PAX6

Chr 11AD

paired box 6

Also known as: AN, AN1, AN2, ASGD5, D11S812E, FVH1, MGDA, WAGR

NCBI Gene: 5080 ENSG00000007372 UniProt: P26367 OMIM: 607108

PAX6 encodes a transcription factor containing paired box and homeobox domains that regulates gene expression essential for eye and neural tissue development. Mutations cause autosomal dominant ocular disorders including aniridia, anterior segment dysgenesis, foveal hypoplasia, microphthalmia/coloboma, and optic nerve abnormalities through loss of function mechanisms. The protein is highly intolerant to loss-of-function variants, reflecting its critical role in eye development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes paired box protein Pax-6, one of many human homologs of the Drosophila melanogaster gene prd. In addition to a conserved paired box domain, a hallmark feature of this gene family, the encoded protein also contains a homeobox domain. Both domains are known to bind DNA and function as regulators of gene transcription. Activity of this protein is key in the development of neural tissues, particularly the eye. This gene is regulated by multiple enhancers located up to hundreds of kilobases distant from this locus. Mutations in this gene or in the enhancer regions can cause ocular disorders such as aniridia and Peter's anomaly. Use of alternate promoters and alternative splicing results in multiple transcript variants encoding different isoforms. Interestingly, inclusion of a particular alternate coding exon has been shown to increase the length of the paired box domain and alter its DNA binding specificity. Consequently, isoforms that carry the shorter paired box domain regulate a different set of genes compared to the isoforms carrying the longer paired box domain. [provided by RefSeq, Mar 2019]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.179 OMIM phenotypes

Clinical Summary— PAX6

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Gene-Disease Validity (ClinGen)

PAX6-related ocular dysgenesis · 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

188 unique Pathogenic / Likely Pathogenic· 184 VUS of 579 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PAX6

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.17LOEUF

pLI 1.000

Z-score 4.74

OE 0.04 (0.01–0.17)

Highly constrained

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

Missense Constraint?

2.82Z-score

OE missense 0.49 (0.42–0.57)

120 obs / 243.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.17)

0≤0.351.4

Missense OE?0.49 (0.42–0.57)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 1 / 28.1Missense obs/exp: 120 / 243.8Syn Z: -0.85

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePAX6-related Peters anomalyOTHERAD

definitivePAX6-related aniridiaLOFAD

This gene — mechanism propensity

0.5869th %ile

GOF

0.3887th %ile

LOF

0.79top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 66% of P/LP variants are LoF · LOEUF 0.17

Literature Evidence

LOFIn humans, haploinsufficiency of either SOX2 or PAX6 is associated with microphthalmia, anophthalmia or aniridia.1

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

References

1.PMID 21205789 ↗

ClinVar Variant Classifications

579 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic134

Likely Pathogenic54

VUS184

Likely Benign143

Benign37

Conflicting17

134

Pathogenic

Likely Pathogenic

184

VUS

143

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	101	21	12	0	134
Likely Pathogenic	23	26	3	2	54
VUS	5	141	30	8	184
Likely Benign	4	13	53	73	143
Benign	1	6	27	3	37
Conflicting	—				17
Total	134	207	125	86	569

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap PAX6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →