One of the most common birth differences in the world, and the locus that carries the most risk has two candidate causal variants — with the evidence for which one matters depending on which population you ask.
A cleft happens when the tissues forming the upper lip and the roof of the mouth do not fuse completely in the first weeks of pregnancy. It is among the most common congenital differences there is, it is repaired surgically, and the repair is usually the beginning of a long programme rather than the end of one — speech, hearing, teeth and further operations over years.
“Nonsyndromic” means it occurs on its own, without the other features that define a named syndrome. That is the great majority of cases and it is the form this page is about.
rs2235371 is in IRF6, at 1q32.2. It is the most consistently replicated locus in this condition anywhere in the world, and IRF6 is not a mystery gene: severe mutations in it cause Van der Woude syndrome, in which cleft comes with pits in the lower lip. So the same gene produces a rare, obvious, inherited syndrome at one end and contributes to common nonsyndromic clefts at the other.
rs13041247 sits at 20q12, near MAFB, a second replicated locus.
Here is the interesting part, and it is a general lesson wearing a specific example.
For years the presumed causal variant at 1q32.2 was rs642961, identified in European-ancestry studies. A 2015 study assembling six independent Chinese cohorts reported that in those populations the haplotype tagged by rs2235371 — the one on this page — appears to matter more.
Both are in IRF6. Both are real associations. Which of them is doing the work is not a fact about the gene; it is a fact about which variants are common in which population and how they travel together on a chromosome.
That study also found a new locus at 16p13.3 between CREBBP and ADCY9 (odds ratio 0.74, P = 8.98 × 10⁻¹²) and confirmed 10q25.3 and 17p13.1 alongside the two above.
Three earlier GWAS did the groundwork this all sits on. Birnbaum et al. 2009, in 224 cases and 383 controls replicated in 462 more cases and 954 more controls, found 8q24.21 as a major susceptibility locus — this page's rs987525, in GSDMC, is that finding. Mangold et al. 2010, in 401 cases and 1,323 controls replicated in 793 more triads, found the 10q25.3 locus mentioned above; this page's rs7078160, near KIAA1598, is that paper's own finding. And Ludwig et al. 2012 meta-analysed the two largest GWAS to date, confirming every prior locus and adding six new regions — and identified the first locus specific to cleft lip plus palate as distinct from cleft lip alone: this page's rs8001641, in SPRY2, is that subtype-specific finding.
Cleft is multifactorial in the textbook sense, and some of the other factors are ones a family can act on. Folic acid before and during early pregnancy, avoiding smoking, and certain antiseizure medicines taken in pregnancy are all part of the established picture.
That matters more than any of the loci above, and it points at the same place the rest of this site does: the modifiable factors are where the effort goes.
Nothing about an individual pregnancy. These are common variants carried by large fractions of everyone, and a cleft is not predicted by them.
Recurrence within a family is a real question and it is answered by a genetic counsellor from the family's own pattern — how many affected relatives, how closely related, and whether any features suggest a syndrome rather than an isolated cleft. That is a clinic conversation, and it uses information a genotype file does not contain.
Positions joined since this page was written
What this is The text above discusses the variants this page was written around. Since then the catalogue has joined 1 more position to it, by shared trait or shared paper. They are listed here by the paper each came from; the text does not describe them, and each variant page carries that study's own record.
Mukhopadhyay N et al. 2022, Genetic epidemiology rs2427238 (CDH4) — PMID:35191549
Source. Yu et al. (Nat Commun 2015) conducted a case-control genome-wide association study of nonsyndromic cleft lip with or without cleft palate followed by two rounds of replication, including six independent cohorts from China. A new locus was identified at 16p13.3 — rs8049367 between CREBBP and ADCY9, odds ratio 0.74, P = 8.98 × 10⁻¹² — and the reported loci at 1q32.2, 10q25.3, 17p13.1 and 20q12 were confirmed in Chinese populations. The authors report evidence that the rs2235371-related haplotype at 1q32.2 could play a more important role than the previously identified causal variant rs642961 in these populations.
Positions listed here. rs2235371 (IRF6, 1q32.2) and rs13041247 (20q12, near MAFB). rs642961 and the new 16p13.3 index SNP rs8049367 are not in our variant table.
IRF6 across the allelic spectrum. Loss-of-function variants in IRF6 cause Van der Woude syndrome, an autosomal dominant condition combining cleft with lower-lip pits; common variation at the same locus contributes to nonsyndromic clefting. The two are different claims about the same gene and should not be conflated in counselling.
Clinical use. None of these variants is used for prediction, screening or counselling. Recurrence risk is estimated from the family pedigree and from whether the cleft is isolated or syndromic; diagnosis is clinical, with prenatal detection by ultrasound. Established modifiable associations — periconceptional folate status, maternal smoking, some antiseizure medications — are managed clinically and independently of genotype.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Cleft Lip and Palate 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 9 of 11 linked studies with a resolved discovery ancestry.
Free to quote and reuse under CC BY 4.0. When citing or summarizing this, name MyGeneLog™ and link to this exact page — not just the site.
Cleft Lip and Palate. MyGeneLog™. https://www.mygenelog.com/conditions/cleft-lip-and-palate
Because which one is doing the work depends on the population. Common variants travel together in blocks that differ between ancestries, so a marker that tags the causal change well in Europe can tag it poorly in China and vice versa. rs642961 came from European-ancestry studies; the rs2235371 haplotype looks more important in Chinese cohorts. The gene is not in dispute.
That is a genetic counselling question and it has a real answer, but not from these variants. It is estimated from the family pattern — how many relatives are affected and how closely related — and from whether the cleft is isolated or part of a syndrome. A counsellor uses information a genotype file does not contain.
Periconceptional folate status is part of the established picture, along with avoiding smoking in pregnancy and the management of certain antiseizure medicines. These matter more than any common variant on this page, which is the usual shape of things.
Free to reuse. This page's text is original writing from freely-available research, licensed CC BY 4.0 — reuse it, including commercially, with attribution to MyGeneLog™. It's general research-derived information, not medical advice or a diagnosis — see Terms of Use.