SOX10

Chr 22AD

SRY-box transcription factor 10

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

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.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
MultiplemechanismADLOEUF 0.213 OMIM phenotypes
Clinical SummarySOX10
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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.
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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
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GeneReview available — SOX10
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.21LOEUF
pLI 0.992
Z-score 3.51
OE 0.00 (0.000.21)
Highly constrained

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

Missense Constraint
2.77Z-score
OE missense 0.55 (0.480.63)
166 obs / 301.1 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.00 (0.000.21)
00.351.4
Missense OE0.55 (0.480.63)
00.61.4
Synonymous OE0.89
01.21.6
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
DN
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.

ClinVar Variant Classifications

504 submitted variants in ClinVar

Classification Summary

Pathogenic120
Likely Pathogenic78
VUS150
Likely Benign99
Benign16
Conflicting30
120
Pathogenic
78
Likely Pathogenic
150
VUS
99
Likely Benign
16
Benign
30
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
97
15
8
0
120
Likely Pathogenic
46
30
2
0
78
VUS
7
128
11
4
150
Likely Benign
0
10
18
71
99
Benign
0
5
10
1
16
Conflicting
30
Total1501884976493

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

View in ClinVar →

Protein Context — Lollipop Plot

SOX10 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