamma-globin induction by downregulation of SOX6 in human erythroblasts derived from beta-thalassemia major. (PMID:29333458)
• miR-671 promotes prostate cancer cell proliferation by inhibiting SOX6 (PMID:29355560)
• Sox6 as a regulator of pancreatic cancer development was shown to interact with the promoter of Twist1, a helix-loop-helix transcription factor involved in the induction of EMT, and to modulate the expression of Twist1 by recruiting HDAC1 to the promoter of the Twist1 gene. (PMID:29369542)
• Chromatin immunoprecipitation (ChIP), quantitative ChIP and dual luciferase activity assays were used to confirm the binding of SOX6 to the promoter region of TWIST1. (PMID:29512775)
• The authors demonstrate for the first time that SOX6 SNPs influence fat-free mass and quantitative ultrasound trait in a population of young adults, suggesting the implication of this gene in obesity and osteoporosis-related phenotypes during early adulthood. (PMID:30062780)
• found no significant differences in the genetic distribution and allelic frequency of MYB and SOX-6 gene polymorphisms (PMID:30200835)
• miR-181b may function as a tumor inhibitor in the development of lung cancer via targeting Sox6 to decrease the proliferation and metastasis of lung cancer cells (PMID:30580904)
• UBE2S mediates tumor progression via SOX6/beta-Catenin signaling in endometrial cancer (PMID:30690078)
• Dual functional nanoparticles containing SOX duo and ANGPT4 shRNA for osteoarthritis treatment. (PMID:30957437)
• USP21 modulates Goosecoid function through deubiquitination. (PMID:31253698)
• microRNA-96 is upregulated in pancreatic beta cells under the pathological condition of T2DM; overexpression of microRNA-96 promotes proliferative ability and inhibits apoptosis in pancreatic beta cells through targeting Foxo1 and Sox6 (PMID:31506178)
• Circular RNA Pleiotrophin promotes carcinogenesis in glioma via regulation of microRNA-122/SRY-box transcription factor 6 axis. (PMID:31609809)
• SOX6 suppresses the development of lung adenocarcinoma by regulating expression of p53, p21(CIPI) , cyclin D1 and beta-catenin. (PMID:31729835)
• miR3423p suppresses the progression of DKD by inducing the degradation of SOX6. Thus, the miR3423p/SOX6 axis may serve as a novel therapeutic target in the treatment of DKD. (PMID:31746345)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	sox6	ENSDARG00000015536
mus_musculus	Sox6	ENSMUSG00000051910
rattus_norvegicus	Sox6	ENSRNOG00000020514
drosophila_melanogaster	Sox14	FBGN0005612
drosophila_melanogaster	Sox21a	FBGN0036411
drosophila_melanogaster	Sox102F	FBGN0039938
caenorhabditis_elegans		WBGENE00001182

Paralogs (20): SOX8 (ENSG00000005513), SOX30 (ENSG00000039600), SOX10 (ENSG00000100146), SOX4 (ENSG00000124766), 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-6 — P35712 (reviewed: P35712)

All UniProt accessions (5): P35712, E9PN02, E9PQ67, E9PQ78, E9PQL4

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that plays a key role in several developmental processes, including neurogenesis, chondrocytes differentiation and cartilage formation. Specifically binds the 5’-AACAAT-3’ DNA motif present in enhancers and super-enhancers and promotes expression of genes important for chondrogenesis. Required for overt chondrogenesis when condensed prechondrocytes differentiate into early stage chondrocytes: SOX5 and SOX6 cooperatively bind with SOX9 on active enhancers and super-enhancers associated with cartilage-specific genes, and thereby potentiate SOX9’s ability to transactivate. Not involved in precartilaginous condensation, the first step in chondrogenesis, during which skeletal progenitors differentiate into prechondrocytes. Together with SOX5, required to form and maintain a pool of highly proliferating chondroblasts between epiphyses and metaphyses, to form columnar chondroblasts, delay chondrocyte prehypertrophy but promote hypertrophy, and to delay terminal differentiation of chondrocytes on contact with ossification fronts. Binds to the proximal promoter region of the myelin protein MPZ gene, and is thereby involved in the differentiation of oligodendroglia in the developing spinal tube. Binds to the gene promoter of MBP and acts as a transcriptional repressor.

