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

The protein encoded by this gene recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It acts during chondrocyte differentiation and, with steroidogenic factor 1, regulates transcription of the anti-Muellerian hormone (AMH) gene. Deficiencies lead to the skeletal malformation syndrome campomelic dysplasia, frequently with sex reversal. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

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

146 unique Pathogenic / Likely Pathogenic· 200 VUS of 543 total submissions

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 OE?0.00 (0.00–0.17)

0≤0.351.4

Missense OE?0.74 (0.66–0.82)

0≤0.61.4

Synonymous OE?1.24

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

This gene — mechanism propensity

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 · 61% of P/LP variants are LoF · LOEUF 0.17 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

Literature Evidence

DNDominant-negative SOX9 mutations in campomelic dysplasia.1

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 SOX2

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

References

ClinVar Variant Classifications

543 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic83

Likely Pathogenic63

VUS200

Likely Benign130

Benign31

Conflicting23

Pathogenic

Likely Pathogenic

200

VUS

130

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	60	17	6	0	83
Likely Pathogenic	29	34	0	0	63
VUS	5	186	7	2	200
Likely Benign	0	20	21	89	130
Benign	0	12	10	9	31
Conflicting	—				23
Total	94	269	44	100	530

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap SOX9 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →