PAX6 rs28936665: Aniridia and Ocular Development
The genetic variant rs28936665 is a rare premature stop-gain (nonsense) alteration located in the PAX6 gene. It leads to PAX6 haploinsufficiency, a state where a single functional copy of the gene cannot produce enough protein for normal ocular development. Consequently, this variant is classically associated with congenital aniridia, a condition marked by the complete or partial absence of the iris, alongside foveal hypoplasia and diminished visual acuity.
What each genotype means
Typical ocular development
You carry two copies of the standard C reference allele for this PAX6 marker. This common genotype provides normal dosage of the PAX6 transcription factor and is not linked to congenital aniridia, iris hypoplasia, or associated structural eye anomalies. It reflects the expected baseline eye development profile observed across all general populations.
Carried by more than 99.99% of individuals across all major global ancestries.
PAX6 haploinsufficiency risk
You carry one copy of the rare nonsense T allele, which introduces a premature stop codon into the PAX6 gene. In clinical and scientific studies, heterozygosity for this variant causes PAX6 haploinsufficiency, which is strongly associated with congenital aniridia, foveal hypoplasia, nystagmus, and reduced visual acuity. Evidence indicates this condition follows an autosomal dominant inheritance pattern with high penetrance, though phenotypic severity can vary.
Extremely rare across all populations, with an estimated carrier frequency of less than 1 in 100,000 individuals in gnomAD.
Biallelic loss-of-function
You carry two copies of the nonsense T allele, resulting in a complete absence of functional PAX6 protein. Biallelic null mutations in PAX6 are associated with lethal or severe developmental phenotypes, including complex central nervous system and severe craniofacial malformations. Because of early lethality or non-viability, this genotype is virtually absent in living individuals and general population cohorts.
Essentially absent in general living human populations due to embryonic or early perinatal lethality.
What Is rs28936665 and Where Is It Located?
The variant rs28936665 is a single nucleotide variation situated in the paired box 6 (PAX6) gene on the short arm of chromosome 11 (11p13). Molecularly, this variant represents a nonsense or stop-gain mutation, in which a base substitution changes an amino acid codon into a premature stop codon. During protein synthesis, cellular machinery recognizes this premature termination signal, typically triggering nonsense-mediated decay (NMD) of the messenger RNA or producing an unstable, truncated protein. As a result, the variant allele fails to produce functional, full-length protein. Because human ocular development relies heavily on precise levels of gene expression, carrying one non-functional copy prevents the eye from developing normally. This specific mutation is cataloged in clinical genomic registries such as ClinVar and dbSNP as a monogenic cause of structural ocular malformations.
The Biological Role of the PAX6 Master Regulator
The PAX6 gene is widely recognized as the master control gene for eye development across animal species. It encodes a transcription factor containing paired DNA-binding domains that regulate the downstream activation of numerous target genes involved in ocular patterning. During embryogenesis, PAX6 coordinates the sequential development of the cornea, lens, iris, and retina. A hallmark biological feature of PAX6 is its strict gene dosage sensitivity. Even a modest reduction below normal cellular protein levels impairs developmental pathways. In classical aniridia, losing 50% of functional protein output due to heterozygous loss-of-function variants disrupts normal anterior and posterior segment morphogenesis. Beyond the iris itself, PAX6 activity is necessary for the continuous maintenance of the corneal epithelium and the differentiation of the fovea, the central region of the retina responsible for sharp, detailed vision.
Clinical Phenotype and Scientific Evidence
Multiple studies demonstrate that premature termination codon variants in PAX6 cause classical congenital aniridia, which follows an autosomal dominant inheritance pattern. This structural condition is characterized by the partial or complete absence of the colored iris, but its clinical impact extends pan-ocularly. Individuals harboring such nonsense variants commonly present with foveal hypoplasia, involuntary rapid eye movements (nystagmus), and significantly reduced visual acuity from early childhood. Over time, individuals may also develop secondary ocular complications, including cataracts, glaucoma, and aniridia-related keratopathy (ARK), which involves progressive corneal clouding due to limbal stem cell deficiency. While literature broadly agrees that loss-of-function variants induce more severe structural disruption than many missense alterations, phenotypic variability is still observed, and visual acuity outcomes can vary widely across affected individuals.
Population Frequency and Detection
In large general reference populations, rs28936665 is an exceptionally rare genetic event. Population genomic repositories, including the Genome Aggregation Database (gnomAD), record its overall allele frequency at well below 0.00001, meaning it is virtually absent among individuals without diagnosed eye conditions. Because of its dominant inheritance and significant impact on visual development, pathogenic PAX6 loss-of-function variants are rarely observed as asymptomatic carrier states in unselected population cohorts. They typically arise either as de novo mutations in an affected individual or are inherited directly from a parent who also displays the characteristic ocular phenotype. Standard consumer genotyping arrays do not systematically validate or reliably call such rare pathogenic variants, meaning confirmation requires targeted diagnostic Sanger sequencing, comprehensive whole-exome sequencing, or specialized clinical ophthalmic panels.
How to Interpret and Apply This Information
Encountering a rare variant like rs28936665 in an unverified genetic report should always be approached with caution. Consumer-grade direct-to-consumer genotyping microarrays often yield false-positive results when reporting exceedingly rare variants. Therefore, raw data indicating the presence of this variant cannot serve as a clinical diagnosis. True pathogenic status requires formal clinical testing ordered by a medical professional. For individuals with a validated variant, management involves comprehensive longitudinal care directed by an ophthalmologist to monitor intraocular pressure, protect corneal health, and address visual impairment. Genetic counseling is strongly recommended for families with aniridia to discuss inheritance patterns, family planning, and differential considerations such as testing for broader contiguous gene deletions on chromosome 11 that could involve nearby genes like WT1.
How common is this variant?
The rs28936665 variant is exceedingly rare in the global population, with an allele frequency documented in gnomAD at less than 0.00001 across all ancestral groups.
Frequently asked questions
What is aniridia?
Aniridia is a rare congenital eye condition characterized by the partial or complete absence of the iris, the colored part of the eye. Because the PAX6 gene regulates total eye development, aniridia also commonly involves reduced retinal development (foveal hypoplasia), nystagmus, and high lifetime risks of glaucoma and cataracts.
Does carrying rs28936665 guarantee severe vision problems?
Heterozygous loss-of-function variants like rs28936665 strongly predispose individuals to congenital aniridia and subnormal visual acuity due to foveal underdevelopment. While expressivity can vary even among family members carrying the same mutation, most individuals with a verified stop-gain variant show noticeable structural eye changes and require ongoing visual care.
How is rs28936665 passed down in families?
Variants in the PAX6 gene responsible for classical aniridia are typically inherited in an autosomal dominant pattern. An individual with the variant has a 50% chance of passing it to each child, although about one-third of cases arise spontaneously as a new (de novo) mutation with no prior family history.
Could my raw consumer DNA test result for rs28936665 be wrong?
Yes, false positives are common when direct-to-consumer DNA tests attempt to report extremely rare variants. Anyone who receives an unexpected finding in raw genomic data should seek evaluation from a medical geneticist or ophthalmologist to obtain validated clinical diagnostic sequencing.
Sources & further reading
Educational information only, last refreshed 9/14/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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Pathogenic loss-of-function nonsense variant in PAX6 resulting in congenital absence of the iris (aniridia) and associated anterior segment dysgenesis.
A high-penetrance single nucleotide substitution disrupting PAX6 function and leading to aniridia and congenital anterior segment dysgenesis.
Nonsense change in PAX6 leading to haploinsufficiency and classical congenital aniridia.
A classic nonsense mutation (p.Arg240Ter) in the PAX6 master regulator of eye development leading to haploinsufficiency and congenital aniridia.
Intronic regulatory polymorphism in the ocular master regulator PAX6 associated with axial length variation and myopia development.
Pathogenic missense variant in PAX6 causing developmental ocular malformations including aniridia and congenital ocular coloboma.