Background <p>Degenerative cervical myelopathy (DCM)– often termed cervical spondylotic myelopathy– is the most common cause of spinal cord injury in adults, arising from age-related degenerative changes in the spine. Genetic susceptibility may modulate which individuals develop myelopathy under these mechanical stresses. <i>Calmodulin-1 (CALM1)</i> is a gene encoding calmodulin, a key calcium-binding protein involved in cartilage maintenance and neural signalling, and CALM1 variants have been implicated in degenerative joint disease. We hypothesized that a CALM1 polymorphism could influence DCM risk.</p> Methods <p>In this pilot case–control study, 48 DCM patients (with imaging-confirmed cervical spondylotic cord compression) {males (<i>n</i> = 42, 84.36%), females (<i>n</i> = 6, 12.76%)}with cervical disc anterolisthesis (degenerative), chronic neck pain (&gt; 3 months duration), and/or quadriparesis with positive bilateral Babinski’s sign, and 57 controls (with imaging- no significant degenerative changes in the disc) {males (<i>n</i> = 47, 82.45%), females (<i>n</i> = 10, 17.54%)} with acute neck pain (&lt; 3months duration), cervical spondylosis or acute traumatic spine injuries were recruited from an Indian population. This design aimed to distinguish genetic factors specific to degenerative pathology. All participants underwent Sanger sequencing of the <i>CALM1</i> gene to identify polymorphisms. The primary variant analyzed was a common single-nucleotide polymorphism (SNP) in <i>CALM1</i>’s regulatory region. Genotype and allele frequencies were compared between DCM cases and controls using Fisher’s exact test, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. No formal sample size calculation was performed due to limited prior data, as this study was exploratory.</p> Results <p>The cases group primarily exhibited three new intronic variations (NG_013338.1: g.11552G &gt; A, NG_013338.1:g.5361T &gt; C, and NG_013338.1:g.11731G &gt; A of the CALM1 gene). Among these, NG_013338.1:g.11731G &gt; A was significantly associated with DCM, with an odds ratio of 0.43 (<i>p</i>-value = 0.0117). In silico (i.e., using computer-based prediction models) analysis revealed that these intronic variations changed the splicing regulatory elements, which could impact gene expression. The CALM1 risk-allele frequency was similar in DCM patients (27.1%) and controls (14.0%, OR = 0.43, 95% CI 0.2–1.35; <i>p</i> = 0.012). No other <i>CALM1</i> coding variants showed significant case–control association. Routine laboratory parameters (e.g., calcium profiling, serum Vitamin B₁₂ levels) were comparable between groups, suggesting no metabolic confounders.</p> Conclusions <p>In this Indian cohort, <i>CALM1</i> polymorphism was not significantly associated with degenerative cervical myelopathy. The variant’s effect, if any, appears to be of low pathogenicity. These findings, while preliminary, provide novel population-specific data and highlight the importance of further research. This pilot study lays the groundwork for larger studies to elucidate genetic contributions to DCM, underscoring that CALM1 and similar variants merit continued investigation as hypothesis-generating candidates.</p>