PAX3

Chr 2ADSomaticAR

paired box 3

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

NCBI Gene: 5077ENSG00000135903UniProt: P23760

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]

Primary Disease Associations & Inheritance

Craniofacial-deafness-hand syndromeMIM #122880
AD
Rhabdomyosarcoma 2, alveolarMIM #268220
Somatic
Waardenburg syndrome, type 1MIM #193500
AD
Waardenburg syndrome, type 3MIM #148820
ADAR
533
ClinVar variants
178
Pathogenic / LP
0.24
pLI score
2
Active trials
Clinical Summary— PAX3
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.
📋
ClinVar Variants
178 Pathogenic / Likely Pathogenic· 140 VUS of 533 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.47LOEUF
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?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.
1.62Z-score
OE missense 0.73 (0.65–0.82)
206 obs / 282.5 exp
Tolerant

Mild missense constraint

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.0.24 (0.13–0.47)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.73 (0.65–0.82)
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.1.08
0≤1.21.6
LoF obs/exp: 6 / 24.9Missense obs/exp: 206 / 282.5Syn Z: -0.68

ClinVar Variant Classifications

533 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic115
Likely Pathogenic63
VUS140
Likely Benign79
Benign22
Conflicting9
115
Pathogenic
63
Likely Pathogenic
140
VUS
79
Likely Benign
22
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
46
17
51
1
115
Likely Pathogenic
17
37
8
1
63
VUS
3
116
18
3
140
Likely Benign
0
6
37
36
79
Benign
0
0
20
2
22
Conflicting
—9
Total6617613443428

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

View in 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.

Gene2Phenotype Curations

PAX3-related craniofacial-deafness-hand syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Ear
G2P ↗

PAX3-related Waardenburg syndrome (biallelic)

moderate
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variant

PAX3-related Waardenburg syndrome (monoallelic)

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersSkin
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
PAIRED BOX GENE 3; PAX3
MIM #606597 · *

Craniofacial-deafness-hand syndrome

MIM #122880

Molecular basis of disorder known

Autosomal dominant

Rhabdomyosarcoma 2, alveolar

MIM #268220

Molecular basis of disorder known

Somatic mutation

Waardenburg syndrome, type 1

MIM #193500

Molecular basis of disorder known

Autosomal dominant

Waardenburg syndrome, type 3

MIM #148820

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Review and update of mutations causing Waardenburg syndrome.
Pingault V et al.·Hum Mutat
2010Review
Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions.
Lupiáñez DG et al.·Cell
2015
Rhabdomyosarcoma in children and young adults.
Chen S et al.·Virchows Arch
2025Review
FAK Signaling in Rhabdomyosarcoma.
Perrone C et al.·Int J Mol Sci
2020Review
Therapeutic targeting of ATR in alveolar rhabdomyosarcoma.
Dorado García H et al.·Nat Commun
2022
Entinostat as a combinatorial therapeutic for rhabdomyosarcoma.
Chauhan S et al.·Sci Rep
2024
The expression and function of PAX3 in development and disease.
Boudjadi S et al.·Gene
2018Review
Dominance and homozygosity.
Zlotogora J·Am J Med Genet
1997Review
Genes, chromosomes, and rhabdomyosarcoma.
Anderson J et al.·Genes Chromosomes Cancer
1999Review
Towards directed therapy for fusion-positive rhabdomyosarcoma.
Turco GM et al.·Pharmacol Ther
2025Review
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
Cerebral Palsy (CP)

Spastic Myopathy in Adults With Cerebral Palsy

RECRUITING
NCT07293988Phase NANeurolocoStarted 2022-05-19
Guided Self-rehabilitation ContractConventional therapy group
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

External Resources

Links to major genomics databases and tools