PAX1

Chr 20AR

paired box 1

Also known as: HUP48, OFC2, OTFCS2

NCBI Gene: 5075 ENSG00000125813 UniProt: P15863

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. This gene plays a role in pattern formation during embryogenesis and may be essential for development of the vertebral column. This gene is silenced by methylation in ovarian and cervical cancers and may be a tumor suppressor gene. Mutations in this gene are also associated with vertebral malformations. [provided by RefSeq, Mar 2012]

Primary Disease Associations & Inheritance

Otofaciocervical syndrome 2 with T-cell deficiencyMIM #615560

Active trials

Pathogenic / LP

497

ClinVar variants

Pubs (1 yr)

-0.8

Missense Z

0.50

LOEUF

Clinical Summary— PAX1

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Gene-Disease Validity (ClinGen)

otofaciocervical syndrome 2 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.70) — some intolerance to loss-of-function variants.

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ClinVar Variants

32 Pathogenic / Likely Pathogenic· 247 VUS of 497 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.50LOEUF

pLI 0.700

Z-score 2.77

OE 0.16 (0.06–0.50)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

-0.76Z-score

OE missense 1.13 (1.03–1.24)

305 obs / 270.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.16 (0.06–0.50)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.13 (1.03–1.24)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.28

0≤1.21.6

LoF obs/exp: 2 / 12.6Missense obs/exp: 305 / 270.0Syn Z: -2.44

0.6260th %ile

GOF

0.4875th %ile

LOF

0.69top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 41% of P/LP variants are LoF · LOEUF 0.50

DNprediction above median

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.

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