SOX4

Chr 6

SRY-box transcription factor 4

Also known as: CSS10, EVI16, IDDSDF

NCBI Gene: 6659ENSG00000124766UniProt: Q06945

This intronless 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, such as syndecan binding protein (syntenin). The protein may function in the apoptosis pathway leading to cell death as well as to tumorigenesis and may mediate downstream effects of parathyroid hormone (PTH) and PTH-related protein (PTHrP) in bone development. The solution structure has been resolved for the HMG-box of a similar mouse protein. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

UniProtIntellectual developmental disorder with speech delay and dysmorphic facies
200
ClinVar variants
18
Pathogenic / LP
0.93
pLI score· haploinsufficient
0
Active trials
Clinical Summary— SOX4
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.93). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
18 Pathogenic / Likely Pathogenic· 146 VUS of 200 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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.
0.36LOEUF
pLI 0.927
Z-score 2.68
OE 0.00 (0.00–0.36)
Highly constrained

More LoF-intolerant than ~75% 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.
1.17Z-score
OE missense 0.77 (0.67–0.88)
150 obs / 196.0 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.0.00 (0.00–0.36)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.77 (0.67–0.88)
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.1.67
0≤1.21.6
LoF obs/exp: 0 / 8.3Missense obs/exp: 150 / 196.0Syn Z: -5.14

ClinVar Variant Classifications

200 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic11
VUS146
Likely Benign30
Benign1
Conflicting5
7
Pathogenic
11
Likely Pathogenic
146
VUS
30
Likely Benign
1
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
1
4
0
7
Likely Pathogenic
1
7
3
0
11
VUS
7
125
13
1
146
Likely Benign
2
4
2
22
30
Benign
0
0
1
0
1
Conflicting
—5
Total121372323200

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

View in ClinVar →

Protein Context — Lollipop Plot

SOX4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SOX4-related neurodevelopmental disease associated with mild dysmorphism

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — SOX4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Antiandrogen treatment induces stromal cell reprogramming to promote castration resistance in prostate cancer.
Wang H et al.·Cancer Cell
2023
Genotype-Phenotype Correlations in 208 Individuals with Coffin-Siris Syndrome.
Vasko A et al.·Genes (Basel)
2021
Identification and validation of glycolysis-related diagnostic signatures in diabetic nephropathy: a study based on integrative machine learning and single-cell sequence.
Wu X et al.·Front Immunol
2025
Senescent fibroblasts secrete CTHRC1 to promote cancer stemness in hepatocellular carcinoma.
Huang H et al.·Cell Commun Signal
2025
Clinical and molecular dissection of CAR T cell resistance in pancreatic cancer.
Aznar MA et al.·Cell Rep Med
2025Clinical trial
Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis.
Komatsu N et al.·Nat Med
2014
NAT10-mediated mRNA N4-acetylcytidine modification promotes bladder cancer progression.
Wang G et al.·Clin Transl Med
2022
Targeting eIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer.
Zhao N et al.·J Clin Invest
2023
Identification of SPP1(+) macrophages in promoting cancer stemness via vitronectin and CCL15 signals crosstalk in liver cancer.
Wang Y et al.·Cancer Lett
2024
A developmental biliary lineage program cooperates with Wnt activation to promote cell proliferation in hepatoblastoma.
Wu PV et al.·Nat Commun
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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