PAX9

Summary

PAX9 (paired box 9, HGNC:8623) is a protein-coding gene on chromosome 14q13.3, encoding Paired box protein Pax-9 (P55771). Transcription factor required for normal development of thymus, parathyroid glands, ultimobranchial bodies, teeth, skeletal elements of skull and larynx as well as distal limbs. It is haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 5083 — RefSeq curated summary.

At a glance

• Gene–disease (curated): tooth agenesis, selective, 3 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 228 total — 47 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 31
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 10 downstream targets (CollecTRI)
• MANE Select transcript: NM_001372076

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8623
Approved symbol	PAX9
Name	paired box 9
Location	14q13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000198807
Ensembl biotype	protein_coding
OMIM	167416
Entrez	5083

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000361487, ENST00000402703, ENST00000553267, ENST00000554201, ENST00000555639, ENST00000557107

RefSeq mRNA: 2 — MANE Select: NM_001372076 NM_001372076, NM_006194

CCDS: CCDS9662

Canonical transcript exons

ENST00000361487 — 4 exons

Exon	Start	End
ENSE00000889736	36662897	36663523
ENSE00001124036	36666462	36666601
ENSE00001356280	36661860	36662093
ENSE00001840784	36676198	36679362

Expression profiles

Bgee: expression breadth ubiquitous, 128 present calls, max score 97.97.

FANTOM5 (CAGE): breadth broad, TPM avg 5.0899 / max 396.1681, expressed in 546 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
139294	4.3727	519
139290	0.2864	54
139297	0.1582	82
139293	0.0886	43
139291	0.0852	34
139292	0.0395	26
139295	0.0351	14
139296	0.0241	8

Top tissues by expression

254 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	97.97	gold quality
parotid gland	UBERON:0001831	96.42	gold quality
esophagus mucosa	UBERON:0002469	95.26	gold quality
oral cavity	UBERON:0000167	93.21	gold quality
esophagus squamous epithelium	UBERON:0006920	92.84	gold quality
epithelium of esophagus	UBERON:0001976	92.03	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.69	gold quality
pharyngeal mucosa	UBERON:0000355	86.74	gold quality
amniotic fluid	UBERON:0000173	85.58	gold quality
saliva-secreting gland	UBERON:0001044	85.57	gold quality
oocyte	CL:0000023	84.74	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.56	gold quality
secondary oocyte	CL:0000655	83.34	gold quality
minor salivary gland	UBERON:0001830	83.28	gold quality
mouth mucosa	UBERON:0003729	82.46	gold quality
tonsil	UBERON:0002372	82.39	gold quality
bronchial epithelial cell	CL:0002328	82.30	gold quality
mucosa of paranasal sinus	UBERON:0005030	81.68	gold quality
body of tongue	UBERON:0011876	80.46	gold quality
tongue	UBERON:0001723	80.45	gold quality
epithelium of nasopharynx	UBERON:0001951	80.01	gold quality
squamous epithelium	UBERON:0006914	79.75	gold quality
nasal cavity mucosa	UBERON:0001826	79.54	gold quality
superior surface of tongue	UBERON:0007371	78.83	gold quality
epithelium of bronchus	UBERON:0002031	78.74	gold quality
bronchus	UBERON:0002185	78.47	gold quality
esophagus	UBERON:0001043	77.61	gold quality
tongue squamous epithelium	UBERON:0006919	77.40	silver quality
buccal mucosa cell	CL:0002336	75.59	gold quality
trachea	UBERON:0003126	74.58	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.55

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

10 targets.

Target	Regulation
BCL2	Activation
BMP4	Unknown
CALCA	Unknown
CIP2A
FGF10	Activation
MSX1	Activation
NKX3-2	Unknown
OSR2	Unknown
SHH
TK1	Activation

JASPAR motifs

Motif	Name	Family
MA0781.1	PAX9	Paired domain only
MA0781.2	PAX9	Paired domain only

JASPAR matrix evidence (PMIDs): PMID:19132093

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• haploinsufficiency is associated with autosomal dominant hypodontia (PMID:11941488)
• Report a case of erroneous direct sequencing, in which a single nucleotide polymorphism (SNP) in the human PAX9 gene was mistyped due to allele-dependent PCR amplification. (PMID:12107448)
• might be involved in the genetic control of cuspid malpositions connected with the specific expression of third molar hypodontia (PMID:12490878)
• BF-1 and PAX9 interact with PLU-1 via a novel conserved sequence motif (Ala-X-Ala-Ala-X-Val-Pro-X4-Val-Pro-X8-Pro, termed the VP motif) (PMID:12657635)
• G151A transition might be responsible for sporadic form of tooth agenesis (PMID:12786960)
• There was a significant reduction in PAX9 expression in fetuses with the Jarcho-Levin syndrome. (PMID:12833407)
• PAX9 has a role in tooth development in humans (PMID:14607846)
• A missense mutation in the paired domain of PAX9 causes non-syndromic anodontia. (PMID:14689302)
• mutation of the initiation codon causes oligodontia (PMID:15615874)
• The functional defects in DNA binding of mutant 109(InsG) PAX9 and 139(C–> T) PAX9, as well as loss-of-function of PAX9 most likely result in its haploinsufficiency during the patterning of dentition and the subsequent loss of posterior teeth. (PMID:16086281)
• Sequencing of PAX9 gene revealed a novel frameshift mutation and a novel missense mutation in Chinese patients with oligodontia. (PMID:16191360)
• Mutations in PAX9 constitute a causative factor in nonsyndromic oligodontia. (PMID:16333316)
• Ile87Phe protein shows that both wild-type and mutant proteins are synthesized in mammalian cells and that the mutation does not alter the nuclear localization of the mutant protein in a family with molar oligodontia. (PMID:16479262)
• calcitonin gene expression could be directly activated by Nkx2.1, whereas Pax9 is not involved in transcription from the 2kbp calcitonin promoter (PMID:17412341)
• A novel nonsense mutation in PAX9 is associated with marked variability in number of missing teeth. (PMID:17697174)
• Missense mutation in the paired domain of human PAX9 causes oligodontia (PMID:17910065)
• A mutation was identified in six subjects in three generations affected by oligodontia. PAX9 mutation was observed in the paired box (exon 2); this was a heterozygote transition of C175 to T, implying the change of arginine 59 for a termination codon. (PMID:18028048)
• the four PAX9 polymorphisms alone have a non-significant main effect on the risk of tooth agenesis but the AGGC haplotype may have a protective effect associated with a decreased risk of tooth agenesis (PMID:18353002)
• genotype-phenotype correlations between PAX9 mutations and dental anomalies can be drawn (PMID:18445003)
• Smaller tooth crown dimensions recorded in the affected family members show that the effect of the PAX9 mutation is seen not only in the congenitally missing teeth but also in smaller crown size throughout the dentition. (PMID:18653171)
• 2 novel missense mutations, gly6arg (G6R) and ser43lys (S43K), in the paired domain of PAX9 in Chinese patients with varying degrees of nonsyndromic tooth agenesis, are reported. (PMID:18701815)
• investigated the clinical implications of lung developmental transcription factors TTF-1, NKX2-8, and PAX9 (PMID:19279207)
• Loss binding of pax9 to promoter correlated well with the severity of the tooth agenesis pattern in vivo. (PMID:19429910)
• A family with tooth agenesis had a homozygous point mutation at the 718 position (G to C) in exon 3 (a nonpaired domain) of PAX9. (PMID:19641755)
• Families with a posterior pattern of tooth agenesis showed changes in the PAX9 gene. (PMID:19816326)
• The findings in this patient illustrate the role of the PAX9 gene in tooth development and provide the first example of a de novo deletion of 14q13.3 manifesting primarily with oligodontia. (PMID:20485064)
• PAX9 and MSX1 gene mutation can cause different phenotypes of tooth agenesis. (PMID:20602873)
• mutations of the PAX9 gene may represent polymorphism associated with sporadic oligodontia (PMID:20618716)
• A polymorphism in the PAX9 gene was detected in individuals with maxillary lateral incisor agenesis, the frequency of which was not, however, statistically different from that in the control population. (PMID:20660504)
• investigation of transcriptional activity of specific regions of promoter region of PAX9 gene: sequences present between -1106 and +92 are important for expression of PAX9 (PMID:20941745)
• 322insG mutation causes insufficient function of PAX9 protein and haploinsufficiency as a genetic model of familial non-syndromic oligodontia (PMID:21098475)
• Common variants located out of the DNA binding domain of the PAX9 gene can be related to tooth agenesis. (PMID:21111400)
• a set of variants in PAX9 and 101 other genes related with dentition can define at least some dental morphological differences between Sub-Saharan Africans and non-Africans, probably associated with adaptations after the modern human exodus from Africa. (PMID:21298044)
• This study describes how the same mutation is responsible for a form of dental agenesis–less severe in the number of missing teeth–leading to hypodontia instead of oligodontia. Mutations of the same gene cause different phenotypes. (PMID:21434731)
• A novel g.-1258G>A mutation in a conserved putative regulatory element of PAX9 is associated with autosomal dominant molar hypodontia. (PMID:21443745)
• findings may imply that the PAX9 A240P mutation is a risk factor for oligodontia in the Chinese population. (PMID:21530942)
• a cohort of 93 Swedish probands with non-syndromic, isolated oligodontia, mutations were identified in the EDARADD), AXIN2, MSX1, and PAX9 genes (PMID:21626677)
• reduced transcriptional activity of the novel nonsense codon mutated PAX9 protein suggested that the severe phenotype may result from haploinsufficiency of PAX9. (PMID:22058014)
• Pax9hapl a may have a protective effect against sporadic oligodontia (PMID:22185249)
• Two novel missense mutations in Chinese families causing oligodontia: Leu27Pro (L27P) and Ile29Thr (I29T) in the paired-domain of PAX9. Analysis of homologous PAX proteins indicated that these two substitutions may affect the function of the PAX9 protein. (PMID:22277187)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pax9	ENSDARG00000053829
mus_musculus	Pax9	ENSMUSG00000001497
rattus_norvegicus	Pax9	ENSRNOG00000065348

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PITX1 (ENSG00000069011), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), CRX (ENSG00000105392), EVX1 (ENSG00000106038), PAX4 (ENSG00000106331), NOBOX (ENSG00000106410), PITX3 (ENSG00000107859), PHOX2B (ENSG00000109132), OTX1 (ENSG00000115507), PRRX1 (ENSG00000116132), VSX2 (ENSG00000119614), ESX1 (ENSG00000123576), PAX8 (ENSG00000125618), PAX1 (ENSG00000125813), RHOXF2 (ENSG00000131721), GSC (ENSG00000133937), RAX (ENSG00000134438), PAX3 (ENSG00000135903), ALX3 (ENSG00000156150), HESX1 (ENSG00000163666), PITX2 (ENSG00000164093), UNCX (ENSG00000164853), PHOX2A (ENSG00000165462), OTX2 (ENSG00000165588), DRGX (ENSG00000165606), PRRX2 (ENSG00000167157), SHOX2 (ENSG00000168779), OTP (ENSG00000171540), RAX2 (ENSG00000173976), EVX2 (ENSG00000174279), PROP1 (ENSG00000175325), ISX (ENSG00000175329), ALX1 (ENSG00000180318), MIXL1 (ENSG00000185155)

Protein

Protein identifiers

Paired box protein Pax-9 — P55771 (reviewed: P55771)

All UniProt accessions (3): P55771, A0A669KBA7, Q2L4T1

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Interacts with KDM5B.

Subcellular location. Nucleus.

Disease relevance. 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). The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (2): NP_001359005, NP_006185 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001523	Paired_dom	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR043182	PAIRED_DNA-bd_site	Conserved_site
IPR043565	PAX_fam	Family

Pfam: PF00292

UniProt features (11 total): region of interest 3, mutagenesis site 3, sequence variant 2, chain 1, DNA-binding region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55771-F1	64.12	0.35

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (3):

Position	Phenotype
173–174	abolishes interaction with kdm5b.
179–180	abolishes interaction with kdm5b.
189	abolishes interaction with kdm5b.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 265 (showing top): MORF_RAGE, RNGTGGGC_UNKNOWN, MODULE_52, GOBP_BODY_MORPHOGENESIS, MORF_FLT1, BENPORATH_ES_WITH_H3K27ME3, MORF_MSH3, MODULE_45, MORF_BRCA1, MORF_ATRX, MORF_ESR1, MODULE_16, MORF_RAD51L3, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, MYOD_01

GO Biological Process (9): regulation of transcription by RNA polymerase II (GO:0006357), endoderm development (GO:0007492), odontogenesis (GO:0042476), regulation of odontogenesis (GO:0042481), negative regulation of DNA-templated transcription (GO:0045892), face morphogenesis (GO:0060325), cellular response to growth factor stimulus (GO:0071363), regulation of DNA-templated transcription (GO:0006355), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (7): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), sequence-specific double-stranded DNA binding (GO:1990837), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (4): chromatin (GO:0000785), nucleoplasm (GO:0005654), nucleolus (GO:0005730), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
cellular anatomical structure	2
nuclear lumen	2
tissue development	1
animal organ morphogenesis	1
odontogenesis	1
regulation of animal organ morphogenesis	1
negative regulation of RNA biosynthetic process	1
anatomical structure morphogenesis	1
head morphogenesis	1
face development	1
response to growth factor	1
cellular response to endogenous stimulus	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
transcription cis-regulatory region binding	1
nucleic acid binding	1
binding	1
chromosome	1
intracellular membraneless organelle	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1168 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAX9	MSX1	P28360	982
PAX9	NKX2-8	O15522	901
PAX9	WNT10A	Q9GZT5	863
PAX9	PRRX2	Q99811	826
PAX9	LHX8	Q68G74	795
PAX9	OSR2	Q8N2R0	790
PAX9	EDA	Q92838	780
PAX9	BMP4	P12644	779
PAX9	IRF6	O14896	745
PAX9	PITX2	Q99697	745
PAX9	MSX2	P35548	736
PAX9	PRRX1	P54821	719
PAX9	LTBP3	Q9NS15	710
PAX9	LTBP2	Q14767	700
PAX9	FGF8	P55075	689

IntAct

79 interactions, top by confidence:

A	B	Type	Score
PAX9	SLAIN1	psi-mi:“MI:0915”(physical association)	0.560
PAX9	ZNF343	psi-mi:“MI:0915”(physical association)	0.560
PAX9	TEPSIN	psi-mi:“MI:0915”(physical association)	0.560
PAX9	TRIP13	psi-mi:“MI:0915”(physical association)	0.560
SFN	PAX9	psi-mi:“MI:0915”(physical association)	0.560
VPS37C	PAX9	psi-mi:“MI:0915”(physical association)	0.560
PAX9	PFDN5	psi-mi:“MI:0915”(physical association)	0.560
LMO2	PAX9	psi-mi:“MI:0915”(physical association)	0.560
PAX9	PLAGL2	psi-mi:“MI:0915”(physical association)	0.560
PAX9	MYLIP	psi-mi:“MI:0915”(physical association)	0.560
PAX9	WWOX	psi-mi:“MI:0915”(physical association)	0.560
EYA2	PAX9	psi-mi:“MI:0915”(physical association)	0.560
KLF4	PAX9	psi-mi:“MI:0915”(physical association)	0.560
PAX9	TLE5	psi-mi:“MI:0915”(physical association)	0.560
PAX9	KRTAP13-3	psi-mi:“MI:0915”(physical association)	0.560
PAX9	TLE1	psi-mi:“MI:0915”(physical association)	0.520
PAX9	FUBP3	psi-mi:“MI:0915”(physical association)	0.520
AKT1	PAX9	psi-mi:“MI:0915”(physical association)	0.450
AKT1	PAX9	psi-mi:“MI:2364”(proximity)	0.450
PAX9	ZER1	psi-mi:“MI:0915”(physical association)	0.400
CCL11	PAX9	psi-mi:“MI:0915”(physical association)	0.370
IL3	PAX9	psi-mi:“MI:0915”(physical association)	0.370
IL36A	PAX9	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (136): PAX9 (Two-hybrid), PAX9 (Proximity Label-MS), PAX9 (Affinity Capture-Western), PAX9 (Two-hybrid), PAX9 (Two-hybrid), PAX9 (Two-hybrid), PAX9 (Two-hybrid), PAX9 (Two-hybrid), PAX9 (Two-hybrid), PAX9 (Two-hybrid), PAX9 (Two-hybrid), PAX9 (Two-hybrid), PAX9 (Two-hybrid), PAX9 (Two-hybrid), PAX9 (Two-hybrid)

