PBX1

Chr 1AD

PBX homeobox 1

Also known as: CAKUHED

NCBI Gene: 5087 ENSG00000185630 UniProt: P40424 OMIM: 176310

This gene encodes PBX1, a transcription factor that binds specific DNA sequences as part of heterodimers with HOX proteins to regulate gene expression during development. Mutations cause congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variation (pLI 0.995, LOEUF 0.255), indicating that functional copies are critical for normal development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a nuclear protein that belongs to the PBX homeobox family of transcriptional factors. Studies in mice suggest that this gene may be involved in the regulation of osteogenesis and required for skeletal patterning and programming. A chromosomal translocation, t(1;19) involving this gene and TCF3/E2A gene, is associated with pre-B-cell acute lymphoblastic leukemia. The resulting fusion protein, in which the DNA binding domain of E2A is replaced by the DNA binding domain of this protein, transforms cells by constitutively activating transcription of genes regulated by the PBX protein family. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.261 OMIM phenotype

Clinical Summary— PBX1

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Gene-Disease Validity (ClinGen)

congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

67 unique Pathogenic / Likely Pathogenic· 87 VUS of 209 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PBX1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.26LOEUF

pLI 0.995

Z-score 4.23

OE 0.08 (0.03–0.26)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.83Z-score

OE missense 0.32 (0.27–0.39)

81 obs / 251.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.08 (0.03–0.26)

0≤0.351.4

Missense OE?0.32 (0.27–0.39)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 2 / 24.7Missense obs/exp: 81 / 251.9Syn Z: 0.92

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongPBX1-related developmental disorderLOFAD

This gene — mechanism propensity

0.4586th %ile

GOF

0.2099th %ile

LOF

0.84top 5%

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 · 1 literature citation · 67% of P/LP variants are LoF · LOEUF 0.26 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

Literature Evidence

DNPBX1-d is novel splice isoform of pre-B-cell leukemia homeobox 1 (PBX1) that lacks its DNA-binding and Hox-binding domains, and functions as a dominant negative.1

LOFOur results indicate that PBX1 haploinsufficiency leads to syndromic CAKUT as supported by the Pbx1-null mice model.2

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

References

ClinVar Variant Classifications

209 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32

Likely Pathogenic35

VUS87

Likely Benign38

Benign8

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	27	5	0	0	32
Likely Pathogenic	18	17	0	0	35
VUS	3	72	9	3	87
Likely Benign	0	3	13	22	38
Benign	0	1	6	1	8
Conflicting	—				1
Total	48	98	28	26	201

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap PBX1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →