PAX1

Chr 20

paired box 1

Also known as: HUP48, OFC2, OTFCS2

NCBI Gene: 5075 ENSG00000125813 UniProt: P15863

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.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.50

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

23 unique Pathogenic / Likely Pathogenic· 249 VUS of 519 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

-0.76Z-score

OE missense 1.13 (1.03–1.24)

305 obs / 270.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.16 (0.06–0.50)

0≤0.351.4

Missense OE?1.13 (1.03–1.24)

0≤0.61.4

Synonymous OE?1.28

0≤1.21.6

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

This gene — mechanism propensity

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 · 87% 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.

ClinVar Variant Classifications

519 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14

Likely Pathogenic9

VUS249

Likely Benign220

Benign14

Conflicting10

Pathogenic

Likely Pathogenic

249

VUS

220

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	3	0	0	14
Likely Pathogenic	9	0	0	0	9
VUS	6	239	4	0	249
Likely Benign	0	16	44	160	220
Benign	0	2	5	7	14
Conflicting	—				10
Total	26	260	53	167	516

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

View in ClinVar →

25 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap PAX1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →