SOX9

Chr 17AD

SRY-box transcription factor 9

Also known as: CMD1, CMPD1, ENH13, SRA1, SRXX2, SRXY10, TESCO

NCBI Gene: 6662 ENSG00000125398 UniProt: P48436 OMIM: 608160

The encoded transcription factor binds DNA to regulate chondrocyte differentiation and, together with steroidogenic factor 1, controls transcription of the anti-Müllerian hormone gene. Loss-of-function mutations cause autosomal dominant campomelic dysplasia, a skeletal malformation syndrome that frequently includes 46,XY or 46,XX sex reversal. The gene is highly intolerant to loss-of-function variation, consistent with the severe skeletal and gonadal developmental abnormalities observed in affected individuals.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

LOFmechanismADLOEUF 0.175 OMIM phenotypes

Clinical Summary— SOX9

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Gene-Disease Validity (ClinGen)

Cooks syndrome · ADLimited

Limited evidence — not for standalone diagnostic reporting

3 total gene-disease associations curated

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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.

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ClinVar Variants

52 unique Pathogenic / Likely Pathogenic· 152 VUS of 300 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SOX9

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

0.17LOEUF

pLI 0.998

Z-score 3.91

OE 0.00 (0.00–0.17)

Highly constrained

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

Missense Constraint

1.63Z-score

OE missense 0.74 (0.66–0.82)

230 obs / 310.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.00 (0.00–0.17)

0≤0.351.4

Missense OE0.74 (0.66–0.82)

0≤0.61.4

Synonymous OE1.24

0≤1.21.6

LoF obs/exp: 0 / 17.8Missense obs/exp: 230 / 310.9Syn Z: -2.26

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSOX9-related campomelic dysplasiaLOFAD

definitiveSOX9-related Pierre Robin sequenceOTHERAD

0.3196th %ile

GOF

0.2497th %ile

LOF

0.87top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 67% of P/LP variants are LoF · LOEUF 0.17

DN1 literature citation

Literature Evidence

DNDominant-negative SOX9 mutations in campomelic dysplasia.PMID:31389106

LOFWhereas mutations in the ORF of SOX9 cause haploinsufficiency and campomelic dysplasia, the effects of translocations 5-prime to SOX9 were unclear and prompted Wunderle et al. (1998) to test whether these rearrangements also cause haploinsufficiency by altering spatial and temporal expression of SOXPMID:9724758

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