G12A

G12A denotes a missense substitution at codon 12 of certain small GTPases, in which glycine (G) at position 12 is replaced by alanine (A). It is most commonly described in members of the Ras family, including KRAS, HRAS, and NRAS, but can be reported in other GTPases as well.

Codon 12 is located in the P-loop GTPase domain; substitutions at this site impair intrinsic GTPase activity and commonly result in constitutive activation of the protein, leading to persistent signaling through downstream pathways such as RAF-MEK-ERK and PI3K-AKT-mTOR.

In cancer, G12A mutations are among the activating mutations observed in several cancers, though less frequent than G12D or G12V; they have been reported in pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

Clinical significance is context dependent: as an oncogenic driver, G12A can influence tumor behavior and treatment response, and may be associated with resistance or sensitivity to certain targeted therapies depending on the tissue.

Therapeutic implications: there are no approved G12A-specific inhibitors; treatment usually targets downstream signaling with MEK inhibitors or PI3K/AKT/mTOR inhibitors, and research is ongoing into allele-specific inhibitors and pan-RAS strategies.

Detection is by DNA sequencing, such as targeted gene panels or next-generation sequencing; annotation indicates the gene (e.g., KRAS) and the codon change (G12A).