Subunit / interactions. Homodimer. Interacts with DAZAP2. May interact with CENPK.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Expressed in a wide variety of tissues, most abundantly in skeletal musclen.

Post-translational modifications. Sumoylation inhibits the transcriptional activity.

Disease relevance. Tolchin-Le Caignec syndrome (TOLCAS) [MIM:618971] An autosomal dominant disorder characterized by mildly to moderately impaired intellectual development and behavioral problems, such as autism, attention deficit and hyperactivity disorder, and aggressive episodes. Highly variable, additional features include osteochondroma, craniosynostosis, dysmorphic facies, arachnodactyly, and large head circumference. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (4)

UniProt ID	Names	Canonical?
P35712-1	1	yes
P35712-2	2
P35712-3	3
P35712-4	4

RefSeq proteins (6): NP_001139283, NP_001139291, NP_001354801, NP_001354802, NP_059978, NP_201583 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009071	HMG_box_dom	Domain
IPR036910	HMG_box_dom_sf	Homologous_superfamily
IPR051356	SOX/SOX-like_TF	Family

Pfam: PF00505

UniProt features (34 total): sequence variant 8, compositionally biased region 5, modified residue 5, splice variant 4, region of interest 3, cross-link 2, mutagenesis site 2, sequence conflict 2, chain 1, DNA-binding region 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35712-F1	56.48	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 (7): 119, 399, 401, 439, 442, 404, 417

Mutagenesis-validated functional residues (2):

Position	Phenotype
404	partial loss of sumoylation. complete loss of sumoylation; when associated with r-417.
417	partial loss of sumoylation. complete loss of sumoylation; when associated with r-404.

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: 484 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CARTILAGE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, MODULE_255, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, AAGTCCA_MIR422B_MIR422A, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, MODULE_317, GOBP_REGULATION_OF_STRIATED_MUSCLE_CELL_DIFFERENTIATION

GO Biological Process (17): cartilage condensation (GO:0001502), chondrocyte differentiation (GO:0002062), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), central nervous system development (GO:0007417), brain development (GO:0007420), muscle organ development (GO:0007517), spinal cord oligodendrocyte cell differentiation (GO:0021529), positive regulation of chondrocyte differentiation (GO:0032332), cell fate commitment (GO:0045165), cartilage development (GO:0051216), positive regulation of cartilage development (GO:0061036), cellular response to transforming growth factor beta stimulus (GO:0071560), negative regulation of cardiac muscle cell differentiation (GO:2000726), positive regulation of mesenchymal stem cell differentiation (GO:2000741), cell differentiation (GO:0030154), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (8): 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 repressor activity (GO:0001217), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737)

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
cartilage development	3
regulation of DNA-templated transcription	3
animal organ development	3
cellular anatomical structure	3
cell differentiation	2
DNA-templated transcription	2
cellular developmental process	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
DNA-binding transcription factor activity	2
transcription cis-regulatory region binding	2
skeletal system morphogenesis	1
cell aggregation	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription by RNA polymerase II	1
nervous system development	1
system development	1
central nervous system development	1
head development	1
muscle structure development	1
cell differentiation in spinal cord	1
oligodendrocyte differentiation	1
chondrocyte differentiation	1
regulation of chondrocyte differentiation	1
positive regulation of cell differentiation	1
positive regulation of cartilage development	1
skeletal system development	1
connective tissue development	1
positive regulation of developmental process	1
positive regulation of multicellular organismal process	1
regulation of cartilage development	1
cellular response to growth factor stimulus	1
response to transforming growth factor beta	1
negative regulation of striated muscle cell differentiation	1
cardiac muscle cell differentiation	1
negative regulation of cardiocyte differentiation	1
regulation of cardiac muscle cell differentiation	1
mesenchymal stem cell differentiation	1
positive regulation of stem cell differentiation	1
regulation of mesenchymal stem cell differentiation	1

Protein interactions and networks

STRING

1960 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SOX6	SOX9	P48436	954
SOX6	SOX5	P35711	941
SOX6	BCL11A	Q9H165	941
SOX6	HDAC1	Q13547	934
SOX6	GATA1	P15976	916
SOX6	PURB	Q96QR8	870
SOX6	MYH7B	A7E2Y1	852
SOX6	COL2A1	P02458	827
SOX6	CTNNB1	P35222	781
SOX6	KLF1	Q13351	733
SOX6	ACAN	P16112	721
SOX6	FOXJ3	Q9UPW0	644
SOX6	NKX3-2	P78367	641
SOX6	ZFPM1	Q8IX07	632
SOX6	SP7	Q8TDD2	629

IntAct

18 interactions, top by confidence:

A	B	Type	Score
SOX5	SOX1	psi-mi:“MI:0914”(association)	0.530
SOX6	SHOX	psi-mi:“MI:0915”(physical association)	0.510
SHOX	SOX6	psi-mi:“MI:0915”(physical association)	0.510
SOX13	SOX6	psi-mi:“MI:0914”(association)	0.480
NFIA	SOX6	psi-mi:“MI:0915”(physical association)	0.470
NFIB	SOX6	psi-mi:“MI:0915”(physical association)	0.470
NFIC	SOX6	psi-mi:“MI:0915”(physical association)	0.470
SOX6	HMGA1	psi-mi:“MI:0915”(physical association)	0.400
SOX6	ZNF184	psi-mi:“MI:0915”(physical association)	0.370
POMGNT1	SOX6	psi-mi:“MI:0915”(physical association)	0.370
SOX2	CBX4	psi-mi:“MI:0914”(association)	0.350
SOX6	IGF2BP3	psi-mi:“MI:0914”(association)	0.350
SOX13	H1-5	psi-mi:“MI:0914”(association)	0.350
SOX6	SMCHD1	psi-mi:“MI:2364”(proximity)	0.270
ERG	SOX6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (173): TAF4 (Affinity Capture-MS), SOX6 (Biochemical Activity), SOX6 (Affinity Capture-MS), SOX6 (Proximity Label-MS), SOX6 (Two-hybrid), CTBP2 (Two-hybrid), SOX6 (Affinity Capture-Western), CENPK (Reconstituted Complex), SOX6 (Affinity Capture-RNA), SOX6 (Affinity Capture-MS), SOX6 (Affinity Capture-MS), CTBP2 (Proximity Label-MS), UBE2I (Proximity Label-MS), HDAC3 (Proximity Label-MS), NR2C1 (Proximity Label-MS)

ESM2 similar proteins: A0A0G2JTZ2, A2BEA6, A4IFD2, B1H349, B3DM43, B3DM47, F1M8W4, O15409, O75030, P0CF24, P23899, P27889, P35680, P35710, P35711, P35712, P40645, P40647, P58463, P70062, P70063, P70064, Q23045, Q2LE08, Q4VYR7, Q4VYS1, Q58NQ4, Q5QL03, Q5RCU4, Q5RER5, Q5W1J5, Q6GL68, Q800Q5, Q86MD3, Q8HZ00, Q8MJ97, Q8MJ98, Q8MJ99, Q8MJA0, Q8STF6

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

14 interactions.

A	Effect	B	Mechanism
SOX6	“up-regulates quantity by expression”	COL2A1	“transcriptional regulation”
SOX6	“down-regulates quantity by repression”	HBG2	“transcriptional regulation”
SOX6	“down-regulates quantity by repression”	HBG1	“transcriptional regulation”
SOX6	“up-regulates quantity by expression”	PPARG	“transcriptional regulation”
SOX6	“up-regulates quantity by expression”	MEST	“transcriptional regulation”
SOX6	“up-regulates quantity by expression”	CEBPA	“transcriptional regulation”
SOX6	“down-regulates quantity by destabilization”	CTNNB1	binding
UBE2I	“down-regulates activity”	SOX6	sumoylation
TRIP12	“down-regulates quantity by destabilization”	SOX6	ubiquitination
CDK5	“down-regulates quantity”	SOX6	phosphorylation
SOX6	“down-regulates activity”	CTNNB1	binding
hsa-mir-17-3p-1	“down-regulates quantity by destabilization”	SOX6	“post transcriptional regulation”
CENPK	“up-regulates activity”	SOX6	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	13
Uncertain significance	149
Likely benign	45
Benign	25

Top pathogenic / likely-pathogenic (28)

Variant ID	HGVS	Classification
1213429	NM_001367873.1(SOX6):c.2077C>T (p.Arg693Ter)	Pathogenic
1298507	NM_001367873.1(SOX6):c.277C>T (p.Arg93Ter)	Pathogenic
1331628	NM_001367873.1(SOX6):c.1433_1434del (p.Ser477_Leu478insTer)	Pathogenic
1699121	NM_001367873.1(SOX6):c.970C>T (p.Gln324Ter)	Pathogenic
2209067	NM_001367873.1(SOX6):c.1038del (p.Phe346fs)	Pathogenic
2389142	NM_001367873.1(SOX6):c.1083C>G (p.Tyr361Ter)	Pathogenic
2408242	NM_001367873.1(SOX6):c.170del (p.Pro57fs)	Pathogenic
2627902	NM_001367873.1(SOX6):c.2026del (p.Arg676fs)	Pathogenic
3363775	NM_001367873.1(SOX6):c.238-2A>G	Pathogenic
3365964	NM_001367873.1(SOX6):c.1188_1192del (p.Thr397fs)	Pathogenic
503665	NM_001367873.1(SOX6):c.718C>T (p.Gln240Ter)	Pathogenic
974904	NM_001367873.1(SOX6):c.242C>G (p.Ser81Ter)	Pathogenic
974906	NM_001367873.1(SOX6):c.1874T>C (p.Met625Thr)	Pathogenic
974907	NM_001367873.1(SOX6):c.1975T>A (p.Trp659Arg)	Pathogenic
985593	NM_001367873.1(SOX6):c.706C>T (p.Gln236Ter)	Pathogenic
1064837	NM_001367873.1(SOX6):c.293C>G (p.Ser98Ter)	Likely pathogenic
1182282	NM_001367873.1(SOX6):c.934A>G (p.Met312Val)	Likely pathogenic
1321955	NM_001367873.1(SOX6):c.1893G>C (p.Trp631Cys)	Likely pathogenic
1496808	NM_001367873.1(SOX6):c.132C>G (p.His44Gln)	Likely pathogenic
1698987	NM_001367873.1(SOX6):c.2074C>T (p.Pro692Ser)	Likely pathogenic
2429033	NM_001367873.1(SOX6):c.535G>A (p.Gly179Ser)	Likely pathogenic
2433671	NM_001367873.1(SOX6):c.1102C>T (p.Gln368Ter)	Likely pathogenic
2641633	NM_001367873.1(SOX6):c.1500del (p.Gln501fs)	Likely pathogenic
3382972	NM_001367873.1(SOX6):c.1420del (p.Arg474fs)	Likely pathogenic
3602000	NM_001367873.1(SOX6):c.976C>T (p.Gln326Ter)	Likely pathogenic
3764714	NM_001367873.1(SOX6):c.1543C>T (p.Gln515Ter)	Likely pathogenic
4072007	NM_001367873.1(SOX6):c.2190dup (p.Pro731fs)	Likely pathogenic
4077153	NM_001367873.1(SOX6):c.769_772delinsAGG (p.Gln257fs)	Likely pathogenic

SpliceAI

4028 predictions. Top by Δscore:

Variant	Effect	Δscore
11:15986202:A:AC	donor_gain	1.0000
11:15986202:AC:A	donor_gain	1.0000
11:15986202:ACC:A	donor_gain	1.0000
11:15986203:C:CC	donor_gain	1.0000
11:15986203:CC:C	donor_gain	1.0000
11:15986203:CCC:C	donor_gain	1.0000
11:15986203:CCCCA:C	donor_gain	1.0000
11:15986417:GATC:G	acceptor_gain	1.0000
11:15986418:ATCC:A	acceptor_loss	1.0000
11:15986419:TC:T	acceptor_gain	1.0000
11:15986420:CC:C	acceptor_gain	1.0000
11:15986421:C:CC	acceptor_gain	1.0000
11:15986421:CTAGA:C	acceptor_loss	1.0000
11:16014937:CTCA:C	donor_loss	1.0000
11:16014938:TCAC:T	donor_loss	1.0000
11:16014939:CA:C	donor_loss	1.0000
11:16014940:A:AC	donor_gain	1.0000
11:16014940:AC:A	donor_gain	1.0000
11:16014940:ACC:A	donor_gain	1.0000
11:16014941:C:CC	donor_gain	1.0000
11:16014941:C:CT	donor_loss	1.0000
11:16014941:CC:C	donor_gain	1.0000
11:16014941:CCC:C	donor_gain	1.0000
11:16014941:CCCT:C	donor_gain	1.0000
11:16015046:CTTTC:C	acceptor_gain	1.0000
11:16049935:CATC:C	acceptor_gain	1.0000
11:16049937:TC:T	acceptor_gain	1.0000
11:16049937:TCCTA:T	acceptor_loss	1.0000
11:16049938:CC:C	acceptor_gain	1.0000
11:16049938:CCTA:C	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000001559 (11:16060239 T>C), RS1000005858 (11:16414553 C>A,G,T), RS1000013408 (11:16006122 C>A,T), RS1000030490 (11:16401361 G>A), RS1000032666 (11:16315086 T>C), RS1000036475 (11:16544036 C>T), RS1000046754 (11:16636966 C>T), RS1000050804 (11:16448857 T>A,G), RS1000052593 (11:16358071 T>C), RS1000058271 (11:16587040 A>G), RS1000082560 (11:16506710 G>T), RS1000094140 (11:16311540 T>G), RS1000095379 (11:16466178 T>C), RS1000108261 (11:15999580 T>C), RS1000111266 (11:16283536 T>C)

Disease associations

OMIM: gene MIM:607257 | disease phenotypes: MIM:618971, MIM:123100

GenCC curated gene-disease

Disease	Classification	Inheritance
Tolchin-Le Caignec syndrome	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (3): neurodevelopmental disorder (MONDO:0700092), Tolchin-Le Caignec syndrome (MONDO:0033544), craniosynostosis (MONDO:0015469)

Orphanet (1): Craniosynostosis (Orphanet:1531)

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000160	Narrow mouth
HP:0000176	Submucous cleft hard palate
HP:0000218	High palate
HP:0000263	Oxycephaly
HP:0000269	Prominent occiput
HP:0000276	Long face
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000369	Low-set ears
HP:0000400	Macrotia
HP:0000407	Sensorineural hearing impairment
HP:0000431	Wide nasal bridge
HP:0000448	Prominent nose
HP:0000574	Thick eyebrow
HP:0000579	Nasolacrimal duct obstruction
HP:0000729	Autistic behavior
HP:0000826	Precocious puberty
HP:0001007	Hirsutism
HP:0001166	Arachnodactyly
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001537	Umbilical hernia
HP:0001540	Diastasis recti
HP:0001751	Abnormal vestibular function
HP:0003186	Inverted nipples
HP:0003593	Infantile onset

GWAS associations

108 associations (top):

