CWH43 Variants in Idiopathic Normal-Pressure Hydrocephalus: An Integrated Population-Aware Interpretation of Genetic and Clinical Evidence

Background/Objectives: Reported CWH43 variants in idiopathic normal-pressure hydrocephalus (iNPH) have been interpreted under differing inheritance models. Methods: We reassessed five previously reported variants (L533Ter, K696fs, A626V, I292T, and A469S) using gnomAD v4.1.1 population data, ancestry-stratified homozygote and gene-constraint analyses, published United States and Nordic cohorts, and structural/transcript annotation. Results: L533Ter and K696fs had allele frequencies of 1.72% and 0.725%, with 300 and 47 observed homozygotes and no obvious homozygote depletion relative to HWE expectation. CWH43 showed little evidence of heterozygous loss-of-function constraint. For carriage of either L533Ter or K696fs, the source-reported OR was 2.60 (95% CI 1.12–6.03) in the United States cohort and 1.23 (95% CI 0.849–1.717) in FinnGen; a random-effects sensitivity summary was OR 1.62 (95% CI 0.80–3.27; I2 = 61%). Eighty-two registry-defined FinnGen controls carried biallelic genotypes involving these variants without a recorded hydrocephalus diagnosis at a median age of 63 years. The two truncating variants also occupy distinct predicted transcript and structural contexts. Conclusions: Population-scale evidence does not support a simple uniformly high-penetrance interpretation of L533Ter and K696fs, while the biallelic observations specifically constrain a highly penetrant recessive model. The available case–control evidence is directionally positive but heterogeneous and does not establish a statistically conclusive common cross-cohort effect; an incompletely penetrant, context-dependent susceptibility contribution remains plausible but requires further investigation. The three missense variants provide population and molecular context but do not define a shared effect size or penetrance model.