SOX9

Summary

SOX9 (SRY-box transcription factor 9, HGNC:11204) is a protein-coding gene on chromosome 17q24.3, encoding Transcription factor SOX-9 (P48436). Transcription factor that plays a key role in chondrocytes differentiation and skeletal development. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It acts during chondrocyte differentiation and, with steroidogenic factor 1, regulates transcription of the anti-Muellerian hormone (AMH) gene. Deficiencies lead to the skeletal malformation syndrome campomelic dysplasia, frequently with sex reversal.

Source: NCBI Gene 6662 — RefSeq curated summary.

At a glance

• Gene–disease (curated): campomelic dysplasia (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 58
• Clinical variants (ClinVar): 415 total — 67 pathogenic, 33 likely-pathogenic
• Phenotypes (HPO): 182
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 2 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 113 downstream targets (CollecTRI)
• MANE Select transcript: NM_000346

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11204
Approved symbol	SOX9
Name	SRY-box transcription factor 9
Location	17q24.3
Locus type	gene with protein product
Status	Approved
Aliases	SRA1
Ensembl gene	ENSG00000125398
Ensembl biotype	protein_coding
OMIM	608160
Entrez	6662

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000245479, ENST00000877559

RefSeq mRNA: 1 — MANE Select: NM_000346 NM_000346

CCDS: CCDS11689

Canonical transcript exons

ENST00000245479 — 3 exons

Exon	Start	End
ENSE00000855029	72121020	72121822
ENSE00000855030	72122719	72122972
ENSE00003842779	72123543	72126416

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 99.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.2107 / max 978.7539, expressed in 1323 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
162530	30.4534	1321
162542	0.4025	148
162541	0.3548	135

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.42	gold quality
cranial nerve II	UBERON:0000941	98.77	gold quality
hair follicle	UBERON:0002073	98.77	gold quality
parotid gland	UBERON:0001831	98.36	gold quality
pigmented layer of retina	UBERON:0001782	98.15	gold quality
retina	UBERON:0000966	98.13	gold quality
medial globus pallidus	UBERON:0002477	98.01	gold quality
mammary duct	UBERON:0001765	97.85	gold quality
epithelium of mammary gland	UBERON:0003244	97.81	gold quality
globus pallidus	UBERON:0001875	97.72	gold quality
buccal mucosa cell	CL:0002336	97.71	gold quality
cartilage tissue	UBERON:0002418	97.68	gold quality
pylorus	UBERON:0001166	97.45	gold quality
ganglionic eminence	UBERON:0004023	97.09	gold quality
lateral globus pallidus	UBERON:0002476	96.92	gold quality
tibia	UBERON:0000979	96.71	gold quality
CA1 field of hippocampus	UBERON:0003881	96.18	gold quality
ventral tegmental area	UBERON:0002691	95.74	gold quality
trachea	UBERON:0003126	95.61	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	95.56	gold quality
superior vestibular nucleus	UBERON:0007227	94.80	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.55	gold quality
medulla oblongata	UBERON:0001896	94.51	gold quality
embryo	UBERON:0000922	94.04	gold quality
choroid plexus epithelium	UBERON:0003911	93.76	gold quality
saliva-secreting gland	UBERON:0001044	93.64	gold quality
pancreatic ductal cell	CL:0002079	93.49	gold quality
subthalamic nucleus	UBERON:0001906	93.37	gold quality
adult organism	UBERON:0007023	93.29	gold quality
minor salivary gland	UBERON:0001830	92.58	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	37.80
E-GEOD-84465	yes	33.78
E-CURD-114	yes	31.30
E-HCAD-10	yes	21.88
E-HCAD-5	yes	19.29
E-GEOD-93593	yes	15.08
E-GEOD-135922	yes	14.07
E-GEOD-83139	yes	11.54
E-HCAD-9	yes	8.59
E-CURD-112	yes	6.89
E-ENAD-27	yes	6.80
E-CURD-10	no	1021.57
E-GEOD-36552	no	99.60
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

113 targets.

Target	Regulation
ACAN	Activation
ADAM17	Activation
AMH	Activation
AR	Activation
BAG1	Unknown
BCL2	Unknown
BEST1	Activation
BHLHE40	Repression
BMI1	Activation
BTN1A1	Activation
CATSPER1	Unknown
CBLN4	Activation
CCN2	Repression
CCND1	Repression
CD74
CDH2	Unknown
CDH5	Unknown
CDK4	Activation
CDKN1A	Activation
CDX2	Repression
CEACAM1	Unknown
CEBPB	Unknown
CEBPD	Repression
CLDN7	Repression
COL10A1	Unknown
COL11A2	Activation
COL1A2	Activation
COL2A1	Activation
COL4A2	Unknown
COL9A1	Unknown

JASPAR motifs

Motif	Name	Family
MA0077.1	SOX9	SOX-related factors
MA0077.2	SOX9	SOX-related factors

JASPAR matrix evidence (PMIDs): PMID:9973626

Upstream regulators (CollecTRI, top): ATF2, BARX1, BMAL1, CEBPZ, CREB1, DLK1, ESRRA, ETV2, FLCN, FOXA2, FOXL2, GATA4, GLI1, HAND2, HEY1, HIF1A, HIVEP1, HNF1B, KLF5, MAPK3, MYC, NFIX, NFKB, NKX3-2, NOS3, NOTCH1, NOTCH2, NR5A1, OSR1, PRRX1, RARA, RBPJ, RELA, RUNX2, SF1, SMAD4, SNAI2, SOX9, SP1, SRY

miRNA regulators (miRDB)

160 targeting SOX9, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3613-3P	100.00	76.36	7965
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-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Sequence analysis of the intergenic regions revealed five regulatory elements, E1-E5, 5’ to SOX9 and three such elements, E6-E8, 3’ to SOX9. (PMID:11707075)
• A chromosomally normal boy with ACD and his clinical follow-up up to the age of 2 years, in whom a heterozygous SOX9 missense mutation (H165Y) was identified. (PMID:11754051)
• discussion of molecular action (REVIEW) (PMID:11990798)
• demonstration that a novel human gene, KIAA0800, is preferentially expressed in the testis and is transactivated by Sox9 (PMID:12111997)
• novel potential role for SOX9 in pancreas development during human embryogenesis and early foetal life (PMID:12128229)
• The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. (PMID:12414734)
• RAR agonists stimulate SOX9 gene expression in breast cancer cell lines: evidence for a role in retinoid-mediated growth inhibition. (PMID:12420222)
• mesenchymal chondrosarcoma showed positive nuclear staining in both primitive mesenchymal and cartilaginous components for Sox9 protein (PMID:12673561)
• SOX9 exerts a bifunctional effect on COL2A1 gene expression in chondrocytes depending on the differentiation state. (PMID:12713737)
• CBP and p300 function as co-activators of Sox9 for cartilage tissue-specific gene expression and chondrocyte differentiation. (PMID:12732631)
• Loss of DNA-dependent dimerization of the transcription factor SOX9 as a cause for campomelic dysplasia (PMID:12783851)
• no positive correlation between SOX9 and COL2A1 expression was observed in articular chondrocytes–to the contrary, the expression of COL2A1 was significantly increased in the diseased cells (PMID:12935820)
• SOX9 contributes to growth regulation by mac25 via inhibition of cell growth and promotion of differentiation in prostate tumor (PMID:15077158)
• It is revealed with an in vitro sumoylated Ad4BP/SF-1 that DNA binding activity and interaction with Sox9 ware unaffected. (PMID:15192080)
• Results suggest that SOX9 is necessary and sufficient to specify pyloric sphincter epithelial properties. (PMID:15240557)
• SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes (PMID:15240568)
• SOX9 is a key regulator of CRTL1 (PMID:15456769)
• Smad3 induces chondrogenesis through the activation of SOX9 via CREB-binding protein/p300 recruitment (PMID:15623506)
• the ubiquitin-proteasome proteolytic system degrades Sox9 and regulates its transcriptional activity (PMID:15694126)
• Transcription factor SOX9 down-regulates CEA gene expression and, as a probable consequence, induces apoptosis in the human colon carcinoma cell line HT29Cl.16E. (PMID:15781631)
• The SOX9, as a potential melanogenic transcriptional regulator, as its expression level is increased following the down-regulation of BRN2 in differentiated melanoblasts. (PMID:15896776)
• Sox9 promoter is regulated by CCAAT-binding factor through its interaction with two functional CCAAT boxes. (PMID:15908194)
• SOX9 may play an important role in the transcriptional activation of the newest collagen gene, COL27A1. (PMID:15922909)
• Sox9 and p300 interact with chromatin and activates transcription via regulation of chromatin modification (PMID:16109717)
• Human SOX9 in undifferentiated mouse ES cells might have dual potentials to induce both chondrogenic commitment and growth capacity in the undifferentiated status. (PMID:16155402)
• by controlling the cellular concentrations of SOX9, PIAS proteins and sumoylation may be part of a major regulatory system of SOX9 functions (PMID:16554309)
• pediatric and adult high grade tumors display strong nuclear staining for SOX9 (PMID:16791471)
• SOX9 mRNA regulation in human articular chondrocytes involves p38 MAPK activation and mRNA stabilization (PMID:17050539)
• Sox9 is variably expressed in ovarian Sertoli cell tumor and other tumors that are in the differential diagnosis (PMID:17197889)
• Results indicate that SOX9 in prostate basal cells supports the development and maintenance of the luminal epithelium and that a subset of prostate cancer cells may escape basal cell requirements through SOX9 expression. (PMID:17234760)
• Here we report that the human SOX9 proximal promoter is also regulated by the cyclic-AMP response element binding protein (CREB) and Sp1. (PMID:17289023)
• Sox9 transcriptionally regulates furin expression during chondrogenesis. (PMID:17360815)
• data support a direct molecular link between the Hh signaling pathway and SOX9 regulation, wherein SHH stimulates SOX9 through its mediator GLI1, and are consistent with a mechanism of SOX9 regulation through distal chromatin interactions (PMID:17409199)
• The embryonic male prostaglandin D synthase (Pgds)/SOX9 pathway is expressed at both the RNA and protein levels in different types of human ovarian tumors. (PMID:17532558)
• These findings suggest that non-syndromic PRS may be caused by both SOX9 and KCNJ2 dysregulation. (PMID:17551083)
• SOX9 signaling is not essential for LE135-induced chondrogenesis in mesenchymal stem cells derived from osteoarthritis patients. (PMID:17615267)
• role of SOX9 in pigmentation emphasizes the impact of SOX proteins in adult tissues. (PMID:17702866)
• The expression of genes in a human chondrosarcoma cell line is altered following SOX9 overexpression. (PMID:17935617)
• Our data suggest that lesions affecting SOX9 expression are the key factor in sex determination in SRY-negative XX males (PMID:17986281)
• new hypoxia-inducible and SOX9-regulated genes, Gdf10 and Chm-I. In addition, Mig6 and InhbA were induced by hypoxia, predominantly via HIF-2alpha (PMID:18077449)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	sox9a	ENSDARG00000003293
danio_rerio	sox9b	ENSDARG00000043923
mus_musculus	Sox9	ENSMUSG00000000567
rattus_norvegicus	Sox9	ENSRNOG00000080699
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), SOX4 (ENSG00000124766), SOX21 (ENSG00000125285), 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-9 — P48436 (reviewed: P48436)

All UniProt accessions (1): P48436

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that plays a key role in chondrocytes differentiation and skeletal development. Specifically binds the 5’-ACAAAG-3’ DNA motif present in enhancers and super-enhancers and promotes expression of genes important for chondrogenesis, including cartilage matrix protein-coding genes COL2A1, COL4A2, COL9A1, COL11A2 and ACAN, SOX5 and SOX6. Also binds to some promoter regions. Plays a central role in successive steps of chondrocyte differentiation. Absolutely required for precartilaginous condensation, the first step in chondrogenesis during which skeletal progenitors differentiate into prechondrocytes. Together with SOX5 and SOX6, required for overt chondrogenesis when condensed prechondrocytes differentiate into early stage chondrocytes, the second step in chondrogenesis. Later, required to direct hypertrophic maturation and block osteoblast differentiation of growth plate chondrocytes: maintains chondrocyte columnar proliferation, delays prehypertrophy and then prevents osteoblastic differentiation of chondrocytes by lowering beta-catenin (CTNNB1) signaling and RUNX2 expression. Also required for chondrocyte hypertrophy, both indirectly, by keeping the lineage fate of chondrocytes, and directly, by remaining present in upper hypertrophic cells and transactivating COL10A1 along with MEF2C. Low lipid levels are the main nutritional determinant for chondrogenic commitment of skeletal progenitor cells: when lipids levels are low, FOXO (FOXO1 and FOXO3) transcription factors promote expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation. Mechanistically, helps, but is not required, to remove epigenetic signatures of transcriptional repression and deposit active promoter and enhancer marks at chondrocyte-specific genes. Acts in cooperation with the Hedgehog pathway-dependent GLI (GLI1 and GLI3) transcription factors. In addition to cartilage development, also acts as a regulator of proliferation and differentiation in epithelial stem/progenitor cells: involved in the lung epithelium during branching morphogenesis, by balancing proliferation and differentiation and regulating the extracellular matrix. Controls epithelial branching during kidney development.

Subunit / interactions. Homodimer; homodimerization is required for activity. Interacts (via C-terminus) with ZNF219; forming a complex that binds to the COL2A1 promoter and activates COL2A1 expression. Interacts with DDRGK1. Interacts with EP300/p300. Interacts with beta-catenin (CTNNB1); inhibiting CTNNB1 activity by competing with the binding sites of TCF/LEF within CTNNB1.

Subcellular location. Nucleus.

Post-translational modifications. Acetylated; acetylation impairs nuclear localization and ability to transactivate expression of target genes. Deacetylated by SIRT1. Phosphorylation at Ser-64 and Ser-211 by PKA increases transcriptional activity and may help delay chondrocyte maturation downstream of PTHLH/PTHrP signaling. Phosphorylation at either Ser-64 or Ser-211 is required for sumoylation, but phosphorylation is not dependent on sumoylation. Phosphorylated on tyrosine residues; tyrosine dephosphorylation by PTPN11/SHP2 blocks SOX9 phosphorylation by PKA and subsequent SUMOylation. Ubiquitinated; ubiquitination leads to proteasomal degradation and is negatively regulated by DDRGK1. Sumoylated; phosphorylation at either Ser-64 or Ser-211 is required for sumoylation. Sumoylation is induced by BMP signaling pathway.

Disease relevance. Campomelic dysplasia (CMD1) [MIM:114290] A rare, often lethal, osteochondrodysplasia characterized by congenital bowing and angulation of long bones. Other skeletal defects include unusually small scapula, deformed pelvis and spine, and a missing pair of ribs. Craniofacial and ear defects are common. Most patients die soon after birth due to respiratory distress which has been attributed to hypoplasia of the tracheobronchial cartilage and small thoracic cage. Up to two-thirds of affected XY individuals have genital defects or may develop as phenotypic females. The disease is caused by variants affecting the gene represented in this entry. 46,XX sex reversal 2 (SRXX2) [MIM:278850] A condition in which male gonads develop in a genetic female (female to male sex reversal). The disease is caused by variants affecting the gene represented in this entry. 46,XY sex reversal 10 (SRXY10) [MIM:616425] A disorder of sex development. Affected individuals have a 46,XY karyotype, show gonadal dysgenesis with streak gonads, look like normal females at birth, do not develop secondary sexual characteristics at puberty and do not menstruate. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The transactivation domains TAM and TAC (for transactivation domain in the middle and at the C-terminus, respectively) are required to contact transcriptional coactivators and basal transcriptional machinery components and thereby induce gene transactivation. The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors. The PQA region (for proline, glutamine and alanine-rich) helps stabilize SOX9 and facilitates transactivation. It lacks intrinsic transactivation capability.

RefSeq proteins (1): NP_000337* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009071	HMG_box_dom	Domain
IPR022151	Sox_N	Domain
IPR036910	HMG_box_dom_sf	Homologous_superfamily
IPR050917	SOX_TF	Family

Pfam: PF00505, PF12444

UniProt features (56 total): sequence variant 21, mutagenesis site 9, region of interest 8, compositionally biased region 7, short sequence motif 3, helix 3, modified residue 2, chain 1, DNA-binding region 1, cross-link 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4EUW	X-RAY DIFFRACTION	2.77

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48436-F1	56.69	0.12

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 (3): 64, 211, 398

Mutagenesis-validated functional residues (9):

Position	Phenotype
278	impaired ability to activate transcription in vitro.
282	impaired ability to activate transcription in vitro.
290	impaired ability to activate transcription in vitro.
293	impaired ability to activate transcription in vitro.
294	does not affect ability to activate transcription in vitro.
294	impaired ability to activate transcription in vitro.
296	impaired, but not abolished, ability to activate transcription in vitro.
297	impaired ability to activate transcription in vitro.
298	impaired ability to activate transcription in vitro.

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-3769402	Deactivation of the beta-catenin transactivating complex
R-HSA-8878166	Transcriptional regulation by RUNX2
R-HSA-9690406	Transcriptional regulation of testis differentiation
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity
R-HSA-9925561	Developmental Lineage of Pancreatic Acinar Cells
R-HSA-9925563	Developmental Lineage of Pancreatic Ductal Cells
R-HSA-9937080	Developmental Lineage of Multipotent Pancreatic Progenitor Cells
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-212436	Generic Transcription Pathway
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9730414	MITF-M-regulated melanocyte development
R-HSA-9734767	Developmental Cell Lineages

MSigDB gene sets: 1180 (showing top): GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_LIPID_MODIFICATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_METANEPHRIC_NEPHRON_MORPHOGENESIS, GOBP_DIGESTION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_URETER_DEVELOPMENT, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, GOBP_LUNG_EPITHELIUM_DEVELOPMENT

GO Biological Process (151): negative regulation of transcription by RNA polymerase II (GO:0000122), skeletal system development (GO:0001501), cartilage condensation (GO:0001502), branching involved in ureteric bud morphogenesis (GO:0001658), cell fate specification (GO:0001708), epithelial to mesenchymal transition (GO:0001837), tissue homeostasis (GO:0001894), hair follicle development (GO:0001942), morphogenesis of an epithelium (GO:0002009), positive regulation of mesenchymal cell proliferation (GO:0002053), chondrocyte differentiation (GO:0002062), glandular epithelial cell differentiation (GO:0002067), negative regulation of immune system process (GO:0002683), heart valve development (GO:0003170), heart valve morphogenesis (GO:0003179), aortic valve morphogenesis (GO:0003180), heart valve formation (GO:0003188), endocardial cushion morphogenesis (GO:0003203), chondrocyte differentiation involved in endochondral bone morphogenesis (GO:0003413), chondrocyte hypertrophy (GO:0003415), growth plate cartilage chondrocyte growth (GO:0003430), nucleosome assembly (GO:0006334), chromatin remodeling (GO:0006338), transcription by RNA polymerase II (GO:0006366), cytoskeleton organization (GO:0007010), signal transduction (GO:0007165), epidermal growth factor receptor signaling pathway (GO:0007173), Notch signaling pathway (GO:0007219), spermatogenesis (GO:0007283), heart development (GO:0007507), positive regulation of cell population proliferation (GO:0008284), male gonad development (GO:0008584), mesenchymal cell proliferation (GO:0010463), regulation of cell cycle process (GO:0010564), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), positive regulation of epithelial cell migration (GO:0010634), neural crest cell development (GO:0014032), neural crest cell fate specification (GO:0014036), male germ-line sex determination (GO:0019100)

GO Molecular Function (15): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), beta-catenin binding (GO:0008013), protein kinase A catalytic subunit binding (GO:0034236), bHLH transcription factor binding (GO:0043425), sequence-specific DNA binding (GO:0043565), pre-mRNA intronic binding (GO:0097157), sequence-specific double-stranded DNA binding (GO:1990837), transcription cis-regulatory region binding (GO:0000976), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Developmental Biology	3
Developmental Cell Lineages of the Exocrine Pancreas	3
TCF dependent signaling in response to WNT	1
Generic Transcription Pathway	1
MITF-M-regulated melanocyte development	1
Signal Transduction	1
Signaling by WNT	1
RNA Polymerase II Transcription	1
Gene expression (Transcription)	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
regulation of transcription by RNA polymerase II	2
cartilage development	2
anatomical structure development	2
heart valve morphogenesis	2
transcription cis-regulatory region binding	2
binding	2
cellular anatomical structure	2
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
system development	1
skeletal system morphogenesis	1
cell aggregation	1
branching morphogenesis of an epithelial tube	1
ureteric bud morphogenesis	1
cell fate commitment	1
cellular developmental process	1
mesenchymal cell differentiation	1
multicellular organismal-level homeostasis	1
anatomical structure homeostasis	1
hair cycle process	1
skin epidermis development	1
tissue morphogenesis	1
epithelium development	1
positive regulation of cell population proliferation	1
mesenchymal cell proliferation	1
regulation of mesenchymal cell proliferation	1
cell differentiation	1
columnar/cuboidal epithelial cell differentiation	1
immune system process	1
regulation of immune system process	1
negative regulation of biological process	1
heart development	1
heart valve development	1
anatomical structure morphogenesis	1
aortic valve development	1
anatomical structure formation involved in morphogenesis	1
heart morphogenesis	1
endocardial cushion development	1
mesenchyme morphogenesis	1

Protein interactions and networks

STRING

4764 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SOX9	CTNNB1	P35222	965
SOX9	SOX6	P35712	954
SOX9	COL2A1	P02458	945
SOX9	SNAI2	O43623	903
SOX9	WT1	P19544	903
SOX9	SOX5	P35711	901
SOX9	ACAN	P16112	897
SOX9	FOXL2	P58012	877
SOX9	NR0B1	P51843	865
SOX9	RUNX2	Q13950	859
SOX9	AMH	P03971	847
SOX9	EP300	Q09472	844
SOX9	DMRT1	Q9Y5R6	841
SOX9	NR5A1	Q13285	835
SOX9	NFIA	Q12857	822

IntAct

43 interactions, top by confidence:

A	B	Type	Score
CALM	SOX9	psi-mi:“MI:0407”(direct interaction)	0.610
SOX9	CALM	psi-mi:“MI:0407”(direct interaction)	0.610
SOX9	CALM	psi-mi:“MI:0915”(physical association)	0.610
Arid5a	SOX9	psi-mi:“MI:0915”(physical association)	0.560
Arid5a	SOX9	psi-mi:“MI:0403”(colocalization)	0.560
SOX9	Arid5a	psi-mi:“MI:0915”(physical association)	0.560
WLS	SOX9	psi-mi:“MI:0915”(physical association)	0.490
FBXW7	SOX9	psi-mi:“MI:2364”(proximity)	0.480
NFIA	SOX9	psi-mi:“MI:0915”(physical association)	0.470
RUNX2	SOX9	psi-mi:“MI:0407”(direct interaction)	0.440
CALM		psi-mi:“MI:0407”(direct interaction)	0.440
SOX9	SMARCA4	psi-mi:“MI:2364”(proximity)	0.410
SMARCA4	SOX9	psi-mi:“MI:2364”(proximity)	0.410
NFIB	SOX9	psi-mi:“MI:0915”(physical association)	0.400
NFIC	SOX9	psi-mi:“MI:0915”(physical association)	0.400
WLS	SOX9	psi-mi:“MI:0915”(physical association)	0.370
SOX9	ATP6V1H	psi-mi:“MI:0915”(physical association)	0.370
	POLR3A	psi-mi:“MI:0914”(association)	0.350
FBXW7	KMT2D	psi-mi:“MI:0914”(association)	0.350
PEX7	UBA6	psi-mi:“MI:0914”(association)	0.350
RAD23A	PIK3C2A	psi-mi:“MI:0914”(association)	0.350

BioGRID (128): SOX9 (Biochemical Activity), BTRC (Affinity Capture-Western), NR5A1 (Two-hybrid), FBXW7 (Affinity Capture-Western), FBXW7 (Reconstituted Complex), SOX9 (Biochemical Activity), SOX9 (Reconstituted Complex), SOX9 (Affinity Capture-RNA), MAF (Two-hybrid), MAF (Affinity Capture-Western), SOX9 (Affinity Capture-Western), SOX9 (Reconstituted Complex), MAF (Reconstituted Complex), NR5A1 (Reconstituted Complex), SOX9 (Affinity Capture-Western)

ESM2 similar proteins: A0A8C0NGY6, A0A8I3PQN6, A1L1N5, A2BEA6, A2ICN5, A2VDZ3, A4QNP0, D6C652, F1LYL9, H2LBU8, O18896, O94842, P19484, P23899, P27889, P35680, P46936, P46937, P46938, P48436, P61753, P61754, Q02078, Q03365, Q04887, Q0P5K4, Q1L8J7, Q2EJA0, Q2LE08, Q2MJT0, Q32NJ6, Q4VYR7, Q571K4, Q5R6A9, Q5RER5, Q5XGD9, Q62431, Q6GQD7, Q7YRJ7, Q7ZXH3

Diamond homologs: A2TED3, A4IIJ8, A4QNG3, A5A763, A5D8R3, B0ZTE1, B0ZTE2, B3DLD3, B7ZR65, F1LYL9, O00570, O15370, O18896, O42342, O42569, O42601, O55170, O57401, O60248, O95416, P0C1G9, P35713, P35716, P40637, P40639, P40646, P40650, P40652, P40656, P40657, P43267, P43680, P47792, P48430, P48431, P48432, P48433, P48434, P48435, P48436

SIGNOR signaling

27 interactions.

A	Effect	B	Mechanism
PRKACA	up-regulates	SOX9	phosphorylation
ROCK1	up-regulates	SOX9	phosphorylation
MAPK3	“up-regulates quantity by expression”	SOX9	“transcriptional regulation”
DLK1	“up-regulates quantity by expression”	SOX9	“transcriptional regulation”
SOX9	“down-regulates quantity by repression”	CEBPB	“transcriptional regulation”
SOX9	“down-regulates quantity by repression”	CEBPD	“transcriptional regulation”
MAPK3	up-regulates	SOX9	“transcriptional regulation”
DLK1	up-regulates	SOX9	“transcriptional regulation”
SOX9	down-regulates	CEBPB	“transcriptional regulation”
ERK1/2	up-regulates	SOX9	“transcriptional regulation”
SOX9	“up-regulates quantity by expression”	COL2A1	“transcriptional regulation”
SOX9	“up-regulates quantity by expression”	COL9A2	“transcriptional regulation”
SOX9	“up-regulates quantity by expression”	COL11A2	“transcriptional regulation”
SOX9	“down-regulates quantity by repression”	CDX2	“transcriptional regulation”
TCF4	“up-regulates quantity by expression”	SOX9	“transcriptional regulation”
SOX9	“up-regulates quantity by expression”	DCC	“transcriptional regulation”
SOX9	“up-regulates quantity by expression”	CDKN1A	“transcriptional regulation”
SOX9	“down-regulates quantity by repression”	PRAME	“transcriptional regulation”
UBE3A	“down-regulates quantity by destabilization”	SOX9	ubiquitination
PRKG2	“down-regulates activity”	SOX9	phosphorylation
CDKL5	“down-regulates activity”	SOX9	phosphorylation
GSK3B	“down-regulates activity”	SOX9	phosphorylation
SOX9	“up-regulates activity”	MITF	binding
SOX9	“up-regulates activity”	OTX2	binding
SOX9	“up-regulates quantity by expression”	BEST1	“transcriptional regulation”
ADCK5	“up-regulates activity”	SOX9	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 27 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
RNA Polymerase III Transcription Termination	5	107.9×	2e-07
RNA Polymerase III Abortive And Retractive Initiation	5	60.5×	2e-06

GO biological processes:

GO term	Partners	Fold	FDR
transcription by RNA polymerase II	6	16.9×	3e-04
gene expression	5	16.0×	7e-04
positive regulation of gene expression	5	7.8×	1e-02

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 2 cancer types — COAD, COADREAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	67
Likely pathogenic	33
Uncertain significance	151
Likely benign	97
Benign	19

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012429	NM_000346.4(SOX9):c.788del (p.Gly263fs)	Pathogenic
1071225	NM_000346.4(SOX9):c.1116_1117del (p.Pro374fs)	Pathogenic
1178322	t(11;17)(p15.4;q24.3)	Pathogenic
1452379	NM_000346.4(SOX9):c.600dup (p.Asn201fs)	Pathogenic
1454687	NM_000346.4(SOX9):c.527C>T (p.Pro176Leu)	Pathogenic
1527950	NM_000346.4(SOX9):c.686-2A>G	Pathogenic
1699296	NM_000346.4(SOX9):c.517A>T (p.Lys173Ter)	Pathogenic
192386	NCBI36/hg18 17q24.3(chr17:67018227-67114737)x3	Pathogenic
192387	NC_000017.10:g.69521863_69670036dup	Pathogenic
192388	NC_000017.10:g.(69472000_?)_(?_69712000)del	Pathogenic
2008010	NC_000017.11:g.72122720_72122736del	Pathogenic
2040173	NM_000346.4(SOX9):c.683C>A (p.Ser228Ter)	Pathogenic
2047766	NM_000346.4(SOX9):c.515A>T (p.Tyr172Phe)	Pathogenic
2106821	NM_000346.4(SOX9):c.685+2T>C	Pathogenic
21163	NM_000346.4(SOX9):c.1320C>A (p.Tyr440Ter)	Pathogenic
2138102	NM_000346.4(SOX9):c.432-2A>C	Pathogenic
2506	NM_000346.4(SOX9):c.583C>T (p.Gln195Ter)	Pathogenic
2508	NM_000346.4(SOX9):c.855_858dup (p.Glu287fs)	Pathogenic
2509	NM_000346.4(SOX9):c.736dup (p.Gln246fs)	Pathogenic
2510	NM_000346.4(SOX9):c.1320C>G (p.Tyr440Ter)	Pathogenic
2511	NM_000346.4(SOX9):c.517A>G (p.Lys173Glu)	Pathogenic
2513	NM_000346.4(SOX9):c.493C>T (p.His165Tyr)	Pathogenic
2516	NM_000346.4(SOX9):c.462C>G (p.Phe154Leu)	Pathogenic
2517	NM_000346.4(SOX9):c.472G>A (p.Ala158Thr)	Pathogenic
2518	NM_000346.4(SOX9):c.1103dup (p.Gln369fs)	Pathogenic
265652	NM_000346.4(SOX9):c.555del (p.Gln186fs)	Pathogenic
2699620	NM_000346.4(SOX9):c.760C>T (p.Arg254Ter)	Pathogenic
2702605	NM_000346.4(SOX9):c.1255del (p.Ala419fs)	Pathogenic
2736641	NM_000346.4(SOX9):c.685+1G>A	Pathogenic
279897	NM_000346.4(SOX9):c.442G>T (p.Glu148Ter)	Pathogenic

SpliceAI

2502 predictions. Top by Δscore:

Variant	Effect	Δscore
17:72121820:G:GT	donor_gain	1.0000
17:72121820:GAG:G	donor_gain	1.0000
17:72121821:AGGTA:A	donor_loss	1.0000
17:72121823:GTA:G	donor_loss	1.0000
17:72122693:T:TA	acceptor_gain	1.0000
17:72122695:T:TA	acceptor_gain	1.0000
17:72122702:C:A	acceptor_gain	1.0000
17:72122707:C:A	acceptor_gain	1.0000
17:72122716:CAGAC:C	acceptor_loss	1.0000
17:72122717:A:AG	acceptor_gain	1.0000
17:72122717:AGACT:A	acceptor_loss	1.0000
17:72122718:G:GG	acceptor_gain	1.0000
17:72122718:GA:G	acceptor_gain	1.0000
17:72122718:GAC:G	acceptor_gain	1.0000
17:72122968:CTCGG:C	donor_gain	1.0000
17:72122971:GG:G	donor_gain	1.0000
17:72122972:GG:G	donor_gain	1.0000
17:72122973:G:GC	donor_loss	1.0000
17:72122973:G:GG	donor_gain	1.0000
17:72122974:T:A	donor_loss	1.0000
17:72122975:GAGTC:G	donor_loss	1.0000
17:72123532:A:AG	acceptor_gain	1.0000
17:72123532:ATT:A	acceptor_gain	1.0000
17:72123533:T:G	acceptor_gain	1.0000
17:72123534:T:A	acceptor_gain	1.0000
17:72123538:CACA:C	acceptor_loss	1.0000
17:72123539:A:AG	acceptor_gain	1.0000
17:72123539:ACAG:A	acceptor_gain	1.0000
17:72123539:ACAGG:A	acceptor_gain	1.0000
17:72123540:CA:C	acceptor_loss	1.0000

AlphaMissense

3352 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:72121596:T:C	F69L	1.000
17:72121597:T:C	F69S	1.000
17:72121597:T:G	F69C	1.000
17:72121598:C:A	F69L	1.000
17:72121598:C:G	F69L	1.000
17:72121609:T:A	I73N	1.000
17:72121609:T:C	I73T	1.000
17:72121609:T:G	I73S	1.000
17:72121612:G:C	R74P	1.000
17:72121617:G:C	A76P	1.000
17:72121618:C:A	A76E	1.000
17:72121620:G:C	V77L	1.000
17:72121620:G:T	V77F	1.000
17:72121621:T:A	V77D	1.000
17:72121621:T:C	V77A	1.000
17:72121629:G:A	V80M	1.000
17:72121630:T:A	V80E	1.000
17:72121633:T:A	L81H	1.000
17:72121633:T:C	L81P	1.000
17:72121633:T:G	L81R	1.000
17:72121638:G:C	G83R	1.000
17:72121641:T:A	Y84N	1.000
17:72121641:T:C	Y84H	1.000
17:72121641:T:G	Y84D	1.000
17:72121645:A:G	D85G	1.000
17:72121645:A:T	D85V	1.000
17:72121647:T:A	W86R	1.000
17:72121647:T:C	W86R	1.000
17:72121648:G:C	W86S	1.000
17:72121649:G:C	W86C	1.000

dbSNP variants (sampled 300 via entrez): RS1000603868 (17:72123412 G>A), RS1000662504 (17:72121939 C>A,T), RS1001505363 (17:72124320 C>A,G,T), RS1002435696 (17:72122908 G>A,C,T), RS1002718948 (17:72120651 G>T), RS1002877037 (17:72122673 C>A,G,T), RS1003095187 (17:72120470 G>A), RS1003179000 (17:72126206 G>C,T), RS1003181071 (17:72120834 T>A), RS1003274099 (17:72126401 T>C), RS1003773272 (17:72119682 A>G), RS1003847603 (17:72121480 C>A,G,T), RS1004445898 (17:72122416 G>A,T), RS1004590645 (17:72121059 C>A,T), RS1006572552 (17:72124222 G>A,C,T)

Disease associations

OMIM: gene MIM:608160 | disease phenotypes: MIM:114290, MIM:278850, MIM:616425, MIM:264600, MIM:114500

GenCC curated gene-disease

Disease	Classification	Inheritance
campomelic dysplasia	Definitive	Autosomal dominant
isolated Pierre-Robin syndrome	Definitive	Autosomal dominant
46,XX ovotesticular disorder of sex development	Supportive	Autosomal dominant
46,XY complete gonadal dysgenesis	Supportive	Autosomal dominant
46,XY partial gonadal dysgenesis	Supportive	Autosomal dominant
46,XX sex reversal 1	Supportive	Autosomal dominant
Cooks syndrome	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (3)

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

Disease	Classification	Inheritance
isolated Pierre-Robin syndrome	Limited	AD
Cooks syndrome	Limited	AD
campomelic dysplasia	Definitive	AD

Mondo (13): campomelic dysplasia (MONDO:0007251), connective tissue disorder (MONDO:0003900), 46,XX sex reversal 2 (MONDO:0010218), 46,XY sex reversal 10 (MONDO:0014634), intellectual disability (MONDO:0001071), 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency (MONDO:0009923), colorectal cancer (MONDO:0005575), Cooks syndrome (MONDO:0007134), isolated Pierre-Robin syndrome (MONDO:0009869), 46,XX ovotesticular disorder of sex development (MONDO:0016281), 46,XY complete gonadal dysgenesis (MONDO:0010765), 46,XY partial gonadal dysgenesis (MONDO:0016674), (MONDO:0010766)

Orphanet (5): Campomelic dysplasia (Orphanet:140), 46,XX testicular difference of sex development (Orphanet:393), 46,XY difference of sex development due to 5-alpha-reductase 2 deficiency (Orphanet:753), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667)

HPO phenotypes

182 total (30 of 182 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000013	Hypoplasia of the uterus
HP:0000022	Abnormal male internal genitalia morphology
HP:0000026	Male hypogonadism
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000030	Testicular gonadoblastoma
HP:0000037	Male pseudohermaphroditism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000045	Abnormal scrotum morphology
HP:0000046	Small scrotum
HP:0000047	Hypospadias
HP:0000048	Bifid scrotum
HP:0000051	Perineal hypospadias
HP:0000054	Micropenis
HP:0000058	Abnormal labia morphology
HP:0000062	Ambiguous genitalia
HP:0000100	Nephrotic syndrome
HP:0000126	Hydronephrosis
HP:0000130	Abnormality of the uterus
HP:0000133	Gonadal dysgenesis
HP:0000142	Abnormal vagina morphology
HP:0000144	Decreased fertility
HP:0000147	Polycystic ovaries
HP:0000149	Ovarian gonadoblastoma
HP:0000150	Gonadoblastoma
HP:0000160	Narrow mouth
HP:0000162	Glossoptosis
HP:0000175	Cleft palate

GWAS associations

58 associations (top):

Study	Trait	p-value
GCST001277_25	Liver enzyme levels (gamma-glutamyl transferase)	1.000000e-09
GCST001444_6	Pulmonary function decline	7.000000e-06
GCST001784_51	Pulmonary function (smoking interaction)	1.000000e-08
GCST001784_52	Pulmonary function (smoking interaction)	7.000000e-08
GCST001856_57	Thyroid hormone levels	1.000000e-07
GCST001856_58	Thyroid hormone levels	2.000000e-07
GCST001856_6	Thyroid hormone levels	8.000000e-13
GCST002097_39	Coronary artery calcification	2.000000e-06
GCST002169_1	Adolescent idiopathic scoliosis (severe)	6.000000e-12
GCST002421_3	Prostate cancer	2.000000e-13
GCST003989_33	Chin dimples	5.000000e-12
GCST003999_13	Nose size	3.000000e-08
GCST004744_6	Lung adenocarcinoma	3.000000e-06
GCST004748_6	Lung cancer	2.000000e-07
GCST006110_1	Nose morphology	1.000000e-09
GCST006110_10	Nose morphology	2.000000e-09
GCST006110_11	Nose morphology	4.000000e-07
GCST006110_12	Nose morphology	2.000000e-10
GCST006110_13	Nose morphology	2.000000e-07
GCST006110_14	Nose morphology	7.000000e-12
GCST006110_15	Nose morphology	1.000000e-10
GCST006110_16	Nose morphology	1.000000e-14
GCST006110_2	Nose morphology	8.000000e-10
GCST006110_20	Nose morphology	3.000000e-11
GCST006110_21	Nose morphology	5.000000e-11
GCST006110_22	Nose morphology	1.000000e-06
GCST006110_24	Nose morphology	4.000000e-07
GCST006110_25	Nose morphology	1.000000e-06
GCST006110_27	Nose morphology	2.000000e-11
GCST006110_28	Nose morphology	3.000000e-11

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0004713	FEV/FVC ratio
EFO:0003892	pulmonary function measurement
EFO:0004314	forced expiratory volume
EFO:0004730	hormone measurement
EFO:0004723	coronary artery calcification
EFO:0007785	femoral neck bone mineral density
EFO:0010075	intertrochanteric region size
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D055036	Campomelic Dysplasia	C05.660.142; C16.131.621.142
D003240	Connective Tissue Diseases	C17.300
D006061	Gonadal Dysgenesis, 46,XY	C12.050.351.875.253.096.687; C12.050.351.875.253.309.388; C12.200.706.316.096.687; C12.200.706.316.309.388; C12.800.316.096.687; C12.800.316.309.388; C16.131.939.316.096.687; C16.131.939.316.309.388; C19.391.119.096.687; C19.391.119.309.388
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D050090	Ovotesticular Disorders of Sex Development	C12.050.351.875.253.343; C12.200.706.316.343; C12.800.316.343; C16.131.939.316.343; C19.391.119.343
D010855	Pierre Robin Syndrome	C05.500.460.606; C05.660.207.540.460.606; C07.320.440.606; C07.650.500.460.606; C16.131.621.207.540.460.606; C16.131.850.500.460.606
C537766	Anonychia-onychodystrophy with hypoplasia or absence of distal phalanges (supp.)
C535830	Pseudovaginal Perineoscrotal Hypospadias (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523231 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases expression, affects cotreatment, decreases expression, affects expression	8
Valproic Acid	increases expression, affects expression, decreases expression, increases methylation, affects cotreatment	7
Resveratrol	affects cotreatment, increases expression, decreases expression, increases reaction, decreases reaction (+3 more)	5
Dexamethasone	affects cotreatment, decreases expression, increases expression, increases reaction, decreases reaction	5
Tetrachlorodibenzodioxin	affects expression, decreases expression, decreases reaction, affects cotreatment, increases expression	5
trichostatin A	affects cotreatment, increases expression	3
Vorinostat	decreases expression, decreases reaction, affects cotreatment, increases expression	3
Silicon Dioxide	decreases methylation, increases expression	3
Tretinoin	affects cotreatment, increases expression	3
bisphenol A	affects expression, increases expression	2
afimoxifene	decreases expression, decreases reaction	2
sodium arsenite	increases response to substance, decreases expression, increases expression	2
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression, decreases expression	2
(+)-JQ1 compound	decreases expression	2
Temozolomide	affects response to substance, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Arsenic	affects cotreatment, decreases expression, decreases response to substance	2
Ascorbic Acid	decreases expression, decreases reaction, increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases expression	2
Calcitriol	increases expression, affects cotreatment, decreases expression	2
Cannabidiol	increases expression, decreases expression	2
Doxorubicin	decreases expression, increases expression	2
Formaldehyde	decreases expression, increases expression	2
Progesterone	affects cotreatment, decreases expression, increases expression	2
Cyclosporine	decreases expression	2
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
1,12-benzoperylene	increases expression, decreases reaction, affects reaction	1
cobaltiprotoporphyrin	decreases reaction, increases expression	1
geraniol	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4421264	Binding	Inhibition of SOX9 in HUVEC assessed as reduction of SOX9-SOX9 interactions incubated for 45 mins by Alpha-screen assay	Inhibitors of sox18 protein activity for treating angiogenesis- and/or lymphangiogenesis-related diseases

Cellosaurus cell lines

16 cell lines: 10 cancer cell line, 3 embryonic stem cell, 3 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A6N8	SEES3-1V human SOX9, clone1	Embryonic stem cell	Male
CVCL_A6N9	SEES3-1V human SOX9, clone2	Embryonic stem cell	Male
CVCL_A6P0	SEES3-1V human SOX9, clone3	Embryonic stem cell	Male
CVCL_A9WN	CTSC#389	Cancer cell line	Male
CVCL_A9WR	CTSC#416	Cancer cell line	Male
CVCL_A9WV	CTSC#438	Cancer cell line	Female
CVCL_A9WW	CTSC#446	Cancer cell line	Female
CVCL_A9WX	CTSC#482	Cancer cell line	Female
CVCL_C1U6	SIGi001-A-20	Induced pluripotent stem cell	Female
CVCL_D8BW	Ubigene A-549 SOX9 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04197050	PHASE4	UNKNOWN	Effect of Sacubitril/Valsartan on Reduced Right Ventricular Ejection Fraction in Patients With CTD
NCT04928586	PHASE4	UNKNOWN	Immunosuppressant Combined With Pirfenidone in CTD-ILD
NCT05440240	PHASE4	RECRUITING	Percutaneous Needle Fasciotomy +/- Corticosteroid Injection for Dupuytren’s Contracture
NCT05505409	PHASE4	UNKNOWN	Efficacy and Safety of Pirfenidone in CTD-ILD
NCT06499233	PHASE4	RECRUITING	Efficacy and Safety of Prophylactic Treatment for Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Inflammatory Rheumatic Disease
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00864201	PHASE3	UNKNOWN	A Study to Evaluate the Use of Bosentan in Patients With Exercise Induced Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
NCT01196091	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01205438	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01488708	PHASE3	TERMINATED	On Open-Label Study in Participants With Systemic Lupus Erythematosus
NCT03626688	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
NCT03683186	PHASE3	ENROLLING_BY_INVITATION	A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
NCT04084678	PHASE3	TERMINATED	A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH
NCT06716606	PHASE3	RECRUITING	A Study to Investigate the Long-term Safety and Efficacy of Belimumab in Adults With Interstitial Lung Disease (ILD) Associated With Systemic Sclerosis (SSc) and Other Connective Tissue Diseases (CTD) (BLISSconneCTD-OLE)
NCT06917690	PHASE3	RECRUITING	A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00004357	PHASE2	COMPLETED	Absorption of Corticosteroids in Children With Juvenile Dermatomyositis
NCT00005675	PHASE2	COMPLETED	Oral Type I Collagen for Relieving Scleroderma
NCT01808196	PHASE2	COMPLETED	Testing Effectiveness of Losartan in Patients With EoE With or Without a CTD
NCT02682511	PHASE2	ACTIVE_NOT_RECRUITING	Oral Ifetroban to Treat Diffuse Cutaneous Systemic Sclerosis (SSc) or SSc-associated Pulmonary Arterial Hypertension
NCT04993885	PHASE2	RECRUITING	Avatrombopag in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT05516758	PHASE2	TERMINATED	A Study of Peresolimab (LY3462817) in Participants With Moderately-to-Severely Active Rheumatoid Arthritis
NCT05998759	PHASE2	RECRUITING	Telitacicept for the Treatment of Connective Tissue Disease-associated Thrombocytopenia
NCT06104228	PHASE2	RECRUITING	129 Xenon MRI as a Biomarker for Diagnosis and Response to Therapy in Pulmonary Arterial Hypertension (PAH)
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT01093911	PHASE1	COMPLETED	Safety Study of CDP7657 in Healthy Volunteers and Patients With Systemic Lupus Erythematosus (SLE)
NCT01764594	PHASE1	COMPLETED	Safety Study of CDP7657 in Patients With Systemic Lupus Erythematosus
NCT02392130	PHASE1	COMPLETED	A Clinical Trial to Assess the Potential of LEO 130852A Gel to Reduce Steroid Induced Skin Atrophy on Healthy Skin
NCT03337165	PHASE1	COMPLETED	Autologous Tolerogenic Dendritic Cells for Treatment of Patients With Rheumatoid Arthritis
NCT03929120	PHASE1	COMPLETED	Allogeneic Bone Marrow Mesenchymal Stem Cells for Patients With Interstitial Lung Disease (ILD) & Connective Tissue Disorders (CTD)
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities