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Background: Esophageal squamous cell carcinoma (ESCC) has a poor prognosis and occurs with high frequency in China. In particular, Fujian is one of the high-incidence areas of ESCC in China and the somatic mutation profile of ESCC there remains unclear. Patients and methods: Whole-exome sequencing (WES) was performed in 49 matched ESCC tumor-normal specimens to examine the somatic mutation profiles. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between mutational profile and survival were derived from Cox regression model. Results: We constructed a preliminary somatic mutation profiling of ESCC in Fujian. Exome sequencing data showed that the main base substitutions in ESCC were C > T transformation (close to 50%), C > A and T > C transversion. The study identified 21 significantly mutated genes, including 8 driver genes and 11 predicted driver genes. Among the 19 driver or predicted driver genes, 9 are novel (OBSCN, PKHD1L1, FSIP2, HRNR, CUBN, CELSR3, SCN7A, TULP4, SRRM2) and 10 have been previously reported. Three mutational signatures were identified to be prevalent in ESCC including Signature_15, Signature_4 and Signature_6, of which Signature_15 was related to prognosis of ESCC (HR 2.81, 95% CI 1.30–6.05; p = 0.008). Survival analysis showed that SCN7A was correlated to overall survival with an HR of 2.76 (95% CI 0.96–7.90, p = 0.058). After controlling for confounding factors such as age, gender, stage and location, the correlation between SCN7A and survival was statistically significant based on multivariate COX regression analysis (HR 4.76, 95% CI 1.20–18.85; p = 0.026, padjust = 0.053). The tumor vascular invasion was associated with SCN7A of ESCC patients (p = 0.028). Conclusion: In summary, this study provided comprehensive analysis of the somatic mutation profiles of ESCC, and identified SCN7A and Signature_15 for the prognosis of ESCC for the first time. The findings might serve as a conceptual basis for molecular diagnosis and prevention of ESCC. [ABSTRACT FROM AUTHOR]