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Chromosome 12
Home of the KRAS oncogene and the PKU-causing PAH locus.
Schematic of chromosome 12 showing the short (p) and long (q) arms. Arm ratio per GRCh38 - banding schematic.
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Overview
Chromosome 12 accounts for roughly 4.3 per cent of the DNA in each human cell and carries approximately 1,034 protein-coding genes. It is classified as submetacentric, meaning the centromere (the pinch point that divides the chromosome into a short arm, designated p, and a long arm, designated q) sits off-centre but not at the very end. This configuration creates a p arm that is noticeably shorter than the q arm when the chromosome condenses during cell division.
Clinically, chromosome 12 is known for several landmark discoveries. It harbours PAH at 12q23.2, the gene responsible for phenylketonuria, the first inherited metabolic disorder to be routinely screened for in newborns. It also carries KRAS at 12p12.1, a member of the RAS oncogene family whose somatic mutations drive a substantial proportion of pancreatic, colorectal and lung cancers. In addition, the chromosome hosts genes linked to bleeding disorders (VWF), inherited heart muscle disease (MYL2, PKP2), and a monogenic form of diabetes (HNF1A), making it a chromosomal hotspot for conditions encountered across NHS Genomic Medicine pathways.
Because chromosome 12 is a numbered autosome rather than a sex chromosome, it is inherited equally in males and females and does not show sex-linked inheritance patterns. Whole-chromosome aneuploidies (having an extra or missing copy of chromosome 12) are extremely rare in liveborn infants; trisomy 12 and monosomy 12 are usually incompatible with foetal survival and may be observed in miscarriage tissue examined by karyotype or chromosomal microarray.
Structure
Like every human chromosome, chromosome 12 consists of a single, continuous molecule of double-stranded DNA tightly compacted into a structure visible under a microscope during cell division. The short arm (12p) and the long arm (12q) are divided at the centromere, a specialised region enriched in repetitive DNA sequences and bound by proteins that attach the chromosome to spindle fibres during mitosis and meiosis. The submetacentric position of the centromere means that 12p is appreciably shorter than 12q, a characteristic readily seen on a karyotype or chromosome spread.
The DNA of chromosome 12 is packaged through multiple levels of organisation. The raw double helix is first wound around protein spools called histones to form nucleosomes, which in turn coil into a fibre of chromatin. During interphase, when cells are not dividing, chromatin exists in a relatively relaxed state, allowing genes to be switched on and off as needed. When a cell prepares to divide, the chromatin condenses further, eventually forming the compact X-shaped structure familiar from textbook images. This extreme compaction ensures that the 133.3 million base pairs of chromosome 12 can be accurately segregated into daughter cells without tangling or breaking.
Video: What is a karyotype?
Notable regions
Region 12p12.1 is the address of KRAS, one of three closely related human RAS genes (the others being HRAS and NRAS). KRAS encodes a small GTPase protein that cycles between active and inactive states, relaying growth signals from cell-surface receptors to the nucleus. Somatic mutations in KRAS (acquired in tumour cells rather than inherited through the germline) are found in roughly 30 per cent of all human cancers and are especially common in pancreatic ductal adenocarcinoma, where they appear in more than 90 per cent of cases. Germline pathogenic variants in KRAS are rare but cause RASopathies such as Noonan syndrome and cardiofaciocutaneous syndrome, developmental disorders characterised by distinctive facial features, heart defects, and an elevated risk of certain childhood tumours. The concentration of cancer-driving mutations at this locus has made KRAS a major focus of precision-oncology drug development, though targeting the active protein has historically proved challenging.
Further along the long arm at 12q23.2 lies PAH, the gene encoding phenylalanine hydroxylase, the enzyme responsible for converting the amino acid phenylalanine into tyrosine in the liver. Pathogenic loss-of-function variants in PAH prevent this conversion, allowing phenylalanine to accumulate in the blood and brain. Untreated, the resulting disorder (phenylketonuria, or PKU) causes irreversible intellectual disability, seizures, and behavioural problems. Because early dietary restriction of phenylalanine prevents these outcomes, every baby born in the UK undergoes newborn bloodspot screening (the heel-prick test) at around five days of age. Infants with persistently raised phenylalanine levels are referred to a specialist metabolic centre for confirmatory testing and lifelong dietary management. PAH was one of the first human disease genes to be cloned, and its study helped establish the principles of newborn screening and precision nutrition.
Region 12q15 contains MDM2, which encodes a protein that regulates the tumour suppressor p53 by tagging it for degradation. In normal cells this feedback loop prevents excessive p53 activity; in cancer cells, amplification of the MDM2 gene (multiple extra copies appearing in the tumour genome) effectively silences p53, removing a critical brake on cell division. MDM2 amplification is particularly common in well-differentiated and de-differentiated liposarcomas, a group of soft-tissue tumours, and testing for MDM2 copy number by fluorescence in-situ hybridisation (FISH) is used diagnostically in specialist sarcoma centres. Additional notable genes on chromosome 12 include VDR (the vitamin D receptor) at 12q13.2, and VWF (von Willebrand factor) at 12p13.31, pathogenic variants in which cause the most common inherited bleeding disorder in the UK.
Notable genes
KRAS is the most clinically consequential gene on chromosome 12 in terms of sheer disease burden, given its central role in common adult cancers. Somatic KRAS mutations are found across tumour types, but they are nearly ubiquitous in pancreatic cancer, present in roughly half of colorectal cancers, and common in lung adenocarcinoma. Germline KRAS variants, though much rarer, cause developmental syndromes with overlapping features including short stature, heart defects, distinctive facial appearance, and an increased risk of certain childhood malignancies. Testing for KRAS mutations in tumour tissue is now a routine part of the diagnostic pathway for advanced colorectal and lung cancer within NHS oncology services, as the mutation status influences eligibility for targeted therapies.
PAH remains the archetypal newborn-screening gene. More than 1,300 different pathogenic variants in PAH have been catalogued worldwide, and the severity of phenylketonuria varies depending on how much residual enzyme activity the variant permits. Individuals with two severe loss-of-function variants (classic PKU) require strict dietary phenylalanine restriction from infancy; those with milder variants may tolerate a less restrictive diet. Genetic testing of PAH is performed after an abnormal newborn screen to confirm the diagnosis, guide prognosis, and inform family planning. Women with PKU require particularly careful metabolic control before and during pregnancy to protect the developing fetus from high maternal phenylalanine levels, which can cause congenital heart defects and microcephaly (maternal PKU syndrome).
Other notable genes on chromosome 12 span a wide range of clinical domains. VWF encodes von Willebrand factor, a large adhesive protein essential for normal blood clotting; pathogenic variants cause von Willebrand disease, the most common inherited bleeding disorder, with clinically significant disease affecting roughly one in a thousand people in the UK. HNF1A encodes a transcription factor critical for insulin secretion in pancreatic beta cells; heterozygous pathogenic variants cause MODY3, a form of maturity-onset diabetes of the young that typically presents in adolescence or early adulthood and is sensitive to low-dose sulfonylurea tablets rather than insulin. PKP2 encodes plakophilin 2, a desmosomal protein in heart muscle; pathogenic variants are a leading cause of arrhythmogenic right ventricular cardiomyopathy, a condition that can trigger life-threatening arrhythmias in young adults and athletes. ACVRL1 encodes a receptor for vascular growth factors; pathogenic variants cause hereditary haemorrhagic telangiectasia type 2, characterised by abnormal blood vessels that bleed easily in the nose, lungs, brain, and liver.
Chromosomal disorders
Whole-chromosome aneuploidies involving chromosome 12 (trisomy 12, in which three copies are present, or monosomy 12, in which one copy is missing) are exceedingly rare in liveborn individuals. These imbalances are typically lethal during foetal development and account for a small proportion of miscarriages. When detected on chorionic-villus sampling or amniocentesis karyotype, they usually reflect true foetal aneuploidy rather than confined placental mosaicism, and the prognosis for ongoing pregnancy is generally poor. Post-natally, trisomy 12 may occasionally be observed in a mosaic state (present in only some cells), though published case reports are sparse and the clinical picture variable. Unlike the common autosomal trisomies (Down, Edwards, and Patau syndromes), trisomy 12 is not included in standard non-invasive prenatal testing (NIPT) panels offered by the NHS, because it is so rarely compatible with survival to term.
Structural rearrangements of chromosome 12 are more commonly encountered. Balanced translocations, in which a segment of chromosome 12 is swapped with a segment from another chromosome without any net loss or gain of genetic material, are usually harmless to the person carrying them but can lead to unbalanced offspring, miscarriage, or infertility. Cytogenetic laboratories within NHS regional genetics centres identify these rearrangements during karyotyping for recurrent pregnancy loss or a child with developmental delay. Unbalanced translocations or deletions involving chromosome 12 can result in intellectual disability, growth delay, and congenital anomalies, with the specific features depending on which genes are lost or duplicated. Chromosomal microarray analysis, which detects submicroscopic copy-number changes across the genome, is the first-tier test for unexplained developmental delay in children and often reveals small deletions or duplications of chromosome 12 regions that would be invisible on a standard karyotype.
Prenatal screening & diagnosis
Because whole-chromosome 12 aneuploidies are so rare and generally lethal early in pregnancy, chromosome 12 abnormalities are not a focus of routine antenatal screening in the way that trisomies 21, 18, and 13 are. The combined first-trimester screening offered by the NHS Fetal Anomaly Screening Programme (nuchal translucency measurement plus maternal serum markers) and non-invasive prenatal testing (which analyses cell-free foetal DNA in maternal blood) are designed to detect the common viable trisomies and do not routinely interrogate chromosome 12. If a structural anomaly is detected on the mid-pregnancy anomaly scan (the 20-week scan), further investigation with foetal karyotype or chromosomal microarray may be offered, and occasionally this will reveal a structural rearrangement involving chromosome 12.
Carrier screening for recessive conditions caused by chromosome 12 genes is available in certain contexts. For example, individuals with a family history of phenylketonuria may be offered PAH variant testing to establish their carrier status before or during pregnancy, particularly in communities where certain pathogenic variants are common. Preconception or prenatal carrier screening panels that include PAH and other metabolic-disease genes are increasingly used in some NHS settings and in the private sector, allowing couples to understand their risk of having a child with a recessive condition. If both partners are found to carry pathogenic variants in the same gene, options including preimplantation genetic testing (PGT) or prenatal diagnosis with chorionic-villus sampling or amniocentesis can be discussed with a clinical genetics team.
Inheritance & recurrence
Most medically significant variants in chromosome 12 genes follow autosomal inheritance patterns. Autosomal recessive conditions, such as phenylketonuria and some forms of von Willebrand disease type 3, require a pathogenic variant on both copies of the gene (one inherited from each parent). Parents are typically unaffected carriers, and each pregnancy has a one-in-four chance of producing an affected child, a one-in-two chance of a carrier, and a one-in-four chance of a non-carrier. Autosomal dominant conditions, such as MODY3 diabetes (HNF1A), hereditary haemorrhagic telangiectasia type 2 (ACVRL1), and arrhythmogenic right ventricular cardiomyopathy (PKP2), require only one pathogenic variant to cause disease. An affected parent has a 50 per cent chance of passing the variant to each child, though expressivity (how severely the condition manifests) can vary widely even within the same family.
De novo (new) pathogenic variants can arise in chromosome 12 genes, particularly in conditions such as Kabuki syndrome (caused by variants in KMT2D at 12q13.12), where a substantial proportion of cases result from new mutations not present in either parent. When a condition is diagnosed in a child and no family history is evident, parental testing is usually recommended to distinguish between inherited and de novo variants, as this distinction affects recurrence risk for future pregnancies. If a variant is confirmed de novo, the recurrence risk is generally low (though not zero, because of the possibility of germline mosaicism, where the variant is present in a proportion of a parent's egg or sperm cells).
Families seeking advice on recurrence risk, carrier testing for relatives, or reproductive options are typically referred to their local NHS clinical genetics service. A genetic counsellor or consultant geneticist can provide tailored risk assessment, arrange predictive testing for at-risk relatives where appropriate, and discuss options such as preimplantation genetic testing for couples at high risk of passing on a serious inherited condition.
Frequently asked questions
What is the most common condition caused by a chromosome 12 gene?
Von Willebrand disease, caused by pathogenic variants in the VWF gene at 12p13.31, is the most common inherited bleeding disorder in the UK, affecting roughly one in a thousand people. Phenylketonuria (PAH gene at 12q23.2) is rarer, with an incidence of approximately one in 10,000 newborns, but is universally screened for on the newborn bloodspot test. Somatic mutations in KRAS, though not inherited, are present in a large proportion of common adult cancers.
Can you inherit an extra or missing copy of chromosome 12?
Whole-chromosome trisomy 12 (three copies) or monosomy 12 (one copy) are almost always incompatible with survival and typically result in miscarriage. Very rarely, mosaic trisomy 12 (where some cells have three copies and others have the usual two) has been reported, but it remains extremely uncommon. Structural rearrangements (deletions, duplications, or translocations involving part of chromosome 12) can be inherited or occur de novo and may cause developmental delay or other features depending on which genes are affected.
Why is every UK baby tested for phenylketonuria?
Phenylketonuria is included in the NHS newborn bloodspot screening programme because it is a treatable condition that, if undetected, causes severe and irreversible intellectual disability. Early diagnosis through the heel-prick test at around five days of age allows babies with PKU to start a low-phenylalanine diet before symptoms develop, preventing brain damage and allowing near-normal development. The test measures phenylalanine levels in a few drops of blood, and elevated results trigger confirmatory genetic testing of the PAH gene.
If I carry a KRAS mutation, will I definitely get cancer?
Germline (inherited) KRAS pathogenic variants cause developmental RASopathies such as Noonan syndrome or cardiofaciocutaneous syndrome, which carry a modestly increased risk of certain childhood tumours, but do not guarantee cancer. The KRAS mutations frequently discussed in the context of adult cancers (pancreatic, colorectal, lung) are somatic mutations, meaning they arise in individual cells during a person's lifetime and are not inherited or passed on to children. Genetic testing in cancer care looks for these acquired mutations in tumour tissue to guide treatment decisions, not to assess inherited cancer risk.
What does it mean if my child's microarray report mentions a chromosome 12 deletion?
A deletion detected on chromosomal microarray means a small piece of chromosome 12 is missing, which can affect one or more genes in that region. The clinical significance depends on the size of the deletion, which genes are involved, and whether the deletion has been reported previously in individuals with similar features. Your child's clinical genetics team will interpret the result in the context of their developmental history and examination findings, and may arrange parental testing to determine whether the deletion is inherited or de novo, which helps refine prognosis and recurrence risk.
Launch-set genes on chromosome 12
Genes on this chromosome that currently have dedicated pages in the library. This list grows as we publish more.