PAX1

Chr 20AR

paired box 1

Also known as: HUP48, OFC2, OTFCS2

PAX1 encodes a transcription factor that activates gene expression and is essential for vertebral column development and formation of segmented embryonic structures. Mutations cause otofaciocervical syndrome 2 with T-cell deficiency, which involves vertebral malformations and immune deficiency, inherited in an autosomal recessive pattern. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.498), consistent with its critical developmental role.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismARLOEUF 0.501 OMIM phenotype
Clinical SummaryPAX1
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Gene-Disease Validity (ClinGen)
otofaciocervical syndrome 2 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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

Moderate LoF intolerance
LoF Constraint
0.50LOEUF
pLI 0.700
Z-score 2.77
OE 0.16 (0.060.50)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
-0.76Z-score
OE missense 1.13 (1.031.24)
305 obs / 270.0 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.16 (0.060.50)
00.351.4
Missense OE1.13 (1.031.24)
00.61.4
Synonymous OE1.28
01.21.6
LoF obs/exp: 2 / 12.6Missense obs/exp: 305 / 270.0Syn Z: -2.44
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
limitedPAX1-related oculo-auriculo-vertebral syndromeOTHERAD
strongPAX1-related otofaciocervical syndromeLOFAR
DN
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 · 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.

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

PAX1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
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