SOX10

Chr 22AD

SRY-box transcription factor 10

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

NCBI Gene: 6663ENSG00000100146UniProt: P56693

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]

Primary Disease Associations & Inheritance

PCWH syndromeMIM #609136
AD
Waardenburg syndrome, type 2E, with or without neurologic involvementMIM #611584
AD
Waardenburg syndrome, type 4CMIM #613266
AD
UniProtPeripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung disease
597
ClinVar variants
257
Pathogenic / LP
0.99
pLI score· haploinsufficient
1
Active trials
Clinical Summary— SOX10
⚡
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
257 Pathogenic / Likely Pathogenic· 160 VUS of 597 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.21)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.55 (0.48–0.63)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.89
0≤1.21.6
LoF obs/exp: 0 / 14.3Missense obs/exp: 166 / 301.1Syn Z: 1.01

ClinVar Variant Classifications

597 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic160
Likely Pathogenic97
VUS160
Likely Benign108
Benign23
Conflicting38
160
Pathogenic
97
Likely Pathogenic
160
VUS
108
Likely Benign
23
Benign
38
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
72
18
70
0
160
Likely Pathogenic
43
35
19
0
97
VUS
3
133
19
5
160
Likely Benign
0
11
19
78
108
Benign
0
5
15
3
23
Conflicting
—38
Total11820214286586

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.

Gene2Phenotype Curations

SOX10-related Kallmann syndrome with deafness

definitive
ADLoss Of FunctionAbsent Gene Product
Ear
G2P ↗

SOX10-related Waardenburg syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersEyeSkin
G2P ↗

SOX10-related Yemenite deaf-blind hypopigmentation syndrome

definitive
ADUndeterminedUncertain
Dev. DisordersEyeSkin
G2P ↗

SOX10-related peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease

definitive
ADDominant NegativeAltered Gene Product Structure
Dev. DisordersEyeSkin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
SRY-BOX 10; SOX10
MIM #602229 · *

PCWH syndrome

MIM #609136

Molecular basis of disorder known

Autosomal dominant

Waardenburg syndrome, type 2E, with or without neurologic involvement

MIM #611584

Molecular basis of disorder known

Autosomal dominant

Waardenburg syndrome, type 4C

MIM #613266

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.
Takahashi M et al.·Cell
2024
Review and update of mutations causing Waardenburg syndrome.
Pingault V et al.·Hum Mutat
2010Review
SOX10: 20 years of phenotypic plurality and current understanding of its developmental function.
Pingault V et al.·J Med Genet
2022Review
Immunohistochemistry in melanocytic lesions: Updates with a practical review for pathologists.
Saleem A et al.·Semin Diagn Pathol
2022Review
Robust gene expression programs underlie recurrent cell states and phenotype switching in melanoma.
Wouters J et al.·Nat Cell Biol
2020
De novo variants underlying monogenic syndromes with intellectual disability in a neurodevelopmental cohort from India.
Pande S et al.·Eur J Hum Genet
2024Cohort
A glia-enriched stem cell 3D model of the human brain mimics the glial-immune neurodegenerative phenotypes of multiple sclerosis.
Fagiani F et al.·Cell Rep Med
2024Functional
SOX10 mediates glioblastoma cell-state plasticity.
Man KH et al.·EMBO Rep
2024
Targeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma.
Capparelli C et al.·Nat Commun
2022
Genetic etiology of non-syndromic hearing loss in Europe.
Del Castillo I et al.·Hum Genet
2022Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Melanoma

Effects of Anti-PD1 Adjuvant Checkpoint Blockade Immunotherapy on Atypical/Dysplastic Nevi

RECRUITING
NCT06599619John KirkwoodStarted 2025-02-20
Single agent, adjuvant anti-PD1 therapy

External Resources

Links to major genomics databases and tools