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…

Primary Disease Associations & Inheritance

PCWH syndromeMIM #609136

Waardenburg syndrome, type 2E, with or without neurologic involvementMIM #611584

Waardenburg syndrome, type 4CMIM #613266

UniProtPeripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung disease

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Waardenburg syndrome type 4C · AD · ClinGen 2018

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

618

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.21

LOEUF· LoF intol.

Multiple*

Mechanism· G2P

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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 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

Background carrier burden — how many people carry a rare variant somewhere in SOX10?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 150

499 rare PASS variants

Rare truncating (LoF)

1 in 660

17 rare PASS variants

Rare synonymous (reference)

1 in 170

307 rare PASS variants

Rare missense and truncating variants are carried at similar rates in SOX10; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 220	1 in 5,300
South Asian	~43k	1 in 120	none seen
Remaining (unassigned)	~30k	1 in 120	≈ 1 in 30,000
European (Finnish)	~27k	1 in 320	≈ 1 in 6,300
Admixed American	~22k	1 in 150	1 in 2,500
African / African American	~21k	1 in 140	1 in 3,800
East Asian	~20k	1 in 140	1 in 1,400
Ashkenazi Jewish	~13k	1 in 2,200	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 150	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.