PBX3

Chr 9

PBX homeobox 3

NCBI Gene: 5090 ENSG00000167081 UniProt: P40426 OMIM: 176312

PBX3 encodes a transcriptional activator that binds specific DNA sequences to regulate gene expression during embryonic development, particularly affecting nervous system, eye, and organ development. Mutations cause autosomal recessive congenital fibrosis of the extraocular muscles with developmental delay, ptosis, and intellectual disability. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.476), and the associated disorder typically presents from birth with characteristic ocular abnormalities.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in several processes, including eye development; nervous system development; and positive regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including adult locomotory behavior; dorsal spinal cord development; and regulation of respiratory gaseous exchange by nervous system process. Predicted to be located in chromatin. Predicted to be part of transcription regulator complex. Predicted to be active in nucleus. Biomarker of esophagus squamous cell carcinoma. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.48

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.48LOEUF

pLI 0.363

Z-score 3.37

OE 0.23 (0.12–0.48)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.16Z-score

OE missense 0.61 (0.53–0.70)

147 obs / 241.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.23 (0.12–0.48)

0≤0.351.4

Missense OE?0.61 (0.53–0.70)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 5 / 22.1Missense obs/exp: 147 / 241.7Syn Z: 0.58

Background carrier burden — how many people carry a rare variant somewhere in PBX3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 210

456 rare PASS variants

Rare truncating (LoF)

1 in 1,200

42 rare PASS variants

Rare synonymous (reference)

1 in 280

222 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PBX3. 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 250	1 in 1,100
South Asian	~43k	1 in 210	1 in 5,400
Remaining (unassigned)	~30k	1 in 190	1 in 4,200
European (Finnish)	~27k	1 in 350	≈ 1 in 8,900
Admixed American	~22k	1 in 260	1 in 3,100
African / African American	~21k	1 in 170	1 in 1,900
East Asian	~20k	1 in 300	≈ 1 in 6,000
Ashkenazi Jewish	~13k	1 in 1,600	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 240	none seen

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): 7 of 9 coding exons well covered in gnomAD exomes; exons 7, 8 marginal. Genomes: 8 of 9 (exon 1 below).? see exons ↓