SOX6

Chr 11AD

SRY-box transcription factor 6

Also known as: HSSOX6, SOXD, TOLCAS

NCBI Gene: 55553ENSG00000110693UniProt: P35712

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]

Primary Disease Associations & Inheritance

Tolchin-Le Caignec syndromeMIM #618971
AD
291
ClinVar variants
46
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— SOX6
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
46 Pathogenic / Likely Pathogenic· 162 VUS of 291 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.21LOEUF
pLI 1.000
Z-score 5.48
OE 0.09 (0.04–0.21)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.93Z-score
OE missense 0.75 (0.68–0.82)
339 obs / 454.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.09 (0.04–0.21)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.75 (0.68–0.82)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 4 / 42.6Missense obs/exp: 339 / 454.7Syn Z: 0.16

ClinVar Variant Classifications

291 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30
Likely Pathogenic16
VUS162
Likely Benign50
Benign27
Conflicting6
30
Pathogenic
16
Likely Pathogenic
162
VUS
50
Likely Benign
27
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
2
21
0
30
Likely Pathogenic
4
7
5
0
16
VUS
6
147
9
0
162
Likely Benign
0
12
18
20
50
Benign
0
5
12
10
27
Conflicting
—6
Total171736530291

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SOX6 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SOX6-related neurodevelopmental syndrome

strong
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
SRY-BOX 6; SOX6
MIM #607257 · *

Tolchin-Le Caignec syndrome

MIM #618971

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Robust gene expression programs underlie recurrent cell states and phenotype switching in melanoma.
Wouters J et al.·Nat Cell Biol
2020
N(6)-methyladenosine modification of CENPK mRNA by ZC3H13 promotes cervical cancer stemness and chemoresistance.
Lin X et al.·Mil Med Res
2022
Clinical implications and genetical insights of SOX6 expression in acute myeloid leukemia.
Li Y et al.·J Cancer Res Clin Oncol
2023
Precision Editing as a Therapeutic Approach for β-Hemoglobinopathies.
Paschoudi K et al.·Int J Mol Sci
2023Review
The Roles of Sox Family Genes in Sarcoma.
Li J et al.·Curr Drug Targets
2016Review
Single-Cell RNA Sequencing Reveals the Tumor Heterogeneity and Immunosuppressive Microenvironment in Urothelial Carcinoma.
Lyu T et al.·Cancer Sci
2025
Epigenetic Insights and Potential Modifiers as Therapeutic Targets in β-Thalassemia.
Zakaria NA et al.·Biomolecules
2021Review
Neurodevelopmental disorder with dystonia due to SOX6 mutations.
Schneider SA et al.·Mol Genet Genomic Med
2022Case report
Association between osteoporosis and menopause in relation to SOX6 rs297325 variant in Taiwanese women.
Hsu TL et al.·Menopause
2020
Single-Nucleus Landscape of Glial Cells and Neurons in Alzheimer's Disease.
Lu M et al.·Mol Neurobiol
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
SOX6 is a novel host factor that promotes hepatitis B virus replication by enhancing the transcriptional activity of enhancer I.
Song Y et al.·Antiviral Res
2026
Directed differentiation of functional corticospinal-like neurons from endogenous SOX6+/NG2+ cortical progenitors.
Ozkan A et al.·Elife
2026🔓 Open AccessFunctional
Sox9-dependent acquisition of a drug resistant "memory state" induces reciprocal expression of Sox6 and Sox7 in BRAF melanoma.
Abou-Hamad J et al.·Biochim Biophys Acta Mol Cell Res
2026
Transcriptomic and experimental validation identifies SOX6 and LDLRAD3 as key factors in vascular dementia.
Hu J et al.·J Gerontol A Biol Sci Med Sci
2026
A novel SOX6 + melanoma cell subtype promotes early microsatellite invasion in Asian acral melanoma through fatty acid transport disorder.
Lv C et al.·J Exp Clin Cancer Res
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools