rs146737847

This is a variant in the SIX6 gene that changes a glutamate to an lysine.

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GWAS Catalog Trait Associations (2)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

refractive error

Guggenheim JA et al. “Whole exome sequence analysis in 51 624 participants identifies novel genes and variants associated with refractive error and myopia.” Human Molecular Genetics 31(11):1909-1919 (2022)

Allele A

OR 0.30

p 2.0e-16

N 51,624

Large GWAS

European

retinal layer thickness

Jackson VE et al. “Multi-omic spatial effects on high-resolution AI-derived retinal thickness.” Nature Communications 16(1):1317 (2025)

Allele A

OR 89.06

p 2.0e-11

N 43,151

Large GWAS

multi-ancestry

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ClinVar annotation

Pathogenic★☆☆☆

6 submitters2 publications

Anophthalmia-microphthalmia syndrome; Anophthalmia/microphthalmia-esophageal atresia syndrome (MCOPS3); Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome (ODRMD); SIX6-related disorder

View on ClinVar →

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Research that mentions this SNP (1)

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Identification and characterization of variants and a novel 4 bp deletion in the regulatory region of SIX6, a risk factor for primary open‐angle glaucoma

AssociationN=2,500Mohd Hussain Shah et al.(2017)· Molecular Genetics & Genomic Medicine

This study examined SIX6 genetic variants in South Indian POAG patients and identified two known common variants (rs33912345: c.421A>C, OR=0.919, p=0.3888; rs10483727/rs1048372, p=0.5879) and a novel 4 bp deletion in the SIX6 retinal enhancer (Chr14:60974427-60974430). While the SNPs showed no significant disease association in the South Indian cohort, patients carrying the risk alleles exhibited dose-dependent reductions in retinal nerve fiber layer thickness and increased vertical cup-disc ratio (p=0.012 and p=0.009 respectively). Functional studies via zebrafish transgenesis and luciferase assays demonstrated that the 4 bp deletion impaired enhancer activity, suggesting SIX6 haploinsufficiency may contribute to POAG pathogenesis.

Traits studied:Primary open-angle glaucomaRetinal nerve fiber layer thicknessVertical cup-disc ratio

PubMed DOI Metascience Observatory

About SIX6

The protein encoded by this gene is a homeobox protein that is similar to the Drosophila 'sine oculis' gene product. This gene is found in a cluster of related genes on chromosome 14 and is thought to be involved in eye development. Defects in this gene are a cause of isolated microphthalmia with cataract type 2 (MCOPCT2). [provided by RefSeq, Jul 2008]