PAX2

Chr 10

paired box 2

Also known as: FSGS7, PAPRS, PAX-2

NCBI Gene: 5076 ENSG00000075891 UniProt: Q02962

PAX2 encodes a transcription factor containing a conserved DNA-binding paired box domain that regulates gene expression in the nucleus. Mutations cause autosomal dominant papillorenal syndrome and focal segmental glomerulosclerosis type 7, characterized by optic nerve colobomas and renal hypoplasia. The pathogenic mechanism involves loss of function of this critical transcriptional regulator.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

PAX2 encodes paired box gene 2, one of many human homologues of the Drosophila melanogaster gene prd. The central feature of this transcription factor gene family is the conserved DNA-binding paired box domain. PAX2 is believed to be a target of transcriptional supression by the tumor suppressor gene WT1. Mutations within PAX2 have been shown to result in optic nerve colobomas and renal hypoplasia. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2014]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.43

Clinical Summary— PAX2

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Gene-Disease Validity (ClinGen)

focal segmental glomerulosclerosis 7 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.67) — some intolerance to loss-of-function variants.

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ClinVar Variants

152 unique Pathogenic / Likely Pathogenic· 253 VUS of 641 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PAX2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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?

0.43LOEUF

pLI 0.670

Z-score 3.45

OE 0.19 (0.09–0.43)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.49Z-score

OE missense 0.73 (0.65–0.83)

178 obs / 243.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.19 (0.09–0.43)

0≤0.351.4

Missense OE?0.73 (0.65–0.83)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 4 / 21.1Missense obs/exp: 178 / 243.4Syn Z: -1.09

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePAX2-related papillorenal syndromeLOFAD

This gene — mechanism propensity

0.6552th %ile

GOF

0.4085th %ile

LOF

0.72top 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 · 1 literature citation · 64% of P/LP variants are LoF · LOEUF 0.43 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DNprediction above median · 1 literature citation

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.

Literature Evidence

DNMoreover, these results indicate PAX2 mutations can cause disease through haploinsufficiency and dominant negative effects, which could have implications for tailoring individualized drug therapy in the future.1

LOFArray comparative genomic hybridization analysis in patients with anophthalmia, microphthalmia, and coloboma2

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

641 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic66

Likely Pathogenic86

VUS253

Likely Benign168

Benign40

Conflicting19

Pathogenic

Likely Pathogenic

253

VUS

168

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	55	6	4	1	66
Likely Pathogenic	43	36	7	0	86
VUS	7	221	18	7	253
Likely Benign	0	4	84	80	168
Benign	0	0	37	3	40
Conflicting	—				19
Total	105	267	150	91	632

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap PAX2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →