rs33912345

This is a variant in the SIX6 gene that changes a histidine to an asparagine.

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GWAS Catalog Trait Associations (10)

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

body height

Loya H et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics 57(2):461-468 (2025)
Allele A
OR 0.02
p 2.0e-117
N 394,642
Large GWAS
European

open-angle glaucoma

Han X et al. “Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci.” Nature Genetics 55(7):1116-1125 (2023)
Allele A
OR 0.16
p 6.0e-85
N 432,017
Large GWAS
multi-ancestry
Verma A et al. “Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.” Science (new York, N.y.) 385(6706):eadj1182 (2024)
Allele A
OR 0.12
p 5.0e-34
N 628,741
Major Consortium StudyLarge GWAS
multi-ancestry
Gharahkhani P et al. “Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.” Nature Communications 12(1):1258 (2021)
Allele A
OR 0.11
p 3.0e-54
N 383,500
Meta-analysisLarge GWAS
multi-ancestry
Bailey JN et al. “Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma.” Nature Genetics 48(2):189-94 (2016)
Allele A
OR —
p 1.0e-9
N 33,365
Large GWAS
European

glaucoma

Verma A et al. “Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.” Science (new York, N.y.) 385(6706):eadj1182 (2024)
Allele C
OR 0.09
p 1.0e-56
N 609,053
Major Consortium StudyLarge GWAS
multi-ancestry

base metabolic rate measurement

Loya H et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics 57(2):461-468 (2025)
Allele A
OR 0.02
p 8.0e-52
N 394,642
Large GWAS
European

lean body mass

Harris BHL et al. “New role of fat-free mass in cancer risk linked with genetic predisposition.” Scientific Reports 14(1):7270 (2024)
Allele A
OR 0.02
p 9.0e-43
N 337,739
Large GWAS
European

IGF-1 measurement

Loya H et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics 57(2):461-468 (2025)
Allele A
OR 0.02
p 5.0e-29
N 394,642
Large GWAS
European

Antiglaucoma preparations and miotics use measurement

Sakaue S et al. “A cross-population atlas of genetic associations for 220 human phenotypes.” Nature Genetics 53(10):1415-1424 (2021)
Allele A
OR 0.13
p 5.0e-18
N 279,594
Large GWAS
multi-ancestry
Wu Y et al. “Genome-wide association study of medication-use and associated disease in the UK Biobank.” Nature Communications 10(1):1891 (2019)
Allele A
OR 0.15
p 1.0e-12
N 100,868
Major Consortium StudyLarge GWAS
European

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 C
OR 0.04
p 5.0e-11
N 51,624
Large GWAS
European

appendicular lean mass

Hernandez Cordero AI et al. “Genome-wide Associations Reveal Human-Mouse Genetic Convergence and Modifiers of Myogenesis, CPNE1 and STC2.” American Journal of Human Genetics 105(6):1222-1236 (2019)
Allele A
OR 0.04
p 8.0e-9
N 181,862
Large GWAS
European

drug use measurement, glaucoma

Verma A et al. “Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.” Science (new York, N.y.) 385(6706):eadj1182 (2024)
Allele C
OR 0.09
p 2.0e-13
N 404,034
Major Consortium StudyLarge GWAS
multi-ancestry
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ClinVar annotation

Benign★★★☆
8 submitters2 publications

Anophthalmia-microphthalmia syndrome; Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome (ODRMD); not specified

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 &amp; 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
PubMedDOIMetascience 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]

View all SIX6 variants →

Gene information from NCBI Gene. Variant classifications from ClinVar.

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