SOX6
protein-codingSRY-box transcription factor 6, the group of SRY-box transcription factors|MicroRNA protein coding host genes
Gene summary
This gene encodes a member of the D subfamily of sex determining region y-related transcription factors that are characterized by a conserved DNA-binding domain termed the high mobility group box and by their ability to bind the minor groove of DNA. The encoded protein is a transcriptional activator that is required for normal development of the central nervous system, chondrogenesis and maintenance of cardiac and skeletal muscle cells. The encoded protein interacts with other family members to cooperatively activate gene expression. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Mar 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~773.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0033544
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0033544
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0033544
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: ClinGen
*SOX6* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2020 in a study involving 19 individuals from 17 unrelated families (Tolchin et al.,PMID: 32442410). Individuals with these variants exhibited developmental delay and intellectual disability. Core clinical features included attention deficit hyperactivity disorder (ADHD), mild facial dysmorphism, craniosynostosis, and osteochondromas. Out of the 19 individuals, 14 had de novo variants, while 4 inherited the variant, including 3 siblings from their affected father and 1 individual from an unaffected father with 22% mosaicism for the variant. Given the spectrum of neurodevelopmental features observed, the gene is curated for autosomal dominant complex neurodevelopmental disorder. Seventeen variants (missense, nonsense, frameshift, copy number variants) have been reported in 19 probands in one publication (Tolchin et al.,PMID: 32442410 ) are included in this curation. Most variants were de novo. Functional assays like immunoblotting and electrophoretic mobility shift assay demonstrated that two of the missense variants significantly affect SOX6's ability to localize within the nucleus and bind to target DNA. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. In summary, there is definitive evidence supporting the relationship between *SOX6* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism expert panel on September 17th, 2024 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0033544
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0033544
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SOX6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001367873.1. 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 | 3 | 24 | 8 | 35 | ||
| missense | 2 | 7 | 177 | 18 | 5 | 209 |
| nonsense | 8 | 5 | 13 | |||
| start loss | 0 | |||||
| frameshift | 7 | 7 | 5 | 19 | ||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 3 | 6 | ||
| Total | 18 | 21 | 188 | 42 | 13 | 282 |
Highest pathogenic variant AF is 0.000004348458
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001354802.1 | 15 | MANE Select | |
| Ensembl | ENSP00000507545.1 | 15 | MANE Select | |
| RefSeq | NP_001139283.1 | 14 | Standard | |
| RefSeq | NP_001139291.2 | 15 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| sox6 | Danio rerio | Structure: fast muscle cell Quality: process quality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- NOTCH1 regulation of human endothelial cell calcification
- Endochondral Ossification
- Signaling by WNT
- Signal Transduction
- Deactivation of the beta-catenin transactivating complex
Biological Process
- negative regulation of transcription by RNA polymerase II
- cell morphogenesis
- in utero embryonic development
- regulation of transcription, DNA-templated
- muscle organ development
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription repressor activity, RNA polymerase II-specific
- DNA binding
- DNA-binding transcription factor activity
Cellular Component
- nucleus
- nucleoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000396356
- Coding exons
- 15
- Length
- 773144
- Individuals with no LoFs
- 125595
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125597
- p
- 0.00000796
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.93 | 339 | 455 | 0.746 | 0.0000262 | 5311 |
| Missense (PolyPhen) | 124 | 207.55 | 0.59744 | 2358 | ||
| Synonymous | 0.162 | 167 | 170 | 0.984 | 0.00000975 | 1560 |
| Loss of Function | 5.48 | 4 | 42.6 | 0.0939 | 0.00000222 | 471 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcriptional activator. Binds specifically to the DNA sequence 5'-AACAAT-3'. Plays a key role in several developmental processes, including neurogenesis and skeleton formation.;
Recessive Scores
- pRec
- 0.188
Intolerance Scores
- LoFtool
- 0.00909
- RVIS EVS
- -1.11
- RVIS percentile EVS
- 6.72
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.372
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |