The combination therapy of lumacaftor and ivacaftor (Orkambi®) is approved for patients bearing the major cystic fibrosis (CF) mutation: ΔF508. It has been predicted that Orkambi® could treat patients with rarer mutations of similar “theratype”; however, a standardized approach confirming efficacy in these cohorts has not been reported. Here, we demonstrate that patients bearing the rare mutation: c.3700 A>G, causing protein misprocessing and altered channel function—similar to ΔF508‐CFTR, are unlikely to yield a robust Orkambi® response. While in silico and biochemical studies confirmed that this mutation could be corrected and potentiated by lumacaftor and ivacaftor, respectively, this combination led to a minor in vitro response in patient‐derived tissue. A CRISPR/Cas9‐edited bronchial epithelial cell line bearing this mutation enabled studies showing that an “amplifier” compound, effective in increasing the levels of immature CFTR protein, augmented the Orkambi® response. Importantly, this “amplifier” effect was recapitulated in patient‐derived nasal cultures—providing the first evidence for its efficacy in augmenting Orkambi® in tissues harboring a rare CF‐causing mutation. We propose that this multi‐disciplinary approach, including creation of CRISPR/Cas9‐edited cells to profile modulators together with validation using primary tissue, will facilitate therapy development for patients with rare CF mutations. Synopsis Potential strategies for improving function in a rare CF‐causing mutation based on a CRISPR/Cas9‐edited bronchial cell line and patient‐derived nasal cultures. Molecular dynamic simulations predicted the consequences of the rare mutation c.3700 A>G on CFTR protein (ΔI1234_R1239‐CFTR) structure. Misprocessing and altered function of ΔI1234_R1239‐CFTR can be partially ameliorated by small molecule modulators of ΔF508‐CFTR. A CRISPR/Cas9‐edited HBE cell line recapitulates the endogenous expression of ΔI1234_R1239‐CFTR and response to ΔF508‐CFTR modulators. A novel small molecule amplifier (PTI‐CH) improves the effect of the corrector (VX‐809) and potentiator (VX‐770) on ΔI1234_R1239‐CFTR in CRISPR/Cas9‐engineered and patient‐specific tissues. Potential strategies for improving function in a rare CF‐causing mutation based on a CRISPR/Cas9‐edited bronchial cell line and patient‐derived nasal cultures.