SOX3
protein-codingSRY-box transcription factor 3, the group of SRY-box transcription factors
Gene summary
This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins. Mutations in this gene have been associated with X-linked cognitive disability with growth hormone deficiency. [provided by RefSeq, Jul 2008]
- PHP
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~2.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0019032
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010614
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0019591
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010712
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0010766
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010252
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010712
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010712
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010442
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0800474
Submitter: ClinGen
The *SOX3* gene is located on the X chromosome at Xq27.1 and 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 the cell fate. *SOX3* was first reported in relation to *SOX3*-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder in 2002 (Laumonnier et al., PMID: 12428212, MONDO:0800474). This X-linked inherited disease is characterized by growth hormone deficiency due to hypopituitarism and in some cases intellectual disability. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in molecular mechanism and phenotypic variability. Therefore, the following disease entities panhypopituitarism, X-linked (OMIM: 312000) and intellectual developmental disorder, X-linked, with isolated growth hormone deficiency (OMIM: 300123) have been lumped and are included in this curation. Whereas, 46,XX sex reversal 3 (MONDO:0010442), X-linked congenital generalized hypertrichosis (ORPHA:79495) and Septo-optic dysplasia spectrum (ORPHA:3157) have been split. At least 9 variants including 3 missense, 2 frameshift, 4 in-frame polyA indels have been reported in 9 probands in 9 publications (PMIDs: 30125608, 29175558, 35295983, 21289259, 15800844, 19654509, 12428212, 39010903; DECIPHER Patient: 279353) and are included in this curation. The mechanism of pathogenicity appears to be gain of function for polyA in-frame deletion variants and loss of function for polyA in-frame insertion variants. This gene-disease relationship is also supported by expression and protein-protein interaction with HESX1 (PMID: 15800844, 39325695), which is associated with pituitary hormone deficiency (PMID: 27000987). Also included is a conditional knockout mouse model which demonstrates lower levels of pituitary growth hormone, luteinizing hormone, follicle stimulating hormone and thyroid stimulating hormone (PMID: 14981518). A new conditional knockout mouse model exhibited slow anterior lobe development, decrease in cellular density, reduced NG2-glia proliferation and differentiation, and impaired oligodendrocyte differentiation and myelination in median eminence (PMID: 39325695). The NG2 proliferation defect and GH deficiencies are rescued by low dose aspirin treatment. Lastly, homologous recombination used to generate XY ES cells carrying a 36 bp expansion in the first PA tract of Sox3 demonstrated that the polyalanine expansion variants in *SOX3* result in both nuclear and functional protein, thereby manifesting as a partial loss-of-function allele (PMID: 23505376). In summary, there is moderate evidence to support the relationship between *SOX3* and *SOX3*-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder. This gene-disease pair was originally evaluated by the ClinGen Syndromic Disorders GCEP on 08/02/23. It was re-evaluated on 06/03/2026. As a result of this reevaluation, the classification did not change (PMIDs: 39010903, 39325695, 23505376; DECIPHER Patient: 279353) (SOP Version 12).
Inheritance Pattern: AD
Disease ID:MONDO:0008428
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010712
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010252
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0016281
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Endocrine; Musculoskeletal; Neurologic
Intervention: Endocrine
Rationale: Treatment for endocrine deficiencies, including those resulting in neonatal electrolyte abnormalities, may be beneficial
Comments: Deletions/insertions involving SOX3 regulatory regions can result in 46,XX sex reversal 3 (XL) or Hypoparathyroidism, X-linked by a position effect (XL)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SOX3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005634.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 4 | 28 | 2 | 34 | ||
| missense | 1 | 72 | 14 | 2 | 89 | |
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 1 | 76 | 42 | 4 | 123 |
Highest pathogenic variant AF is 0.0000010551049
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005625.2 | 1 | MANE Select | |
| Ensembl | ENSP00000359567.2 | 1 | MANE Select |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| sox3 | Danio rerio | Structure: epibranchial ganglion Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Signaling by WNT
- Signal Transduction
- Deactivation of the beta-catenin transactivating complex
- TCF dependent signaling in response to WNT
Biological Process
- regulation of transcription, DNA-templated
- regulation of transcription by RNA polymerase II
- central nervous system development
- sensory organ development
- sex determination
Molecular Function
- RNA polymerase II core promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA binding
- transcription corepressor activity
Cellular Component
- nucleus
- nucleoplasm
- nuclear transcription factor complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000370536
- Coding exons
- 1
- Length
- 2074
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.21 | 76 | 153 | 0.497 | 0.0000101 | 2786 |
| Missense (PolyPhen) | 23 | 79.217 | 0.29034 | 1316 | ||
| Synonymous | 1.11 | 57 | 68.7 | 0.830 | 0.00000494 | 997 |
| Loss of Function | 1.79 | 1 | 5.54 | 0.180 | 3.50e-7 | 101 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcription factor required during the formation of the hypothalamo-pituitary axis. May function as a switch in neuronal development. Keeps neural cells undifferentiated by counteracting the activity of proneural proteins and suppresses neuronal differentiation. Required also within the pharyngeal epithelia for craniofacial morphogenesis. Controls a genetic switch in male development. Is necessary for initiating male sex determination by directing the development of supporting cell precursors (pre-Sertoli cells) as Sertoli rather than granulosa cells (By similarity). {ECO:0000250, ECO:0000269|PubMed:21183788}.;
- Disease
- DISEASE: Panhypopituitarism X-linked (PHPX) [MIM:312000]: Affected individuals have absent infundibulum, anterior pituitary hypoplasia, and ectopic posterior pituitary. {ECO:0000269|PubMed:15800844}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mental retardation, X-linked, with isolated growth hormone deficiency (MRXGH) [MIM:300123]: A disorder characterized by the association of variable degrees of mental retardation with panhypopituitarism, variable combinations of hypothyroidism, delayed pubertal development, and short stature due to growth hormone deficiency. {ECO:0000269|PubMed:12428212}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 46,XX sex reversal 3 (SRXX3) [MIM:300833]: A condition in which male gonads develop in a genetic female (female to male sex reversal). {ECO:0000269|PubMed:21183788}. Note=The disease is caused by mutations affecting the gene represented in this entry. Copy number variations (CNV) encompassing or in close proximity to SOX3 are responsible for XX male reversal. These variations include two duplications of approximately 123 kb and 85 kb, the former of which spans the entire SOX3 gene; a 343 kb deletion immediately upstream of SOX3 that is probably responsible of altered regulation (and not increased dosage) of SOX3; a large (approximately 6 Mb) duplication that encompasses SOX3 and at least 18 additional distally located genes. Its proximal breakpoint falls within the SOX3 regulatory region. This large rearrangement has been found in a patient with XX male reversal and a complex phenotype that also includes a scrotal hypoplasia, microcephaly, developmental delay, and growth retardation.;
Recessive Scores
- pRec
- 0.399
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.539
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |