PAX1

Chr 20AR

paired box 1

Also known as: HUP48, OFC2, OTFCS2

NCBI Gene: 5075 ENSG00000125813 UniProt: P15863 OMIM: 167411

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.

OMIM 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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Otofaciocervical syndrome 2 with T-cell deficiencyMIM #615560

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · otofaciocervical syndrome 2 · AR · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.50

LOEUF

LOF

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in PAX1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 48

1,112 rare PASS variants

Rare truncating (LoF)

1 in 480

122 rare PASS variants

Rare synonymous (reference)

1 in 100

525 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PAX1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 60	1 in 630
South Asian	~43k	1 in 51	1 in 470
Remaining (unassigned)	~30k	1 in 46	1 in 500
European (Finnish)	~27k	1 in 140	1 in 760
Admixed American	~22k	1 in 50	1 in 950
African / African American	~21k	1 in 47	1 in 460
East Asian	~20k	1 in 65	1 in 870
Ashkenazi Jewish	~13k	1 in 170	≈ 1 in 2,600
Middle Eastern	~2,884	1 in 47	1 in 380

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 4 of 5 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 5.? see exons ↓