ESM2 similar proteins: A0JMA6, O08656, O57682, O57685, P06601, P09022, P23759, P23760, P24610, P32114, P47239, P47240, P47242, P49639, P51974, P55166, P55771, P70056, Q00288, Q02548, Q02650, Q02962, Q06710, Q0IH87, Q28D67, Q28DP6, Q2L4T2, Q2VL50, Q2VL51, Q2VL52, Q2VL53, Q2VL54, Q2VL57, Q2VL58, Q2VL59, Q2VL60, Q2VL62, Q32NP8, Q5R9M8, Q645N4

Diamond homologs: A0JMA6, G5ED14, G5ED66, G5EDS1, O18381, O43316, O57682, O57685, O73917, O88436, P06601, P09082, P09083, P09084, P15863, P23757, P23758, P23759, P23760, P24610, P26367, P26630, P32114, P32115, P47236, P47238, P47239, P47240, P47242, P51974, P55166, P55771, P55864, P63015, P63016, Q00288, Q02548, Q02650, Q02962, Q06710

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
KDM5B	“up-regulates activity”	PAX9	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 36 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of miRNA transcription	5	42.7×	6e-05
negative regulation of canonical Wnt signaling pathway	5	17.3×	1e-03
transcription by RNA polymerase II	5	10.4×	6e-03
positive regulation of gene expression	8	9.1×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

228 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	47
Likely pathogenic	14
Uncertain significance	110
Likely benign	26
Benign	21

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1064704	NM_001372076.1(PAX9):c.146C>T (p.Ser49Leu)	Pathogenic
1064705	NM_001372076.1(PAX9):c.140G>C (p.Arg47Pro)	Pathogenic
1064706	NM_001372076.1(PAX9):c.243del (p.Thr82fs)	Pathogenic
1064707	NM_001372076.1(PAX9):c.409C>T (p.Gln137Ter)	Pathogenic
1070666	NM_001372076.1(PAX9):c.451C>T (p.Gln151Ter)	Pathogenic
1075023	NM_001372076.1(PAX9):c.608del (p.Gly203fs)	Pathogenic
1076521	NM_001372076.1(PAX9):c.72_76dup (p.Arg26fs)	Pathogenic
1119978	NM_001372076.1(PAX9):c.152G>T (p.Gly51Val)	Pathogenic
1351209	NM_001372076.1(PAX9):c.482C>A (p.Ser161Ter)	Pathogenic
1351539	NM_001372076.1(PAX9):c.420C>A (p.Tyr140Ter)	Pathogenic
13767	NM_001372076.1(PAX9):c.218dup (p.Ser74fs)	Pathogenic
13768	NM_001372076.1(PAX9):c.340A>T (p.Lys114Ter)	Pathogenic
13771	NM_001372076.1(PAX9):c.62T>C (p.Leu21Pro)	Pathogenic
13772	NM_001372076.1(PAX9):c.176_182delinsAGCCACACAGTCTTGCCACACACAGTCTTCTGCCTCATCTCAAACTACCAGACCCATAACATCCCCCCATCCCAACACATGGTTCGCATTTTCCACCTCCCCCGCCTCTCGCGCCGAGGCAGCCTCAGCCCGGCTTGCTCACTTGGAGAGTGCGGCCGGGGCTGGACTTGGGGCGCAGCCCGGGAGGCCCGAGCCTGCTTGGGGCTGCCGGCTGCAGACTCCGCTGTGGGCAGAGCAGCTTGCTTGGGGACTACTACGGCCGGGATCGGTAATCAGGCCAAGAT (p.Arg59_Asn61delinsGlnProHisSerLeuAlaThrHisSerLeuLeuProHisLeuLysLeuProAspProTer)	Pathogenic
13773	NM_001372076.1(PAX9):c.83G>C (p.Arg28Pro)	Pathogenic
13774	NM_001372076.1(PAX9):c.76C>T (p.Arg26Trp)	Pathogenic
13776	NM_001372076.1(PAX9):c.792_793insC (p.Val265fs)	Pathogenic
13777	NM_001372076.1(PAX9):c.1A>G (p.Met1Val)	Pathogenic
13778	NM_001372076.1(PAX9):c.619_621delinsTACCGACCAAGGTAGGGCATCCCT (p.Ile207delinsTyrArgProArgTer)	Pathogenic
13780	PAX9, 1-BP INS, 190G	Pathogenic
13781	NM_001372076.1(PAX9):c.139C>T (p.Arg47Trp)	Pathogenic
1458120	NM_001372076.1(PAX9):c.428dup (p.Tyr143Ter)	Pathogenic
155939	NM_001372076.1(PAX9):c.336C>G (p.Cys112Trp)	Pathogenic
1693560	NM_001372076.1(PAX9):c.354del (p.Ser119fs)	Pathogenic
1693561	NM_001372076.1(PAX9):c.648dup (p.Tyr217fs)	Pathogenic
1693562	NM_001372076.1(PAX9):c.191G>T (p.Gly64Val)	Pathogenic
1710579	NM_001372076.1(PAX9):c.433C>T (p.Gln145Ter)	Pathogenic
2022895	NM_001372076.1(PAX9):c.593_596dup (p.Asp200fs)	Pathogenic
2094636	NM_001372076.1(PAX9):c.285del (p.Gly96fs)	Pathogenic
2577026	NM_001372076.1(PAX9):c.112C>T (p.Arg38Ter)	Pathogenic

SpliceAI

1160 predictions. Top by Δscore:

Variant	Effect	Δscore
14:36666460:A:AG	acceptor_gain	1.0000
14:36666460:A:C	acceptor_loss	1.0000
14:36666460:AGT:A	acceptor_gain	1.0000
14:36666461:G:GA	acceptor_gain	1.0000
14:36666461:GT:G	acceptor_gain	1.0000
14:36666461:GTG:G	acceptor_gain	1.0000
14:36666461:GTGA:G	acceptor_gain	1.0000
14:36666584:G:GT	donor_gain	1.0000
14:36666457:A:AG	acceptor_gain	0.9900
14:36666458:T:G	acceptor_gain	0.9900
14:36666459:CAGTG:C	acceptor_gain	0.9900
14:36666460:AGTGA:A	acceptor_gain	0.9900
14:36666461:GTGAG:G	acceptor_gain	0.9900
14:36666592:G:GG	donor_gain	0.9900
14:36666598:TC:T	donor_gain	0.9900
14:36675871:GA:G	donor_gain	0.9900
14:36659590:GCA:G	donor_gain	0.9800
14:36661968:G:A	acceptor_gain	0.9700
14:36662895:A:AG	acceptor_gain	0.9700
14:36662896:G:GG	acceptor_gain	0.9700
14:36663519:CCAAG:C	donor_loss	0.9700
14:36663520:CAAGG:C	donor_loss	0.9700
14:36663521:AAG:A	donor_loss	0.9700
14:36663522:AG:A	donor_loss	0.9700
14:36663523:GG:G	donor_loss	0.9700
14:36663524:GT:G	donor_loss	0.9700
14:36663525:T:A	donor_loss	0.9700
14:36675873:G:GG	donor_gain	0.9700
14:36657896:CGCAG:C	donor_loss	0.9600
14:36657898:CAGGT:C	donor_loss	0.9600

AlphaMissense

2189 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:36662917:A:C	N9H	1.000
14:36662917:A:G	N9D	1.000
14:36662918:A:T	N9I	1.000
14:36662919:C:A	N9K	1.000
14:36662919:C:G	N9K	1.000
14:36662922:G:C	Q10H	1.000
14:36662922:G:T	Q10H	1.000
14:36662924:T:A	L11Q	1.000
14:36662924:T:C	L11P	1.000
14:36662926:G:A	G12R	1.000
14:36662926:G:C	G12R	1.000
14:36662927:G:A	G12E	1.000
14:36662927:G:T	G12V	1.000
14:36662929:G:A	G13R	1.000
14:36662929:G:C	G13R	1.000
14:36662930:G:A	G13E	1.000
14:36662930:G:T	G13V	1.000
14:36662935:T:A	F15I	1.000
14:36662935:T:C	F15L	1.000
14:36662935:T:G	F15V	1.000
14:36662936:T:C	F15S	1.000
14:36662936:T:G	F15C	1.000
14:36662937:C:A	F15L	1.000
14:36662937:C:G	F15L	1.000
14:36662943:C:A	N17K	1.000
14:36662943:C:G	N17K	1.000
14:36662944:G:A	G18R	1.000
14:36662944:G:C	G18R	1.000
14:36662944:G:T	G18W	1.000
14:36662945:G:A	G18E	1.000

dbSNP variants (sampled 300 via entrez): RS1000110154 (14:36664603 C>T), RS1000351593 (14:36664152 T>G), RS1000361298 (14:36670067 C>A,G,T), RS1000383586 (14:36659692 CA>C), RS1000397475 (14:36676659 A>G), RS1000679085 (14:36658835 C>G,T), RS1000733703 (14:36659965 C>A), RS1001048210 (14:36669256 A>G), RS1001071036 (14:36664527 C>G,T), RS1001178007 (14:36658639 T>C), RS1001312031 (14:36659393 C>G,T), RS1001319888 (14:36656160 G>A), RS1001490676 (14:36666253 G>A), RS1001660089 (14:36677215 A>G), RS1001702044 (14:36665225 G>A)

Disease associations

OMIM: gene MIM:167416 | disease phenotypes: MIM:106600, MIM:604625

GenCC curated gene-disease

Disease	Classification	Inheritance
tooth agenesis, selective, 3	Definitive	Autosomal dominant
tooth agenesis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
tooth agenesis, selective, 3	Definitive	AD

Mondo (2): tooth agenesis (MONDO:0005486), tooth agenesis, selective, 3 (MONDO:0011477)

Orphanet (2): Oligodontia (Orphanet:99798), NON RARE IN EUROPE: Hypodontia (Orphanet:2227)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000202	Orofacial cleft
HP:0000677	Oligodontia
HP:0000679	Taurodontia
HP:0000684	Delayed eruption of teeth
HP:0000685	Hypoplasia of teeth
HP:0000687	Widely spaced teeth
HP:0000689	Dental malocclusion
HP:0000690	Agenesis of maxillary lateral incisor
HP:0000691	Microdontia
HP:0000696	Delayed eruption of permanent teeth
HP:0000970	Anhidrosis
HP:0001231	Abnormal fingernail morphology
HP:0001595	Abnormal hair morphology
HP:0003621	Juvenile onset
HP:0005216	Impaired mastication
HP:0006289	Agenesis of central incisor
HP:0006297	Enamel hypoplasia
HP:0006336	Short dental root
HP:0006342	Peg-shaped maxillary lateral incisors
HP:0006344	Abnormal primary molar morphology
HP:0006482	Abnormal dental morphology
HP:0011051	Agenesis of premolar
HP:0011053	Agenesis of mandibular premolar
HP:0011055	Agenesis of permanent molar
HP:0011056	Agenesis of first permanent molar tooth
HP:0011078	Abnormality of canine
HP:0011121	Abnormal skin morphology
HP:0011219	Short face
HP:0012225	Oligodontia of primary teeth

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001937_20	Breast cancer	2.000000e-13
GCST004988_50	Breast cancer	4.000000e-21
GCST005192_43	Lobe attachment (rater-scored or self-reported)	3.000000e-66
GCST005193_2	Lobe attachment (rater scored)	5.000000e-09
GCST006085_60	Prostate cancer	2.000000e-12
GCST008163_421	Height	2.000000e-06
GCST009356_8	Nonsyndromic cleft palate	3.000000e-16

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007667	lobe attachment

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567036	Tooth Agenesis, Selective, 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
Benzo(a)pyrene	affects methylation, increases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
trichostatin A	decreases expression	1
2,4-di-tert-butylphenol	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
SAG compound	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
Arsenic Trioxide	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Calcitriol	decreases expression	1
Camptothecin	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Estradiol	increases expression	1
N-Nitrosopyrrolidine	increases expression	1
Tobacco Smoke Pollution	affects expression	1
Tretinoin	affects expression	1
Valproic Acid	decreases methylation	1
Vanadates	decreases expression	1
Fibroblast Growth Factor 2	affects cotreatment, decreases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A5E7	SEES3-1V human PAX9, clone1	Embryonic stem cell	Male
CVCL_A5E8	SEES3-1V human PAX9, clone2	Embryonic stem cell	Male
CVCL_A5E9	SEES3-1V human PAX9, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

3 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01470235	Not specified	UNKNOWN	Hypodontia and Ovarian Cancer
NCT03445026	Not specified	UNKNOWN	Frequency of Hypodontia After Chemotherapy in Childhood Cancer Survivors Study
NCT05771246	Not specified	COMPLETED	Craniofacial Morphology And Sella Turcica Bridging Associated With Third Molar Agenesis.