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

This 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 activator after forming a protein complex with other proteins. This protein acts as a nucleocytoplasmic shuttle protein and is important for neural crest and peripheral nervous system development. Mutations in this gene are associated with Waardenburg-Shah and Waardenburg-Hirschsprung disease. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.213 OMIM phenotypes

Clinical Summary— SOX10

🧬

Gene-Disease Validity (ClinGen)

Waardenburg syndrome type 4C · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

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.

📋

ClinVar Variants

236 unique Pathogenic / Likely Pathogenic· 164 VUS of 582 total submissions

💊

Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — SOX10

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?

0.21LOEUF

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 OE?0.00 (0.00–0.21)

0≤0.351.4

Missense OE?0.55 (0.48–0.63)

0≤0.61.4

Synonymous OE?0.89

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

This gene — mechanism propensity

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 · 75% of P/LP variants are LoF · LOEUF 0.21 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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.1

GOFSox10 gain-of-function causes XX sex reversal in mice: implications for human 22q-linked disorders of sex development2

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/+)).3

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

582 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic138

Likely Pathogenic98

VUS164

Likely Benign110

Benign23

Conflicting38

138

Pathogenic

Likely Pathogenic

164

VUS

110

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	117	20	1	0	138
Likely Pathogenic	61	35	2	0	98
VUS	9	138	12	5	164
Likely Benign	0	11	20	79	110
Benign	0	5	15	3	23
Conflicting	—				38
Total	187	209	50	87	571

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

View in ClinVar →

27 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap SOX10 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →