SOX2

Summary

SOX2 (SRY-box transcription factor 2, HGNC:11195) is a protein-coding gene on chromosome 3q26.33, encoding Transcription factor SOX-2 (P48431). Transcription factor that forms a trimeric complex with OCT4 on DNA and controls the expression of a number of genes involved in embryonic development such as YES1, FGF4, UTF1 and ZFP206. It is haploinsufficient (ClinGen: sufficient evidence).

This intronless gene encodes a member of the SRY-related HMG-box (SOX) family of transcription factors involved in the regulation of embryonic development and in the determination of cell fate. The product of this gene is required for stem-cell maintenance in the central nervous system, and also regulates gene expression in the stomach. Mutations in this gene have been associated with optic nerve hypoplasia and with syndromic microphthalmia, a severe form of structural eye malformation. This gene lies within an intron of another gene called SOX2 overlapping transcript (SOX2OT).

Source: NCBI Gene 6657 — RefSeq curated summary.

At a glance

• Gene–disease (curated): anophthalmia/microphthalmia-esophageal atresia syndrome (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 17
• Clinical variants (ClinVar): 100 total — 22 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 76
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 93 downstream targets (CollecTRI)
• MANE Select transcript: NM_003106

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11195
Approved symbol	SOX2
Name	SRY-box transcription factor 2
Location	3q26.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000181449
Ensembl biotype	protein_coding
OMIM	184429
Entrez	6657

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000325404

RefSeq mRNA: 1 — MANE Select: NM_003106 NM_003106

CCDS: CCDS3239

Canonical transcript exons

ENST00000325404 — 1 exons

Exon	Start	End
ENSE00001228743	181711925	181714436

Expression profiles

Bgee: expression breadth ubiquitous, 203 present calls, max score 99.60.

FANTOM5 (CAGE): breadth broad, TPM avg 35.4480 / max 7479.2049, expressed in 566 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40001	26.3903	545
40002	7.7743	473
40003	0.6426	205
40000	0.4455	196
40004	0.0851	44
203040	0.0651	39
40005	0.0450	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.60	gold quality
bronchial epithelial cell	CL:0002328	99.43	gold quality
ganglionic eminence	UBERON:0004023	98.55	gold quality
lateral globus pallidus	UBERON:0002476	98.50	gold quality
epithelium of bronchus	UBERON:0002031	97.48	gold quality
bronchus	UBERON:0002185	97.43	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.30	gold quality
embryo	UBERON:0000922	97.28	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.95	gold quality
ventral tegmental area	UBERON:0002691	96.91	gold quality
superior vestibular nucleus	UBERON:0007227	96.90	gold quality
esophagus squamous epithelium	UBERON:0006920	96.89	gold quality
medulla oblongata	UBERON:0001896	96.83	gold quality
oral cavity	UBERON:0000167	96.72	gold quality
subthalamic nucleus	UBERON:0001906	96.43	gold quality
substantia nigra pars compacta	UBERON:0001965	96.28	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.84	gold quality
endothelial cell	CL:0000115	95.58	gold quality
inferior vagus X ganglion	UBERON:0005363	95.55	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.54	gold quality
nucleus accumbens	UBERON:0001882	95.25	gold quality
epithelium of nasopharynx	UBERON:0001951	95.24	gold quality
caudate nucleus	UBERON:0001873	95.19	gold quality
amygdala	UBERON:0001876	95.19	gold quality
nasal cavity mucosa	UBERON:0001826	94.90	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.85	gold quality
entorhinal cortex	UBERON:0002728	94.69	gold quality
temporal lobe	UBERON:0001871	94.68	gold quality
globus pallidus	UBERON:0001875	94.39	gold quality
inferior olivary complex	UBERON:0002127	93.62	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	1189.58
E-MTAB-10485	yes	912.71
E-HCAD-5	yes	901.78
E-MTAB-8271	yes	318.33
E-MTAB-9388	yes	35.71
E-GEOD-137537	yes	31.86
E-GEOD-84465	yes	29.94
E-MTAB-7316	yes	28.23
E-GEOD-135922	yes	23.02
E-MTAB-8410	yes	16.64
E-ANND-3	yes	12.11
E-MTAB-8894	no	2206.59
E-MTAB-11121	no	628.45
E-MTAB-10018	no	596.98
E-MTAB-6108	no	588.91

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

93 targets.

Target	Regulation
ABCC3	Activation
ABCC6	Activation
ADAM10	Activation
AGR2	Activation
AHR	Activation
ASXL1	Activation
ATOH1	Unknown
BDNF	Activation
BIRC5	Unknown
BMP4	Repression
CCN2
CCND1	Unknown
CCNE1	Activation
CDKN1A	Repression
CDKN1B	Unknown
CDX2	Unknown
CTBP2	Activation
CTNNB1	Repression
DKK1	Activation
DLGAP1	Unknown
DPPA4	Unknown
EGFR	Activation
FABP7	Activation
FGF3	Repression
FGF4	Activation
FOXJ1	Activation
GADD45B	Activation
GATA6	Activation
GFAP	Activation
GLI2	Activation

JASPAR motifs

Motif	Name	Family
MA0143.4	SOX2	SOX-related factors
MA0143.5	SOX2	SOX-related factors
MA1962.1	POU2F1::SOX2	POU domain factors::SOX-related factors

JASPAR matrix evidence (PMIDs): PMID:15863505, PMID:29335749

Upstream regulators (CollecTRI, top): AR, CDX2, CHD8, DACH1, EGFR, EMX2, FEZF1, FOXM1, FOXO1, GLI2, GSK3B, HMGA2, ID4, IRX4, KDM2A, KLF4, LEF1, MSX2, MYC, NEUROD1, NEUROG1, OTX2, PAX6, PITX3, POU2F1, POU3F1, POU5F1, PROX1, RBPJ, SALL4, SIX3, SOX2-OT, SOX2, SOX3, SOX4, SOX9, STAT3, TFAP2A

miRNA regulators (miRDB)

98 targeting SOX2, 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-7110-3P	100.00	73.18	2486
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-450B-5P	99.92	71.48	3175

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• SOX2 has a role in eye development, and its mutation can cause anophthalmia (PMID:12612584)
• Sox-11 activates transcription more strongly than Sox-2; the transactivation domain of Sox-11 is primarily responsible for this capability (PMID:12637543)
• Sox2 can dimerize onto DNA in a distinct conformational arrangement. (PMID:12923055)
• OCT1 and SOX2 have roles in transcriptional activation of the Oct1.Sox2.Hoxb1-DNA ternary transcription factor complex (PMID:14559893)
• Down-regulation of Sox2 may be an important factor for the development of intestinal metaplasia (PMID:14655050)
• SOX2 may play a role in differentiation of the human gastric epithelium and may be involved in gastric carcinogenesis (PMID:14719100)
• Sox2 may play an important role in maintaining a gastric phenotype in stomach cancers as well as in normal tissue. (PMID:15910596)
• Identification of Sox2 as a novel c-myc BUR-binding protein was achieved through yeast one-hybrid screening and the Sox2/DNA interaction was confirmed by electrophoretic mobility shift assay and immunoprecipitation with Sox2 antibody. (PMID:15920534)
• The SOX2 protein co-occupy a substantial portion of its target genes, and collaborate to form regulatory circuitry consisting of autoregulatory and feedforward loops. (PMID:16153702)
• Bilateral anophthalmia and brain malformations caused by a 20-bp deletion through a slipped-strand mispairing event in the SOX2 gene. (PMID:16283891)
• Expression of SOX2 is involved in later events of pancreaatic carcinogenesis. (PMID:16552336)
• Increased SOX2 is associated with the pancreatobiliary phenotype of ampulla of vater carcinoma and involved in later events in carcinogenesis, such as invasion and metastasis (PMID:16596179)
• This review describes how cross regulation for PAX6, SOX2 and perhaps OTX2 has now been uncovered, pointing to the mechanisms that can fine-tune the expression of three such essential components in eye development. (PMID:16712695)
• SOX2 is necessary for the normal development and function of the hypothalamo-pituitary and reproductive axes in both humans and mice. (PMID:16932809)
• These data suggest that SOX2 plays an important role in regulation of pepsinogen A, and ectopic expression of SOX2 may be associated with abnormal differentiation of colorectal cancer cells. (PMID:17136346)
• SOX2 mutation associated with AEG syndrome. (PMID:17219395)
• Sox-2 immunoreactivity showed a nuclear labeling pattern and colocalised on GFAP immunoreactive cell in the human subventricular zone. (PMID:17291498)
• Sox2 is preferentially expressed in breast tumours with basal-like phenotype. (PMID:17334350)
• Detection of anti-SOX2 T cells predicts favorable clinical outcome in patients with asymptomatic plasmaproliferative disorders (PMID:17389240)
• Sox2 was observed in all cases of immature teratomas in primitive neuroepithelial tissues, but was not expressed in mature tissues. (PMID:17464316)
• RNAi-mediated silencing of SOX2 induced differentiation with mesodermal characteristics in EC cells (PMID:17506876)
• Results provide further evidence that SOX2 haploinsufficiency is a common cause of severe developmental ocular malformations and that background genetic variation determines the varying phenotypes. (PMID:17522144)
• have implicated duplications of SOX3 and mutations of both SOX2 and SOX3 in the aetiology of variants of septo-optic dysplasia (PMID:17587179)
• PAX6 and SOX2 are obvious candidates in RE genetic studies because of their biological roles and prior linkage studies. The present findings strongly suggest refractive error is not directly affected in this population by variants in either gene. (PMID:17898260)
• expression of both SOX2 and MUC5AC in serrated polyps supports the hypothesis that these polyps may be predominant precursors of mucinous and signet ring cell carcinomas of the colorectum (PMID:18027866)
• only SOX2 has been identified as a major causative gene of anophthalima and microphthalmia. (PMID:18039390)
• Using ectopic expression of Oct4, Sox2, Klf4 and Myc, we have derived iPS cells from fetal, neonatal and adult human primary cells (PMID:18157115)
• Sox2 may be a tumor marker of glial lineages (PMID:18162777)
• Sox2-expressing MSCs showed consistent proliferation and osteogenic capability in culture media containing bFGF (PMID:18187129)
• The human primordial germ cells is the first primary cell type described to express POU5F1 and NANOG but not SOX2. (PMID:18199879)
• SOX2 is frequently downregulated in gastric cancers (PMID:18268498)
• SOX2 plays a critical role in the pituitary, forebrain, and eye during human embryonic development. (PMID:18285410)
• A high level of SOX2 expression correlates with epigenetic modifications of distant enhancers SRR1 and SRR2 during creation of cell-specific epigenomes. (PMID:18293417)
• SOX2 enhancers SRR1 and SRR2 are each differentially methylated and acetylated, on a temporal basis, contributing to the generation of neuron- and astrocyte-specific epigenomes from a common progenitor cell. (PMID:18293417)
• Thsi study identifies DPPA4 and other genes as putative Sox2:Oct-3/4 target genes using a combination of in silico analysis and transcription-based assays. (PMID:18366076)
• These results support the role of SOX2 in ocular development. Loss of SOX2 function results in severe eye malformation. CHX10 was not implicated with microphthalmia/anophthalmia in our patient cohort. (PMID:18385794)
• Sox2, Oct4 and Nanog are linked together in a pluripotent regulatory network (PMID:18388306)
• SMAD 2/3 signaling directly supports NANOG expression, while SMAD 1/5/8 activation moderately represses SOX2. (PMID:18393632)
• SOX2 and beta-catenin act in synergy in the transcription regulation of CCND1 in breast cancer cells (PMID:18456656)
• Mutation in SOX2 is associated with typical ocular coloboma and probably other anomalies in this Chinese family. (PMID:18474784)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	sox2	ENSDARG00000070913
mus_musculus	Sox2	ENSMUSG00000074637
rattus_norvegicus	Sox2	ENSRNOG00000090426
drosophila_melanogaster	Sox14	FBGN0005612
drosophila_melanogaster	Sox21a	FBGN0036411
caenorhabditis_elegans		WBGENE00004949
caenorhabditis_elegans		WBGENE00004950

Paralogs (20): SOX8 (ENSG00000005513), SOX30 (ENSG00000039600), SOX10 (ENSG00000100146), SOX6 (ENSG00000110693), 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), SOX1 (ENSG00000182968), SRY (ENSG00000184895), SOX18 (ENSG00000203883)

Protein

Protein identifiers

Transcription factor SOX-2 — P48431 (reviewed: P48431)

All UniProt accessions (2): P48431, A0A0U3FYV6

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that forms a trimeric complex with OCT4 on DNA and controls the expression of a number of genes involved in embryonic development such as YES1, FGF4, UTF1 and ZFP206. Binds to the proximal enhancer region of NANOG. Critical for early embryogenesis and for embryonic stem cell pluripotency. Downstream SRRT target that mediates the promotion of neural stem cell self-renewal. Keeps neural cells undifferentiated by counteracting the activity of proneural proteins and suppresses neuronal differentiation. May function as a switch in neuronal development.

Subunit / interactions. Interacts with ZSCAN10. Interacts with SOX3 and FGFR1. Interacts with GLIS1. Interacts with POU5F1; binds synergistically with POU5F1 to DNA. Interacts with DDX56. Interacts with L3MBTL3 and DCAF5; the interaction requires methylation at Lys-42 and is necessary to target SOX2 for ubiquitination by the CRL4-DCAF5 E3 ubiquitin ligase complex. Interacts with RCOR1/CoREST. Interacts with PHF20L1; the interaction requires methylation at Lys-42 and Lys-117 and protects SOX2 from degradation. Interacts with TRIM26; this interaction prevents ubiquitination by WWP2.

Subcellular location. Nucleus speckle. Cytoplasm. Nucleus.

Post-translational modifications. Sumoylation inhibits binding on DNA and negatively regulates the FGF4 transactivation. Methylation at Lys-42 and Lys-117 is necessary for the regulation of SOX2 proteasomal degradation. Ubiquitinated by WWP2, leading to proteasomal degradation.

Disease relevance. Microphthalmia, syndromic, 3 (MCOPS3) [MIM:206900] A disease characterized by the rare association of malformations including uni- or bilateral anophthalmia or microphthalmia, and esophageal atresia with trachoesophageal fistula. Microphthalmia is a disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). In many cases, microphthalmia/anophthalmia occurs in association with syndromes that include non-ocular abnormalities. The disease is caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (1): NP_003097* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009071	HMG_box_dom	Domain
IPR022097	SOX_fam	Family
IPR036910	HMG_box_dom_sf	Homologous_superfamily
IPR050140	SRY-related_HMG-box_TF-like	Family

Pfam: PF00505, PF12336

UniProt features (23 total): mutagenesis site 5, helix 4, sequence variant 3, region of interest 3, modified residue 3, chain 1, DNA-binding region 1, cross-link 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
6WX8	X-RAY DIFFRACTION	2.3
6WX7	X-RAY DIFFRACTION	2.7
6WX9	X-RAY DIFFRACTION	2.8
6T90	ELECTRON MICROSCOPY	3.05
6YOV	ELECTRON MICROSCOPY	3.42
9RL4	ELECTRON MICROSCOPY	3.5
9RN2	ELECTRON MICROSCOPY	4.1
9RMC	ELECTRON MICROSCOPY	4.2
6T7B	ELECTRON MICROSCOPY	5.1
9RN1	ELECTRON MICROSCOPY	5.9
1O4X	SOLUTION NMR
2LE4	SOLUTION NMR
9QPF	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48431-F1	61.91	0.27

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 (4): 245, 42, 117, 251

Mutagenesis-validated functional residues (5):

Position	Phenotype
42–43	in mt1; reduced nuclear import; when associated with 56-a–a-58. in mt1.2; reduced nuclear import; when associated with
42	loss of interaction with l3mbtl3. loss of ubiquitination by the crl4-dcaf5 e3 ubiquitin ligase complex. loss of interact
56–58	in mt1; reduced nuclear import; when associated with 56-a–a-58. in mt1.2; reduced nuclear import; when associated with
113–115	in mt2; reduced nuclear import. in mt1.2; reduced nuclear import; when associated with 42-a-a-43 and 56-a–a-58.
117	loss of interaction with phf20l1; when associated with r-42.

Function

Pathways and Gene Ontology

Reactome pathways

25 pathways

ID	Pathway
R-HSA-2892245	POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation
R-HSA-2892247	POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation
R-HSA-3769402	Deactivation of the beta-catenin transactivating complex
R-HSA-452723	Transcriptional regulation of pluripotent stem cells
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-8986944	Transcriptional Regulation by MECP2
R-HSA-9754189	Germ layer formation at gastrulation
R-HSA-9823739	Formation of the anterior neural plate
R-HSA-9832991	Formation of the posterior neural plate
R-HSA-9834899	Specification of the neural plate border
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity
R-HSA-9926550	Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition
R-HSA-1266738	Developmental Biology
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-162582	Signal Transduction
R-HSA-168256	Immune System
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-212436	Generic Transcription Pathway
R-HSA-449147	Signaling by Interleukins
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9730414	MITF-M-regulated melanocyte development
R-HSA-9758941	Gastrulation
R-HSA-9856651	MITF-M-dependent gene expression

MSigDB gene sets: 480 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, RRAGTTGT_UNKNOWN, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, YAGI_AML_WITH_INV_16_TRANSLOCATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, GCANCTGNY_MYOD_Q6, GOZGIT_ESR1_TARGETS_DN, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_PITUITARY_GLAND_DEVELOPMENT, GOBP_NEUROGENESIS, CERVERA_SDHB_TARGETS_1_DN

GO Biological Process (31): negative regulation of transcription by RNA polymerase II (GO:0000122), osteoblast differentiation (GO:0001649), eye development (GO:0001654), endodermal cell fate specification (GO:0001714), chromatin organization (GO:0006325), regulation of DNA-templated transcription (GO:0006355), brain development (GO:0007420), response to wounding (GO:0009611), regulation of gene expression (GO:0010468), glial cell fate commitment (GO:0021781), pituitary gland development (GO:0021983), adenohypophysis development (GO:0021984), positive regulation of cell-cell adhesion (GO:0022409), neuron differentiation (GO:0030182), forebrain development (GO:0030900), somatic stem cell population maintenance (GO:0035019), tissue regeneration (GO:0042246), positive regulation of MAPK cascade (GO:0043410), response to ethanol (GO:0045471), positive regulation of cell differentiation (GO:0045597), negative regulation of neuron differentiation (GO:0045665), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), inner ear development (GO:0048839), response to growth factor (GO:0070848), cellular response to hypoxia (GO:0071456), negative regulation of canonical Wnt signaling pathway (GO:0090090), response to oxygen-glucose deprivation (GO:0090649), neuronal stem cell population maintenance (GO:0097150), negative regulation of cell cycle G1/S phase transition (GO:1902807), regulation of myofibroblast cell apoptotic process (GO:1904520)

GO Molecular Function (10): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), miRNA binding (GO:0035198), sequence-specific DNA binding (GO:0043565), nitric-oxide synthase binding (GO:0050998), protein binding (GO:0005515)

GO Cellular Component (7): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear speck (GO:0016607)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Gastrulation	4
Transcriptional regulation of pluripotent stem cells	2
TCF dependent signaling in response to WNT	1
Developmental Biology	1
Signaling by Interleukins	1
Generic Transcription Pathway	1
MITF-M-regulated melanocyte development	1
MITF-M-dependent gene expression	1
Immune System	1
Signal Transduction	1
Signaling by WNT	1
RNA Polymerase II Transcription	1
Cytokine Signaling in Immune system	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cell differentiation	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
anatomical structure development	2
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
ossification	1
sensory organ development	1
visual system development	1
cell fate specification	1
endodermal cell fate commitment	1
cellular component organization	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
central nervous system development	1
animal organ development	1
head development	1
response to stress	1
gene expression	1
regulation of macromolecule biosynthetic process	1
glial cell differentiation	1
cell fate commitment	1
diencephalon development	1
endocrine system development	1
gland development	1
pituitary gland development	1
regulation of cell-cell adhesion	1
positive regulation of cell adhesion	1
cell-cell adhesion	1
generation of neurons	1
brain development	1
stem cell population maintenance	1
regeneration	1
developmental growth	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
response to alcohol	1

Protein interactions and networks

STRING

7892 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SOX2	NANOG	Q9H9S0	999
SOX2	POU5F1	P31359	999
SOX2	KLF4	P78338	995
SOX2	PAX6	P26367	965
SOX2	LIN28A	Q9H9Z2	962
SOX2	CTNNB1	P35222	957
SOX2	MYC	P01106	933
SOX2	CDK1	P06493	922
SOX2	TP63	Q9H3D4	918
SOX2	HDAC1	Q13547	907
SOX2	SALL4	Q9UJQ4	901
SOX2	OTX2	P32243	897
SOX2	TP53	P04637	883
SOX2	NES	P48681	883
SOX2	POU3F2	P20265	876

IntAct

81 interactions, top by confidence:

A	B	Type	Score
SUMO1	SOX2	psi-mi:“MI:0915”(physical association)	0.670
SOX2	SUMO1	psi-mi:“MI:0915”(physical association)	0.670
VRK1	SOX2	psi-mi:“MI:0403”(colocalization)	0.610
SOX2	VRK1	psi-mi:“MI:0403”(colocalization)	0.610
SOX2	VRK1	psi-mi:“MI:0915”(physical association)	0.610
VRK1	SOX2	psi-mi:“MI:0915”(physical association)	0.610
SOX2	POU5F1	psi-mi:“MI:0914”(association)	0.560
POU5F1	SOX2	psi-mi:“MI:0915”(physical association)	0.560
KDM6A	SOX2	psi-mi:“MI:0915”(physical association)	0.540
SOX2	PDLIM1	psi-mi:“MI:0914”(association)	0.530
SOX2	MYH10	psi-mi:“MI:0914”(association)	0.530
H2AC4	H2BC12	psi-mi:“MI:0915”(physical association)	0.530
MBD3	KLF4	psi-mi:“MI:0914”(association)	0.500
MBD3	SOX2	psi-mi:“MI:0915”(physical association)	0.500
NFIA	SOX2	psi-mi:“MI:0915”(physical association)	0.470
NFIB	SOX2	psi-mi:“MI:0915”(physical association)	0.470

BioGRID (1672): DMAP1 (Affinity Capture-MS), SOX2 (Affinity Capture-Western), TBX2 (Affinity Capture-Western), TBX2 (Affinity Capture-Luminescence), SUMO1 (Two-hybrid), SOX2 (Affinity Capture-Western), POU5F1 (Affinity Capture-Western), CTNNB1 (Affinity Capture-Western), ANXA1 (Affinity Capture-MS), PROSC (Affinity Capture-MS), FAHD2A (Affinity Capture-MS), OXSM (Affinity Capture-MS), SOX14 (Affinity Capture-MS), SOX21 (Affinity Capture-MS), RBP1 (Affinity Capture-MS)

ESM2 similar proteins: A2TED3, O00570, O57401, O95409, P06602, P07548, P09085, P14734, P16241, P20264, P22544, P23441, P23757, P31361, P32027, P32182, P32242, P35583, P39768, P40764, P41225, P43241, P43698, P43699, P48430, P48431, P48432, P50220, P53783, P53784, P54231, P54269, P56224, P80205, Q04649, Q07687, Q24255, Q24533, Q2PG84, Q2Z1R2

Diamond homologs: A2TED3, A4QNG3, B0ZTE1, B0ZTE2, O00570, O42569, O57401, O60248, O95416, P36389, P36390, P36393, P36395, P36396, P41225, P43267, P47792, P48046, P48430, P48431, P48432, P48433, P51501, P53783, P53784, P54231, P55863, P61259, Q04892, Q05066, Q20201, Q21305, Q24533, Q28447, Q28778, Q28783, Q28798, Q2PG84, Q2Z1R2, Q32PP9

SIGNOR signaling

28 interactions.

A	Effect	B	Mechanism
EGFR	“up-regulates quantity by expression”	SOX2	“transcriptional regulation”
SOX2	“up-regulates quantity by expression”	EGFR	“transcriptional regulation”
SOX2	“up-regulates quantity by expression”	NR2E1	“transcriptional regulation”
CTNNB1	“down-regulates activity”	SOX2	binding
SOX2	up-regulates	Pluripotency
POU5F1	“up-regulates quantity by expression”	SOX2	“transcriptional regulation”
ID4	“up-regulates quantity by expression”	SOX2	“transcriptional regulation”
SOX2	“up-regulates quantity by expression”	ABCC3	“transcriptional regulation”
SOX2	“up-regulates quantity by expression”	ABCC6	“transcriptional regulation”
KDM5B	“down-regulates quantity by repression”	SOX2	“transcriptional regulation”
AKT1	“up-regulates quantity by stabilization”	SOX2	phosphorylation
UBR5	“down-regulates quantity by destabilization”	SOX2	polyubiquitination
WWP2	“down-regulates quantity”	SOX2	ubiquitination
EGFR	“up-regulates quantity by stabilization”	SOX2	phosphorylation
MAPK3	“down-regulates activity”	SOX2	phosphorylation
CDK2	“up-regulates activity”	SOX2	phosphorylation
VRK1	“up-regulates activity”	SOX2	phosphorylation
PAK6	“up-regulates quantity”	SOX2	phosphorylation
SOX2	“form complex”	SOX2/POU5F1	binding
ERK1/2	“up-regulates quantity by expression”	SOX2	“transcriptional regulation”
CTNNB1	“up-regulates activity”	SOX2	binding
“Av/b1 integrin”	“up-regulates quantity by expression”	SOX2
“A6/b1 integrin”	“up-regulates quantity by expression”	SOX2
CHD8	“down-regulates quantity”	SOX2	“transcriptional regulation”
SOX2/POU5F1	“up-regulates quantity by expression”	SOX2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 39 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.

GO biological processes:

GO term	Partners	Fold	FDR
chromatin remodeling	6	11.5×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	5
Uncertain significance	35
Likely benign	15
Benign	12

Top pathogenic / likely-pathogenic (27)

Variant ID	HGVS	Classification
1275797	NM_003106.4(SOX2):c.621del (p.Gln206_Tyr207insTer)	Pathogenic
12814	NM_003106.4(SOX2):c.529C>T (p.Gln177Ter)	Pathogenic
1387489	NM_003106.4(SOX2):c.497G>A (p.Trp166Ter)	Pathogenic
1695088	NM_003106.4(SOX2):c.905del (p.Pro302fs)	Pathogenic
1700169	NM_003106.4(SOX2):c.329A>C (p.Tyr110Ser)	Pathogenic
2823248	NM_003106.4(SOX2):c.25del (p.Glu8_Leu9insTer)	Pathogenic
2844603	NM_003106.4(SOX2):c.142_144del (p.Phe48del)	Pathogenic
29890	NM_003106.4(SOX2):c.58_59dup (p.Gly21fs)	Pathogenic
3246890	NC_000003.11:g.(?180702428)(181592675_?)del	Pathogenic
39805	NM_003106.4(SOX2):c.837del (p.Gly280fs)	Pathogenic
4721391	NM_003106.4(SOX2):c.90_96del (p.Gly31fs)	Pathogenic
577696	NM_003106.4(SOX2):c.337C>T (p.Arg113Trp)	Pathogenic
859786	NM_003106.4(SOX2):c.3dup (p.Tyr2fs)	Pathogenic
986760	GRCh37/hg19 3q26.33(chr3:180913778-181432287)x1	Pathogenic
986763	NM_003106.4(SOX2):c.131C>G (p.Pro44Arg)	Pathogenic
986764	NM_003106.4(SOX2):c.310G>T (p.Glu104Ter)	Pathogenic
986766	NM_003106.4(SOX2):c.828del (p.Met276fs)	Pathogenic
986769	NM_003106.4(SOX2):c.-13_43del (p.Met1fs)	Pathogenic
986770	NM_003106.4(SOX2):c.166C>G (p.Arg56Gly)	Pathogenic
986775	NM_003106.4(SOX2):c.542del (p.Pro181fs)	Pathogenic
986776	NM_003106.4(SOX2):c.538_542dup (p.Gln182fs)	Pathogenic
986777	NM_003106.4(SOX2):c.59del (p.Gly20fs)	Pathogenic
3062095	NM_003106.4(SOX2):c.142T>G (p.Phe48Val)	Likely pathogenic
3235168	NM_003106.4(SOX2):c.775_778del (p.Ser259fs)	Likely pathogenic
3337616	NM_003106.4(SOX2):c.940del (p.Leu314fs)	Likely pathogenic
3338557	NM_003106.4(SOX2):c.758del (p.Pro253fs)	Likely pathogenic
3340875	NM_003106.4(SOX2):c.871A>T (p.Arg291Ter)	Likely pathogenic

SpliceAI

19 predictions. Top by Δscore:

Variant	Effect	Δscore
3:181712727:GA:G	donor_gain	0.5100
3:181712728:A:G	donor_gain	0.4300
3:181712151:G:T	donor_gain	0.3900
3:181712084:GCT:G	donor_gain	0.3400
3:181712151:G:GT	donor_gain	0.3000
3:181712961:GAC:G	donor_gain	0.2700
3:181712963:C:G	donor_gain	0.2700
3:181712964:G:GG	donor_gain	0.2600
3:181712886:G:GT	donor_gain	0.2400
3:181713088:TGGTC:T	donor_gain	0.2400
3:181712726:GGA:G	donor_gain	0.2300
3:181712063:G:GT	donor_gain	0.2200
3:181713103:C:T	donor_gain	0.2200
3:181713120:G:GA	acceptor_gain	0.2200
3:181713200:CGCCG:C	acceptor_gain	0.2200
3:181712977:A:AG	donor_gain	0.2100
3:181712978:G:GG	donor_gain	0.2100
3:181713062:C:T	donor_gain	0.2100
3:181712720:G:GT	donor_gain	0.2000

AlphaMissense

2100 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:181712478:C:A	R40S	1.000
3:181712482:T:A	V41D	1.000
3:181712482:T:C	V41A	1.000
3:181712484:A:G	K42E	1.000
3:181712485:A:T	K42M	1.000
3:181712486:G:C	K42N	1.000
3:181712486:G:T	K42N	1.000
3:181712487:C:G	R43G	1.000
3:181712487:C:T	R43W	1.000
3:181712488:G:A	R43Q	1.000
3:181712488:G:T	R43L	1.000
3:181712490:C:A	P44T	1.000
3:181712490:C:G	P44A	1.000
3:181712490:C:T	P44S	1.000
3:181712491:C:A	P44H	1.000
3:181712491:C:G	P44R	1.000
3:181712491:C:T	P44L	1.000
3:181712494:T:A	M45K	1.000
3:181712494:T:C	M45T	1.000
3:181712494:T:G	M45R	1.000
3:181712495:G:A	M45I	1.000
3:181712495:G:C	M45I	1.000
3:181712495:G:T	M45I	1.000
3:181712496:A:C	N46H	1.000
3:181712496:A:G	N46D	1.000
3:181712496:A:T	N46Y	1.000
3:181712497:A:C	N46T	1.000
3:181712497:A:G	N46S	1.000
3:181712497:A:T	N46I	1.000
3:181712498:T:A	N46K	1.000

dbSNP variants (sampled 300 via entrez): RS1000118579 (3:181710048 G>A), RS1000575571 (3:181710267 T>C), RS1000792606 (3:181710231 G>T), RS1000846691 (3:181710593 C>T), RS1001129423 (3:181711692 T>A), RS1001181848 (3:181711893 C>T), RS1001764076 (3:181710612 C>T), RS1003028996 (3:181711760 G>A,C), RS1003412207 (3:181713453 C>A), RS1004356947 (3:181709971 G>A,T), RS1004537039 (3:181714927 G>T), RS1004634634 (3:181710906 T>C,G), RS1004916616 (3:181714475 A>T), RS1006308193 (3:181711928 G>A), RS1006788647 (3:181712231 G>A,T)

Disease associations

OMIM: gene MIM:184429 | disease phenotypes: MIM:206900

GenCC curated gene-disease

Disease	Classification	Inheritance
anophthalmia/microphthalmia-esophageal atresia syndrome	Definitive	Autosomal dominant
isolated anophthalmia-microphthalmia syndrome	Supportive	Autosomal dominant
septooptic dysplasia	Supportive	Autosomal dominant

Mondo (3): anophthalmia/microphthalmia-esophageal atresia syndrome (MONDO:0008799), isolated anophthalmia-microphthalmia syndrome (MONDO:0016764), septooptic dysplasia (MONDO:0008428)

Orphanet (1): Anophthalmia/microphthalmia-esophageal atresia syndrome (Orphanet:77298)

HPO phenotypes

76 total (30 of 76 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000175	Cleft palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000458	Anosmia
HP:0000486	Strabismus
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000518	Cataract
HP:0000528	Anophthalmia
HP:0000568	Microphthalmia
HP:0000572	Visual loss
HP:0000589	Coloboma
HP:0000609	Optic nerve hypoplasia
HP:0000610	Abnormal choroid morphology
HP:0000612	Iris coloboma
HP:0000639	Nystagmus
HP:0000647	Sclerocornea
HP:0000717	Autism
HP:0000864	Abnormality of the hypothalamus-pituitary axis
HP:0000873	Diabetes insipidus
HP:0000878	11 pairs of ribs
HP:0000902	Rib fusion
HP:0000921	Missing ribs

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST003542_44	Night sleep phenotypes	5.000000e-06
GCST003996_27	Monobrow	2.000000e-31
GCST006095_4	Excessive hairiness	8.000000e-09
GCST006461_24	Self-reported risk-taking behaviour	7.000000e-13
GCST006706_3	Eyebrow thickness	1.000000e-19
GCST007325_119	General risk tolerance (MTAG)	3.000000e-11
GCST007325_96	General risk tolerance (MTAG)	1.000000e-10
GCST007576_386	Chronotype	2.000000e-13
GCST007576_387	Chronotype	7.000000e-10
GCST007576_78	Chronotype	2.000000e-13
GCST009963_4	Cataracts (operation)	2.000000e-14
GCST010988_125	Adult body size	1.000000e-09
GCST012013_21	Cataracts	5.000000e-09
GCST012013_8	Cataracts	5.000000e-30
GCST90006927_1	Toxoplasma gondii sag1 antibody levels	4.000000e-08
GCST90013423_1	Age-related nuclear cataracts	2.000000e-19
GCST90014268_13	Cataracts	2.000000e-32

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007906	synophrys measurement
EFO:0008579	risk-taking behaviour
EFO:0008328	chronotype measurement
EFO:0009353	Anti-Toxoplasma gondii IgG measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D025962	Septo-Optic Dysplasia	C10.292.562.700.375.875; C10.500.034.937; C10.500.760.500; C11.590.436.400.875; C16.131.666.034.937; C16.131.666.763.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases reaction, affects reaction, decreases reaction, affects expression, decreases expression (+1 more)	10
Valproic Acid	affects cotreatment, decreases expression, decreases methylation	8
Arsenic Trioxide	decreases expression, increases reaction, affects reaction, decreases response to substance, decreases reaction (+2 more)	7
Estradiol	affects cotreatment, decreases expression, affects binding, increases expression, increases activity	7
Tretinoin	affects cotreatment, decreases expression, decreases reaction, increases reaction, affects expression	7
bisphenol A	increases reaction, decreases expression, increases expression, affects binding	5
(+)-JQ1 compound	affects binding, decreases reaction, decreases expression, increases expression	5
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression, decreases reaction	4
Arsenic	increases expression, increases abundance, affects expression, affects cotreatment, decreases expression	4
Cisplatin	increases expression, affects reaction, affects expression, affects response to substance, decreases response to substance (+1 more)	4
trichostatin A	affects cotreatment, decreases expression	3
cobaltous chloride	increases expression, increases response to substance, decreases reaction, decreases expression	3
methylmercuric chloride	decreases expression, increases expression	2
decabromobiphenyl ether	decreases expression, increases expression	2
diallyl trisulfide	decreases expression, decreases reaction	2
mercuric bromide	decreases expression, affects cotreatment	2
Chir 99021	decreases expression, decreases reaction, affects binding, affects cotreatment	2
bisphenol S	affects cotreatment, decreases expression, increases expression	2
XAV939	affects binding, affects cotreatment, decreases expression, decreases reaction, increases expression	2
LDN 193189	affects cotreatment, increases expression	2
Resveratrol	decreases expression	2
Vorinostat	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Ascorbic Acid	affects binding, affects cotreatment, decreases expression, increases expression	2
Oxygen	increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Silicon Dioxide	decreases expression, decreases reaction	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
Particulate Matter	increases abundance, increases expression	2

Cellosaurus cell lines

15 cell lines: 9 transformed cell line, 3 embryonic stem cell, 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A6M6	SEES3-1V human SOX2, clone1	Embryonic stem cell	Male
CVCL_A6M7	SEES3-1V human SOX2, clone2	Embryonic stem cell	Male
CVCL_A6M8	SEES3-1V human SOX2, clone3	Embryonic stem cell	Male
CVCL_B7TV	e-hChon-2	Transformed cell line	Female
CVCL_B7TW	e-hChon-3	Transformed cell line	Female
CVCL_B7U6	e-hMEC-1	Transformed cell line
CVCL_B7UD	e-hStr-1	Transformed cell line	Female
CVCL_B7UF	e-hStr-3	Transformed cell line	Female
CVCL_B7UG	e-hStr-4	Transformed cell line	Female
CVCL_B7UH	e-hStr-5	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00140413	PHASE4	COMPLETED	Endocrine Dysfunction and Growth Hormone Deficiency in Children With Optic Nerve Hypoplasia
NCT06760546	PHASE3	RECRUITING	A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756)
NCT05717855	Not specified	COMPLETED	Screening of Septo-optic Dysplasia During a Fetal Examination at 16-20 Weeks of Gestation
NCT06262152	Not specified	UNKNOWN	Sleep Profile of Patients With Septo-optic Dysplasia