PAX3

Chr 2ADSomaticAR

paired box 3

Also known as: CDHS, HUP2, PAX-3, WS1, WS3

NCBI Gene: 5077 ENSG00000135903 UniProt: P23760 OMIM: 606597

This transcription factor contains a paired box domain and homeodomain and regulates cell proliferation, migration, and apoptosis during neural development and myogenesis. Mutations cause Waardenburg syndrome types 1 and 3 (characterized by congenital hearing loss and pigmentary abnormalities), craniofacial-deafness-hand syndrome, and alveolar rhabdomyosarcoma through both germline and somatic mechanisms. The gene follows autosomal dominant inheritance for the syndromic conditions and autosomal recessive inheritance for some presentations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of the paired box (PAX) family of transcription factors. Members of the PAX family typically contain a paired box domain and a paired-type homeodomain. These genes play critical roles during fetal development. Mutations in paired box gene 3 are associated with Waardenburg syndrome, craniofacial-deafness-hand syndrome, and alveolar rhabdomyosarcoma. The translocation t(2;13)(q35;q14), which represents a fusion between PAX3 and the forkhead gene, is a frequent finding in alveolar rhabdomyosarcoma. Alternative splicing results in transcripts encoding isoforms with different C-termini. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/Somatic/ARLOEUF 0.474 OMIM phenotypes

Clinical Summary— PAX3

🧬

Gene-Disease Validity (ClinGen)

Waardenburg syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

💊

Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.47LOEUF

pLI 0.241

Z-score 3.51

OE 0.24 (0.13–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.62Z-score

OE missense 0.73 (0.65–0.82)

206 obs / 282.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.24 (0.13–0.47)

0≤0.351.4

Missense OE?0.73 (0.65–0.82)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 6 / 24.9Missense obs/exp: 206 / 282.5Syn Z: -0.68

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePAX3-related craniofacial-deafness-hand syndromeLOFAD

moderatePAX3-related Waardenburg syndrome (biallelic)OTHERAR

definitivePAX3-related Waardenburg syndrome (monoallelic)LOFAD

This gene — mechanism propensity

0.73top 25%

GOF

0.5170th %ile

LOF

0.56top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.47 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DNprediction above median · 1 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

DNHeterozygous mutations could either reflect a unique dominant-negative effect or possibly the contribution of other unlinked genetic modifiers in determining the phenotype.1

GOFThe transcriptional activator PAX3-FKHR rescues the defects of Pax3 mutant mice but induces a myogenic gain-of-function phenotype with ligand-independent activation of Met signaling in vivo2

LOFWaardenburg's syndrome patients have mutations in the human homologue of the Pax-3 paired box gene3

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

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

PAX3 · protein map & ClinVar variants

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

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Rhabdomyosarcoma

A Clinical Study on the Efficacy and Safety of All-trans Retinoic Acid Combined With VAC Regimen in the Treatment of Intermediate-to-high-risk Rhabdomyosarcoma

NOT YET RECRUITING

NCT07355855Phase PHASE2Fudan UniversityStarted 2026-01

ATRA+VACATRA+VAC+Anlotinib

Cerebral Palsy (CP)

Spastic Myopathy in Adults With Cerebral Palsy

RECRUITING

NCT07293988Phase NANeurolocoStarted 2022-05-19

Guided Self-rehabilitation ContractConventional therapy group

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

Full-Text Mentions