One of the most common congenital malformations of the male genitalia, corrected surgically in infancy. One gene, found in the field's first GWAS, has an unusually large effect for a common condition; eighteen more loci together explain a modest share of the rest.
Hypospadias is a congenital condition in which the urethral opening sits on the underside of the penis rather than at the tip, caused by incomplete development of the urethra before birth. It is one of the most common urogenital malformations in newborn boys, though reported prevalence varies substantially by region and surveillance method — a 2025 population-based study in Hainan, China found 5.53 cases per 10,000 births over a 10-year period, rising from 3.15 to 8.36 per 10,000 across that decade.
van der Zanden et al. 2011 ran the field's first genome-wide association study — 436 cases and 494 controls of European descent, using pooled DNA — and found something unusual for a common condition: two SNPs in DGKK (diacylglycerol kinase κ) with a genuinely large effect. rs1934179 carried an odds ratio of 2.5 (P=2.5×10⁻¹¹) in the discovery sample, and replicated even more strongly in a Dutch trio sample (OR up to 3.9) and a Swedish sample (OR up to 2.5). An effect size that large, for a variant this common, is unusual in complex-trait genetics — most common-disease variants carry odds ratios closer to 1.1–1.3.
Geller et al. 2014 scaled the search up considerably: 1,006 surgically-confirmed cases and 5,486 controls in Denmark, replicated in 1,972 more cases and 1,812 controls across Denmark, the Netherlands and Sweden. It found 18 independent genomic regions, together explaining 9% of liability to the condition — a modest share, consistent with most of these being smaller-effect loci than DGKK. Several sit in genes with well-established roles in embryonic development, including HOXA4, IRX5, IRX6 and EYA1. Ten of this page's twelve variants come from this study; the other two are DGKK variants, one from each paper.
Both studies were conducted in European-ancestry populations, a real scope limit worth stating rather than assuming these findings generalise everywhere.
Hypospadias is diagnosed by physical examination at birth, not by genotype. Surgical correction, typically performed in infancy, is standard and usually successful. None of that is decided by the variants on this page.
DGKK's effect size is the one genuinely notable finding here — large enough that it approaches what a single-gene test might tell a family, in a way most of the loci on this page do not. Even so, no clinical guideline uses DGKK genotype to inform diagnosis, timing of surgery, or counselling; the diagnosis is made at physical examination, and treatment decisions rest on the anatomy found there.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Hypospadias comes down to these specific, well-studied positions — not a diagnosis.
The studies behind these variants recruited participants from different ancestries — a result found in one population doesn't always transfer to another. Based on 12 of 12 linked studies with a resolved discovery ancestry.
Databases, guidelines and references
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Hypospadias. MyGeneLog™. https://www.mygenelog.com/conditions/hypospadias
No. Hypospadias is diagnosed by physical examination at birth. These variants come from genome-wide association studies and are not used diagnostically.
Its effect size is unusually large for a common genetic variant — an odds ratio up to 3.9 in one replication sample, compared with the 1.1-1.3 range typical of most common-disease variants. That makes it a genuinely notable finding, though it still is not used diagnostically.
The 18 loci found in the larger 2014 study together explain about 9% of liability to the condition — a real but modest share, leaving most of the trait's heritability still unaccounted for by known common variants.
Yes — surgical correction, typically performed in infancy, is standard and usually successful.
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