PAX9

Chr 14AD

paired box 9

Also known as: STHAG3

NCBI Gene: 5083 ENSG00000198807 UniProt: P55771 OMIM: 167416

This transcription factor is required for normal development of the thymus, parathyroid glands, teeth, and skeletal elements of the skull, larynx, and distal limbs. Mutations cause selective tooth agenesis-3, characterized by congenital absence of specific teeth. This condition follows autosomal dominant inheritance.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.611 OMIM phenotype

Clinical Summary— PAX9

🧬

Gene-Disease Validity (ClinGen)

tooth agenesis, selective, 3 · 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.

📋

ClinVar Variants

63 unique Pathogenic / Likely Pathogenic· 115 VUS of 240 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — PAX9

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.61LOEUF

pLI 0.309

Z-score 2.51

OE 0.24 (0.11–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.62Z-score

OE missense 0.88 (0.77–0.99)

173 obs / 197.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.24 (0.11–0.61)

0≤0.351.4

Missense OE?0.88 (0.77–0.99)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 3 / 12.6Missense obs/exp: 173 / 197.5Syn Z: -1.12

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePAX9-related tooth agenesis, selectiveLOFAD

This gene — mechanism propensity

0.7230th %ile

GOF

0.4974th %ile

LOF

0.64top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). 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 · 59% of P/LP variants are LoF · ClinGen HI: Sufficient evidence for dosage pathogenicity

DNprediction above median · 1 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

DNOur findings broaden the spectrum of PAX9 variants in patients with non-syndromic oligodontia and support that paired domain structural impairment and the dominant-negative effect are likely the underlying mechanisms of PAX9-related non-syndromic oligodontia.1

LOFNine Novel PAX9 Mutations and a Distinct Tooth Agenesis Genotype-Phenotype2

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

240 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic49

Likely Pathogenic14

VUS115

Likely Benign28

Benign26

Conflicting4

Pathogenic

Likely Pathogenic

115

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	29	13	6	1	49
Likely Pathogenic	8	6	0	0	14
VUS	2	76	33	4	115
Likely Benign	0	3	10	15	28
Benign	0	2	22	2	26
Conflicting	—				4
Total	39	100	71	22	236

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

View in ClinVar →

33 pathogenic / likely-pathogenic (of 44) ClinVar copy-number / structural variants overlap PAX9 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →