SOX10

Chr 22AD

SRY-box transcription factor 10

Also known as: DOM, PCWH, SOX-10, WS2E, WS4, WS4C

NCBI Gene: 6663 ENSG00000100146 UniProt: P56693 OMIM: 602229

This protein is a transcription factor essential for neural crest and peripheral nervous system development that acts as a transcriptional activator and nucleocytoplasmic shuttle protein. Loss-of-function mutations cause autosomal dominant Waardenburg syndrome (types 2E and 4C) and PCWH syndrome, with variable neurologic involvement and Hirschsprung disease. The high constraint scores (pLI 0.99, LOEUF 0.21) reflect strong intolerance to haploinsufficiency, consistent with the dominant inheritance pattern.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

MultiplemechanismADLOEUF 0.213 OMIM phenotypes

Clinical Summary— SOX10

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Gene-Disease Validity (ClinGen)

Waardenburg syndrome type 4C · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

198 unique Pathogenic / Likely Pathogenic· 150 VUS of 504 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 — SOX10

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.21LOEUF

pLI 0.992

Z-score 3.51

OE 0.00 (0.00–0.21)

Highly constrained

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

Missense Constraint

2.77Z-score

OE missense 0.55 (0.48–0.63)

166 obs / 301.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.00 (0.00–0.21)

0≤0.351.4

Missense OE0.55 (0.48–0.63)

0≤0.61.4

Synonymous OE0.89

0≤1.21.6

LoF obs/exp: 0 / 14.3Missense obs/exp: 166 / 301.1Syn Z: 1.01

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSOX10-related Kallmann syndrome with deafnessLOFAD

definitiveSOX10-related Waardenburg syndromeLOFAD

definitiveSOX10-related Yemenite deaf-blind hypopigmentation syndromeOTHERAD

definitiveSOX10-related peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung diseaseDNAD

0.3792th %ile

GOF

0.2994th %ile

LOF

0.86top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). 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 · 72% of P/LP variants are LoF · LOEUF 0.21

DN1 literature citation

GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNFunctional analysis of Waardenburg syndrome-associated PAX3 and SOX10 mutations: report of a dominant-negative SOX10 mutation in Waardenburg syndrome type II.PMID:21965087

GOFSox10 gain-of-function causes XX sex reversal in mice: implications for human 22q-linked disorders of sex developmentPMID:19933217

LOFHaploinsufficiency for the transcription factor SOX10 is associated with the pigmentary deficiencies of Waardenburg syndrome (WS) and is modeled in Sox10 haploinsufficient mice (Sox10(LacZ/+)).PMID:18397875

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