The Jetpack comment submission results in a 404 inside the iframe when the plugin is connected with WP.com. This does not happen if Jetpack is activated and the plugin is disconnected from WP.com.
I have seen multiple fixes for this around the internet, ranging from checking whether wp-comments-post.php is in the WP root folder and has the correct permissions, to complex htaccess/Apache server modification.
This began happening last Jetpack update. It appears to be the result of a redirect URL in the plugin that is 404ing for some reason.