We investigated the impact of the human‐specific gene CHRFAM7A on the function of α7 nicotinic acetylcholine receptors (α7 nAChRs) in two different types of neurons: human‐induced pluripotent stem cell (hiPSC)‐derived cortical neurons, and superior cervical ganglion (SCG) neurons, taken from transgenic mice expressing CHRFAM7A. dupα7, the gene product of CHRFAM7A , which lacks a major part of the extracellular N‐terminal ligand‐binding domain, co‐assembles with α7, the gene product of CHRNA7 . We assessed the receptor function in hiPSC‐derived cortical and SCG neurons with Fura‐2 calcium imaging and three different α7‐specific ligands: PNU282987, choline, and 4BP‐TQS. Given the short‐lived open state of α7 receptors, we combined the two orthosteric agonists PNU282987 and choline with the type‐2 positive allosteric modulator (PAM II) PNU120596. In line with different cellular models used previously, we demonstrate that CHRFAM7A has a major impact on nicotinic α7 nAChRs by reducing calcium transients in response to all three agonists.