BackgroundCongenital insensitivity to pain (CIP) is a rare autosomal recessive disorder characterized primarily by an inability to perceive physical pain from birth, resulting in the accumulation of bruising, inflammation, and fractures that affect patient’s life expectancy. CIP has different forms including CIP and CIPA. CIP with Anhidrosis (CIPA) is the most common type of CIP, which is caused mainly by mutations inNTRK1andNGFgenes, and is characterized by mental retardation and the inability to sweat (Anhidrosis). Because of high consanguinity rates in Palestine, this rare disease appears to have a higher frequency than in other communities. However, there were no systematic studies to address the genetic factors that cause CIP in the Palestinian community.MethodsIn our study, we used Sanger and Whole exome sequencing to genotype members of five CIP-affected Palestinian families.ResultsOur results confirm the presence of the founder c.1860-1861insT mutation in theNTRK1gene of Palestinian Bedouin CIPA patients. Furthermore, one CIPA family carried a missense c.2170 G > A (G724 S) mutation in exon 16 of theNTRK1gene. Finally, a novel nonsense c.901 A > T mutation (K301*) was detected in exon 7 of theSCN9Agene in CIP without anhidrosis family.ConclusionsOur study revealed three mutations that cause CIP and CIPA in the Palestinian community, which can help in improving the process of diagnosis and genetic counseling and establishing protocols for the diagnosis and follow-up for the affected individuals. This is especially important given that early diagnosis and medical care interference can prevent unpleasant CIP and CIPA complications.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12920-023-01544-5.