Include Berlin in southern Germany trip?

interested in is historical sites, museums, local charm/ food

Definitely yes: Berlin plus Potsdam. Around 170 museums available. Charm differs very much from Kiez to Kiez (neighborhood, not district). I could start a long list with possibilities easily filling 4 full days but most available already written in this forum.

Train travel is very easy and comfortable by fast direct connections: https://int.bahn.de/en

Cars are not a plus in the big cities for most visitors.

but the long drive between Frankfurt and Berlin without much to see in between

There are dozens of places matching your interests. If you mean "much to see" by driving by on the Autobahn alone I would agree.

Bavaria offers you the natural beauty & local charm on your list. And—while Munich has great museums— many of the best museum collections are to be found in Berlin. It is about a four-hour train ride from either Frankfurt or Munich to Berlin. You might want to check into Deutsche Bahn’s “D-Ticket ” and other ticket packages offered by Deutsche Bahn. www.Seat61.com has more info by searching under Germany.

Kenko, mentioning the D-Ticket after promising a 4-hours train ride could lead to wrong conclusions by OP because D-ticket does not include using long-distance trains which are the only trains operating a 4-hour direct connection.

Mark, Yes— and the D-Ticket also doesn’t cover the whole family. Depending on the OP’s itinerary, some of the Regional Train passes might pencil out along with Sparspreis tickets for the trip to Berlin, if Berlin is included.
I definitely wouldn’t recommend travelling into Munich, Frankfurt or Berlin in a rental car. Better to rent when departing Munich and return it when first anrriving in Frankfurt. Note the price of a vehicle that’s going to hold all 6 passengers along with their luggage will be double that of a sedan. It’s not going to be as inexpensive as it is in the U.S.

Brace yourselves for sticker shock and start pricing car rental alternatives at www.AutoEurope.com which brokers car rentals for the big-name agencies.

Thank you great information so far! Yes, as suggested in the thread we definitely not plan on bringing a vehicle into the big cities. Original plan is to rent in Munich and drive to the southern Germany locations and drop off in Frankfurt if we decide to include Berlin that in the itinerary.
Our family is used to packing light, just a travel backpack per person. My mom is not, but we’re good on that front collectively.
We did a similar trip when I was pregnant with my oldest son minus the Frankfurt to Berlin. Rented a van for my parents, sister and our husbands.
However, when traveling only with our immediate family, we prefer and are comfortable using public transportation, metro tubes, and buses ect.

I am interested in learning more about the in city public transport and how mobility accessible it is. Also very interested in learning more about the different types of trains specifically for the longer distance between Frankfurt and Berlin.

more about the different types of trains specifically for the longer distance between Frankfurt and Berlin

The long-distance trains of Deutsche Bahn (DB) are shown and shortly explained here:
https://int.bahn.de/en/trains/long-distance-trains

Link to ICE network plan: https://cms.static-bahn.de/wmedia/redaktion/aushaenge/streckenkarte/Liniennetz-ICE-IC-2026-Stand-09-2025.pdf

Sprinters are ICE connections with less stops. More details and network map of DB sprinters.

Between Frankfurt and Berlin a lot of ICE 1 and 2 are used, they have 2-3 stairs at entry. For assistance see MSC below. If you add Cologne before / after Berlin you can enjoy a very new ICE L. The "L" stands for low floor - no stairs between train and station. Their high speed is only 230 km/h, not 300, and they are designed to people with various special needs, also mobility issues. More details about about ICE L in German language. For photos see the bottom or click on the pluses in "Virtueller Rundgang".

DB has also a free-of-charge service for accessible travel: Mobility Service Centre (MSC). English PDF brochure;
https://assets.static-bahn.de/dam/jcr:b5a2b19d-487a-4ff8-8e4a-e4480e2b43ca/Informations%20for%20people%20with%20reduced%20mobility.pdf

Tip: for groups 6+ persons you can use group travel journey planner: https://int.bahn.de/en/offers/group-travel

more about the in city public transport and how mobility accessible it is

The Special Olympics World Games were held in Germany for the first time in 2023 and hosted by Berlin. One year before, the National Games 2022 already took place in the German capital as well. So, some advanced experience in town.

Berlin is widely flat (runners love it) and offers a lot of accessible sights:
https://www.visitberlin.de/en/accessible-berlin

Berlin's public transport has various supports, e. g. lifts at stations, buses lowering height of entry, and so on. They have also journey planning apps which allow to find and plan an accessible route / journey. More:
https://nachgefragt.bvg.de/planning-an-accessible-route/

This map contains Berlin's train network (S-Bahn and U-Bahn / subway). You can switch on/off station services such as lifts:
https://sbahn.berlin/en/route-map/

For S-Bahn usage elevator and escalator outages are listed:
https://sbahn.berlin/en/plan-a-journey/rail-stations/accessible-travel/elevator-and-escalator-outages/?acc=acc2000-tab130

Hope, this helps.

A quick addendum, just in case: Going with local trains as the D-Ticket requires would possibly be even cheaper when using a shared ticket like „Quer-Durchs-Land“, but regardless of the ticket it will be about 10 hours one way - so it might be really beneficial to have an intermediate stop on the way for 2 nights, if the schedule allows for this.
It also seems that going from Munich might be quicker than from Frankfurt (much to my surprise), local trains would amount to 8 hours with fewer changes, and long distance is with about 4 hours just as fast from either point - if that helps planning.

"I am interested in learning more about the in city public transport and how mobility accessible it is"

Mobility is indeed the issue here.

Berlin is a gigantic place.. Inner-city transportation is everywhere - it is streamlined and efficient, but due to its size, it is not at all simple to figure out how to get from A to B (even if you are accustomed to public transport) and multiple means of transport are often required to accomplish a single trip. Local Germans know the system, and they are experienced, well trained and normally in good shape after using Berlin's subways, trams, buses, etc. - even the older ones seem to do well. But you have a 78-year-old with you with "mobility limitations" who does not share your travel experiences in Europe's inner cities, who may or may not have your level of stamina and may or may not end up exhausted making all the moves that are needed to get on/off transportation equipment, to use staircases and escalators, and to share tight spaces with crowds of others in a busy urban environment.

Berlin is worth seeing. But not at the expense of a consequential fall for someone who is even a bit fragile. Unless your mom has insisted on going to Berlin, I would strike it from your plans, and if she has insisted, I would go deep into the "what ifs" with her before giving in.

How many days will you be in Germany?

If a week or less, stay in Bavaria.
If 10 days or more, do Berlin for about 4 days. Also, consider stopping in Dresden on your way to Munich.

The length of your trip should be considered.
I have a special fondness for Berlin, having summered there with my grandparents as a child. There are many sights to experience there and of course, it has always been a fun place to visit. If you have at least a few days to spare, the train from Frankfurt to Berlin is an easy way to travel. I can remember making the trip on a coal fired train before the wall came down. Now, it's as easy as can be. Drop the car, hop on the train and go. In Berlin, the public transportation makes getting around super. Even someone pushing 80 should be fine visiting there. There will be stairs, lots of stairs in and out of subways, but it's not like a visit to Italy, the land of a million steps. If you have the time, go for it.

Only you and the family can decide if it is worth it to go to Berlin. I have never felt the desire to do so. Other than the Berlin question, I wonder at Frankfurt being the northernmost point. No middle Rhine ? My teenage or 9 year old self would love the Rhine with all its castles. Burg Rheinfels, especially if you can tour the tunnels, and for a ruin probably all to your own, Burg Ruine Stahlberg by Bacharach. Maybe a night in the castle hostel Stahleck above Bacharach.

I would also look at round trip flights to/from Frankfurt. That has always been the cheapest for me. There are countless scenic routes between there and Munich.

I am slightly younger than your mom. We are visiting family in Stuttgart this May, with RT flights in and out of Frankfurt. After a week with them we are flying to Berlin from Stuttgart for a few days, and then flying to Frankfurt the night before our flight home.

I agree that the length of your trip matters very much. Berlin is massive and has so many things to see and do. I think you'd need a week there to see half of it. Also, it can be VERY hot there in summer. It was the hottest place I visited in 2018 (which was a very hot summer), with temperatures in the 90s.
My recommendation would be to slow down and spend more time with your family. I agree that the Rhine valley (and the Mosel!) would make a nice 2-3 day addition.

Berlin is massive and honestly not as handicapped friendly as the IS. There are often long distances to walk and stairs in Ubahn stations. I went to Berlin first and while I liked seeing the sites I thought Munich much more slowpaced and easier to navigate. Plus it’s undeniably more beautiful. Try to go to Potsdam if you go to Berlin because it’s a beautiful old town.

Whether it’s worth it is up to your family. I will also say that my opinion is an outlier since most people prefer Berlin to Munich.