SOX4

Chr 6AD

SRY-box transcription factor 4

Also known as: CSS10, EVI16, IDDSDF

NCBI Gene: 6659 ENSG00000124766 UniProt: Q06945 OMIM: 184430

The SOX4 protein is a transcription factor that regulates embryonic development, cell fate determination, and skeletal muscle differentiation by binding to specific DNA sequences and activating gene expression. Mutations cause autosomal dominant intellectual developmental disorder with speech delay and dysmorphic facies. This gene is highly constrained against loss-of-function variants (pLI 0.93, LOEUF 0.36), indicating that mutations are likely to have significant clinical consequences.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.361 OMIM phenotype

Clinical Summary— SOX4

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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.

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ClinVar Variants

26 unique Pathogenic / Likely Pathogenic· 189 VUS of 273 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SOX4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

1.17Z-score

OE missense 0.77 (0.67–0.88)

150 obs / 196.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.36)

0≤0.351.4

Missense OE?0.77 (0.67–0.88)

0≤0.61.4

Synonymous OE?1.67

0≤1.21.6

LoF obs/exp: 0 / 8.3Missense obs/exp: 150 / 196.0Syn Z: -5.14

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongSOX4-related neurodevelopmental disease associated with mild dysmorphismOTHERAD

This gene — mechanism propensity

0.2698th %ile

GOF

0.2895th %ile

LOF

0.89top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 46% of P/LP variants are LoF · LOEUF 0.36

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

273 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic18

VUS189

Likely Benign41

Benign7

Conflicting10

Pathogenic

Likely Pathogenic

189

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	2	0	0	8
Likely Pathogenic	6	12	0	0	18
VUS	16	170	2	1	189
Likely Benign	2	7	1	31	41
Benign	0	3	2	2	7
Conflicting	—				10
Total	30	194	5	34	273

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap SOX4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →