PAX3

Chr 2

paired box 3

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

NCBI Gene: 5077 ENSG00000135903 UniProt: P23760

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.

GeneReviews 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]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtWaardenburg syndrome 1

UniProtWaardenburg syndrome 3

UniProtCraniofacial-deafness-hand syndrome

UniProtRhabdomyosarcoma 2

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Waardenburg syndrome · AD · ClinGen 2017

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

159

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.47

LOEUF

LOF*

Mechanism· G2P

📖

GeneReview available — PAX3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Background carrier burden — how many people carry a rare variant somewhere in PAX3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 96

661 rare PASS variants

Rare truncating (LoF)

1 in 910

38 rare PASS variants

Rare synonymous (reference)

1 in 160

312 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PAX3. 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 130	1 in 7,100
South Asian	~43k	1 in 140	1 in 5,400
Remaining (unassigned)	~30k	1 in 100	1 in 890
European (Finnish)	~27k	1 in 650	1 in 4,400
Admixed American	~22k	1 in 100	1 in 3,800
African / African American	~21k	1 in 140	1 in 1,200
East Asian	~20k	1 in 110	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 280	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 91	1 in 480

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.

Exome coverage (gnomAD): All 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