Cuff Tear Arthropathy is characterised by massive rotator cuff tears, glenohumeral joint destruction and joint effusions containing basic calcium phosphate and calcium pyrophosphate dihydrate crystals. We have investigated the role of the ANKH gene in patients with cuff tear arthropathy and the effect of mutations on protein function. The transmembrane protein ANKH transports inorganic pyrophosphate (PPi) from the intracellular to extracellular space. Control of the extracellular levels of PPi is crucial in preventing calcium crystal formation. Genomic DNA was prepared from peripheral blood leucocytes from 22 patients with cuff tear arthropathy diagnosed clinically and radiologically. All 12 exons and exon-intron boundaries from the ANKH gene were PCR amplified and sequenced with BigDye version 3.1 terminator kit (ABI), and analysed using ABI PRISM ® 3100 Genetic Analyser. ANKH complementary DNA (cDNA) was ligated with mammalian expression vector pcDNA3 and site directed mutagenesis was used to make the ANKH mutation detected in the cases. Human articular chondrocytes were transfected with the cDNA variants and PPi concentrations measured. A G-to-A single nucleotide polymorphism in the 3′ untranslated region (3′UTR) of ANKH was identified. The G/A genotype was seen more frequently in the cases (45%) when compared to controls (20%) (p= 0.0008). We observed altered levels of extracellular PPi in human chondrocytes transfected with ANKH cDNA with the 3′ UTR variant when compared with control cells and normal ANKH cDNA. Cuff Tear Arthropathy appears to be heritable via a G-to-A transition in the 3′UTR of ANKH that alters extracellular PPi concentrations in chondrocyte cells. This supports a hypothesis of a primary crystal mediated arthropathy in patients with Cuff Tear Arthropathy.