The short answer is, no, there were no significant trails along the route of US 395.

Even back in the 1840s the bulk of the (white) population of Oregon lay to the west of the Cascades; predominantly in the Willamette Valley. What little overland travel existed between Oregon and California followed the western section of the Applegate Trail; largely along the route of I-5 between Medford and Redding and sticking to the Willamette in Oregon, and the Central Valley in California. The US 395 route roaming as it does across a ton of deserts and mountains would have been avoided at all costs.

The bulk of the travel was from the East to the West though. Few if any settlers would have travelled from Oregon to California. The Willamette Valley was filled with exceptionally rich farmland. So anyone who made it to Portland, Salem, or Eugene would have had little inclination to head somewhere else. And if someone did decide to seek their fortune in California from Oregon, they typically would have done so by ship.

Those traveling cross country to Southern California would take various trails either following the northern route along the Oregon Trail till SW Wyoming where they would cut south following the Mormon Trail and the Old Spanish Trail or following the Santa Fe/Cimarron Trails to Santa Fe and then either the Old Spanish Trail or the Butterfield Overland route to Southern California.

Were there Native American tribes along the way?

California was heavily settled with native peoples pretty much everywhere.

Was the climate good for travel at that time?

Passing through harsh desert like 395 does, much of the route would have been unusable for much of the year.

Was southern California seen as a good place to settle?

Not especially. Los Angeles and San Diego saw only moderate growth until the 20th century. For the first 5 decades under US control, the population of California was dominated by San Francisco, Sacramento, Stockton, and the Central Valley. Southern California was too dry for significant growth until the major water projects of the late 19th century and early 20th century were built. Local agriculture was dominated by dryland farming and cattle. It was only once the aqueducts, railroads, and ports were all developed that Southern California began to be seen as a particularly desirable place to live.