Study	Trait	p-value
GCST000469_1	Obesity and osteoporosis	5.000000e-07
GCST000469_2	Obesity and osteoporosis	4.000000e-07
GCST000495_3	Bone mineral density (hip)	6.000000e-10
GCST000881_1	Bone mineral density (wrist)	5.000000e-06
GCST001368_17	Capecitabine sensitivity	2.000000e-06
GCST002143_11	Blood pressure	1.000000e-06
GCST002143_6	Blood pressure	5.000000e-10
GCST002276_7	Bone mineral density	1.000000e-15
GCST002599_4	Longevity (90 years and older)	4.000000e-06
GCST002627_10	Hypertension	3.000000e-06
GCST002630_11	Systolic blood pressure	5.000000e-09
GCST002631_1	Diastolic blood pressure	5.000000e-09
GCST002652_10	Cotinine glucuronidation	3.000000e-09
GCST002710_4	Anti-saccade response	6.000000e-06
GCST004602_191	Mean corpuscular volume	3.000000e-09
GCST004602_192	Mean corpuscular volume	5.000000e-18
GCST004611_177	High light scatter reticulocyte count	2.000000e-12
GCST004612_115	High light scatter reticulocyte percentage of red cells	7.000000e-15
GCST004619_177	Reticulocyte fraction of red cells	2.000000e-14
GCST004619_20	Reticulocyte fraction of red cells	8.000000e-23
GCST004621_22	Red cell distribution width	2.000000e-49
GCST004622_34	Reticulocyte count	6.000000e-19
GCST004630_246	Mean corpuscular hemoglobin	1.000000e-18
GCST005194_214	Coronary artery disease	2.000000e-08
GCST005232_46	Neuroticism	2.000000e-08
GCST005544_1	Femoral neck bone mineral density	1.000000e-09
GCST005545_3	Lumbar spine bone mineral density	2.000000e-08
GCST005795_31	Femoral neck bone mineral density	3.000000e-20
GCST005993_51	Mean corpuscular hemoglobin	7.000000e-14
GCST006011_82	Mean corpuscular volume	1.000000e-12

EFO canonical traits (34, from GWAS)

EFO ID	Trait name
EFO:0004512	bone measurement
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0006508	cotinine glucuronidation measurement
EFO:0006874	antisaccade response measurement
EFO:0007986	reticulocyte count
EFO:0009188	Red cell distribution width
EFO:0004527	mean corpuscular hemoglobin
EFO:0007660	neuroticism measurement
EFO:0007785	femoral neck bone mineral density
EFO:0007701	spine bone mineral density
EFO:0004329	alcohol drinking
EFO:0006340	mean arterial pressure
EFO:0006527	smoking status measurement
EFO:0009270	heel bone mineral density
EFO:0008475	mood instability measurement
EFO:0003924	hair color
EFO:0005763	pulse pressure measurement
EFO:0008328	chronotype measurement
EFO:0009929	Beta blocking agent use measurement
EFO:0009928	Diuretic use measurement
EFO:0009930	Calcium channel blocker use measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0010100	multisite chronic pain
EFO:0010091	tea consumption measurement
EFO:0004319	smoking cessation
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
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

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	5
methylmercuric chloride	decreases expression, affects cotreatment	4
bisphenol A	decreases methylation, increases expression, affects cotreatment	2
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	decreases expression, affects cotreatment	2
Vorinostat	affects cotreatment, decreases expression	2
Glucose	increases expression, decreases reaction, decreases expression, increases cleavage, increases secretion	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cyclosporine	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
Particulate Matter	increases expression, decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
tris(2-butoxyethyl) phosphate	affects expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	increases expression	1
coumarin	increases phosphorylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
belinostat	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation, increases methylation	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Vehicle Emissions	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation	1

Cellosaurus cell lines

5 cell lines: 3 embryonic stem cell, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A6N2	SEES3-1V human SOX6, clone1	Embryonic stem cell	Male
CVCL_A6N3	SEES3-1V human SOX6, clone2	Embryonic stem cell	Male
CVCL_A6N4	SEES3-1V human SOX6, clone3	Embryonic stem cell	Male
CVCL_B8Q0	Abcam HCT 116 SOX6 KO	Cancer cell line	Male
CVCL_B9SG	Abcam A-549 SOX6 KO	Cancer cell line	Male

Clinical trials (associated diseases)

202 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,
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
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
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice