PAX9
protein-codingpaired box 9, the group of Paired boxes
Gene summary
This gene is a member of the paired box (PAX) family of transcription factors. Members of this gene family typically contain a paired box domain, an octapeptide, and a paired-type homeodomain. These genes play critical roles during fetal development and cancer growth. Mice lacking this gene exhibit impaired development of organs, musculature and the skeleton, including absent and abnormally developed teeth, and neonatal lethality. Mutations in the human gene are associated with selective tooth agenesis-3. [provided by RefSeq, Sep 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~21.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0011477
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0005486
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011477
Submitter: ClinGen
*PAX9* was first reported in relation to autosomal dominant *PAX9*-related selective tooth agenesis in 2000 (Stockton et al., PMID: 10615120). A single disease assertion was identified and curated for PAX9. Seven variants (frameshift, nonsense) that have been reported in seven probands with selective tooth agenesis in three publications (PMIDs: 10615120, 37056289, 36071541) are included in this curation. Variants in this gene segregated with disease in 19 additional family members (Stockton et al., PMID: 10615120). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function, though functional data supports a dominant-negative effect for at least one missense variant (Pan et al. 2025, PMID: 40227334). This gene-disease relationship is also supported by experimental evidence, including expression in relevant tissue, functional alteration in non-patient cells, and two mouse models (PMIDs: 40227334, 17394220, 9732271, 16236760). In summary, there is definitive evidence supporting the relationship between *PAX9* and autosomal dominant *PAX9*-related selective tooth agenesis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date April 17, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0011477
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011477
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Dental
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PAX9 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001372076.1. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 4 | 18 | 1 | 24 | |
| missense | 10 | 6 | 79 | 6 | 1 | 102 |
| nonsense | 10 | 2 | 12 | |||
| start loss | 4 | 4 | ||||
| frameshift | 21 | 8 | 1 | 30 | ||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 2 | 4 | ||
| Total | 47 | 17 | 86 | 24 | 2 | 176 |
Highest pathogenic variant AF is 0.000001239271
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001359005.1 | 4 | MANE Select | |
| Ensembl | ENSP00000355245.6 | 4 | MANE Select | |
| RefSeq | NP_006185.1 | 4 | Standard | |
| Ensembl | ENSP00000384817.2 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pax9 | Danio rerio | Structure: neurocranium Quality: decreased length abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Endoderm Differentiation
Biological Process
- endoderm development
- odontogenesis
- regulation of odontogenesis
- negative regulation of transcription, DNA-templated
- positive regulation of transcription by RNA polymerase II
Molecular Function
- RNA polymerase II regulatory region sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- protein binding
Cellular Component
- nucleus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000361487
- Coding exons
- 4
- Length
- 22148
- Individuals with no LoFs
- 125745
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125748
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.619 | 173 | 197 | 0.876 | 0.00000968 | 2177 |
| Missense (PolyPhen) | 88 | 106.35 | 0.82749 | 1214 | ||
| Synonymous | -1.12 | 100 | 86.8 | 1.15 | 0.00000459 | 743 |
| Loss of Function | 2.51 | 3 | 12.6 | 0.237 | 5.53e-7 | 138 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcription factor required for normal development of thymus, parathyroid glands, ultimobranchial bodies, teeth, skeletal elements of skull and larynx as well as distal limbs. {ECO:0000250, ECO:0000269|PubMed:12657635}.;
- Disease
- DISEASE: Tooth agenesis, selective, 3 (STHAG3) [MIM:604625]: A form of selective tooth agenesis, a common anomaly characterized by the congenital absence of one or more teeth. Selective tooth agenesis without associated systemic disorders has sometimes been divided into 2 types: oligodontia, defined as agenesis of 6 or more permanent teeth, and hypodontia, defined as agenesis of less than 6 teeth. The number in both cases does not include absence of third molars (wisdom teeth). {ECO:0000269|PubMed:12786960}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.240
Intolerance Scores
- LoFtool
- 0.0763
- RVIS EVS
- 0.06
- RVIS percentile EVS
- 58.53
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.899
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |