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

LOFmechanismADLOEUF 0.611 OMIM phenotype

Clinical Summary— PAX9

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Gene-Disease Validity (ClinGen)

tooth agenesis, selective, 3 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

95 unique Pathogenic / Likely Pathogenic· 123 VUS of 283 total submissions

Explore recent and relevant literature in Research Assistant →

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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 OE0.24 (0.11–0.61)

0≤0.351.4

Missense OE0.88 (0.77–0.99)

0≤0.61.4

Synonymous OE1.15

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

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 · 39% of P/LP variants are LoF

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.PMID:33078491

LOFNine Novel PAX9 Mutations and a Distinct Tooth Agenesis Genotype-PhenotypePMID:28910570

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.