PAX6

Chr 11AD

paired box 6

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

NCBI Gene: 5080 ENSG00000007372 UniProt: P26367

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]

Primary Disease Associations & Inheritance

?Coloboma of optic nerveMIM #120430

?Morning glory disc anomalyMIM #120430

AniridiaMIM #106210

Anterior segment dysgenesis 5, multiple subtypesMIM #604229

Cataract with late-onset corneal dystrophyMIM #106210

Foveal hypoplasia 1MIM #136520

KeratitisMIM #148190

Microphthalmia/coloboma 12MIM #120200

Optic nerve hypoplasiaMIM #165550

UniProtAniridia 1

UniProtKeratitis hereditary

UniProtBilateral optic nerve hypoplasia

UniProtAniridia 2

526

ClinVar variants

256

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

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

256 Pathogenic / Likely Pathogenic· 149 VUS of 526 total submissions

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Clinical Trials

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.04 (0.01–0.17)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.49 (0.42–0.57)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.11

0≤1.21.6

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

ClinVar Variant Classifications

526 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic194

Likely Pathogenic62

VUS149

Likely Benign86

Benign22

Conflicting13

194

Pathogenic

Likely Pathogenic

149

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	94	29	71	0	194
Likely Pathogenic	20	31	10	1	62
VUS	5	114	27	3	149
Likely Benign	1	2	29	54	86
Benign	1	3	15	3	22
Conflicting	—				13
Total	121	179	152	61	526

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

View in ClinVar →

Protein Context — Lollipop Plot

PAX6 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PAX6-related Peters anomaly

definitive

ADUndeterminedUncertain

Dev. DisordersEye

G2P ↗

PAX6-related aniridia

definitive

ADLoss Of FunctionAbsent Gene Product

Dev. DisordersEye

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

PAIRED BOX GENE 6; PAX6

MIM #607108 · *

?Coloboma of optic nerve

MIM #120430