diff --git a/moto/ec2/models.py b/moto/ec2/models.py
index 33eaef774..e9e375d26 100644
--- a/moto/ec2/models.py
+++ b/moto/ec2/models.py
@@ -4689,7 +4689,7 @@ class RouteTableBackend(object):
                 route_table_id,
                 destination_cidr_block=None,
                 local=True,
-                destination_ipv6_cidr_block=ipv6_cidr,
+                destination_ipv6_cidr_block=ipv6_cidr.get("cidr_block"),
             )
 
         return route_table
@@ -4785,6 +4785,7 @@ class Route(CloudFormationModel):
         route_table,
         destination_cidr_block,
         destination_ipv6_cidr_block,
+        prefix_list=None,
         local=False,
         gateway=None,
         instance=None,
@@ -4800,6 +4801,7 @@ class Route(CloudFormationModel):
         self.route_table = route_table
         self.destination_cidr_block = destination_cidr_block
         self.destination_ipv6_cidr_block = destination_ipv6_cidr_block
+        self.prefix_list = prefix_list
         self.local = local
         self.gateway = gateway
         self.instance = instance
@@ -5071,6 +5073,7 @@ class RouteBackend(object):
         route_table_id,
         destination_cidr_block,
         destination_ipv6_cidr_block=None,
+        destination_prefix_list_id=None,
         local=False,
         gateway_id=None,
         instance_id=None,
@@ -5085,6 +5088,7 @@ class RouteBackend(object):
         transit_gateway = None
         egress_only_igw = None
         interface = None
+        prefix_list = None
 
         route_table = self.get_route_table(route_table_id)
 
@@ -5111,11 +5115,14 @@ class RouteBackend(object):
                 egress_only_igw = self.get_egress_only_igw(egress_only_igw_id)
             if transit_gateway_id is not None:
                 transit_gateway = self.transit_gateways.get(transit_gateway_id)
+            if destination_prefix_list_id is not None:
+                prefix_list = self.managed_prefix_lists.get(destination_prefix_list_id)
 
         route = Route(
             route_table,
             destination_cidr_block,
             destination_ipv6_cidr_block,
+            prefix_list,
             local=local,
             gateway=gateway,
             instance=self.get_instance(instance_id) if instance_id else None,
@@ -5134,25 +5141,46 @@ class RouteBackend(object):
         self,
         route_table_id,
         destination_cidr_block,
+        destination_ipv6_cidr_block=None,
+        destination_prefix_list_id=None,
+        nat_gateway_id=None,
+        egress_only_igw_id=None,
+        transit_gateway_id=None,
         gateway_id=None,
         instance_id=None,
         interface_id=None,
         vpc_peering_connection_id=None,
     ):
         route_table = self.get_route_table(route_table_id)
-        route_id = generate_route_id(route_table.id, destination_cidr_block)
+        route_id = generate_route_id(
+            route_table.id, destination_cidr_block, destination_ipv6_cidr_block
+        )
         route = route_table.routes[route_id]
 
         if interface_id:
             self.raise_not_implemented_error("ReplaceRoute to NetworkInterfaceId")
 
         route.gateway = None
+        route.nat_gateway = None
+        route.egress_only_igw = None
+        route.transit_gateway = None
         if gateway_id:
             if EC2_RESOURCE_TO_PREFIX["vpn-gateway"] in gateway_id:
                 route.gateway = self.get_vpn_gateway(gateway_id)
             elif EC2_RESOURCE_TO_PREFIX["internet-gateway"] in gateway_id:
                 route.gateway = self.get_internet_gateway(gateway_id)
 
+        if nat_gateway_id is not None:
+            route.nat_gateway = self.nat_gateways.get(nat_gateway_id)
+        if egress_only_igw_id is not None:
+            route.egress_only_igw = self.get_egress_only_igw(egress_only_igw_id)
+        if transit_gateway_id is not None:
+            route.transit_gateway = self.transit_gateways.get(transit_gateway_id)
+        if destination_prefix_list_id is not None:
+            route.prefix_list = self.managed_prefix_lists.get(
+                destination_prefix_list_id
+            )
+
         route.instance = self.get_instance(instance_id) if instance_id else None
         route.interface = None
         route.vpc_pcx = (
diff --git a/moto/ec2/responses/route_tables.py b/moto/ec2/responses/route_tables.py
index 137bc92e1..3f4fc6716 100644
--- a/moto/ec2/responses/route_tables.py
+++ b/moto/ec2/responses/route_tables.py
@@ -18,6 +18,7 @@ class RouteTables(BaseResponse):
         route_table_id = self._get_param("RouteTableId")
         destination_cidr_block = self._get_param("DestinationCidrBlock")
         destination_ipv6_cidr_block = self._get_param("DestinationIpv6CidrBlock")
+        destination_prefix_list_id = self._get_param("DestinationPrefixListId")
         gateway_id = self._get_param("GatewayId")
         instance_id = self._get_param("InstanceId")
         nat_gateway_id = self._get_param("NatGatewayId")
@@ -30,6 +31,7 @@ class RouteTables(BaseResponse):
             route_table_id,
             destination_cidr_block,
             destination_ipv6_cidr_block,
+            destination_prefix_list_id,
             gateway_id=gateway_id,
             instance_id=instance_id,
             nat_gateway_id=nat_gateway_id,
@@ -83,14 +85,24 @@ class RouteTables(BaseResponse):
     def replace_route(self):
         route_table_id = self._get_param("RouteTableId")
         destination_cidr_block = self._get_param("DestinationCidrBlock")
+        destination_ipv6_cidr_block = self._get_param("DestinationIpv6CidrBlock")
+        destination_prefix_list_id = self._get_param("DestinationPrefixListId")
         gateway_id = self._get_param("GatewayId")
         instance_id = self._get_param("InstanceId")
         interface_id = self._get_param("NetworkInterfaceId")
         pcx_id = self._get_param("VpcPeeringConnectionId")
+        nat_gateway_id = self._get_param("NatGatewayId")
+        egress_only_igw_id = self._get_param("EgressOnlyInternetGatewayId")
+        transit_gateway_id = self._get_param("TransitGatewayId")
 
         self.ec2_backend.replace_route(
             route_table_id,
             destination_cidr_block,
+            destination_ipv6_cidr_block,
+            destination_prefix_list_id,
+            nat_gateway_id,
+            egress_only_igw_id,
+            transit_gateway_id,
             gateway_id=gateway_id,
             instance_id=instance_id,
             interface_id=interface_id,
@@ -176,13 +188,18 @@ DESCRIBE_ROUTE_TABLES_RESPONSE = """
                 {% if route.destination_ipv6_cidr_block %}
                 <destinationIpv6CidrBlock>{{ route.destination_ipv6_cidr_block }}</destinationIpv6CidrBlock>
                 {% else %}
-                <destinationCidrBlock>{{ route.destination_cidr_block }}</destinationCidrBlock>
+                <destinationCidrBlock>{{ route.destination_cidr_block or "" }}</destinationCidrBlock>
                 {% endif %}
                 {% if route.local %}
                   <gatewayId>local</gatewayId>
                   <origin>CreateRouteTable</origin>
                   <state>active</state>
                 {% endif %}
+                {% if route.prefix_list %}
+                  <destinationPrefixListId>{{ route.prefix_list.id }}</destinationPrefixListId>
+                  <origin>CreateRoute</origin>
+                  <state>active</state>
+                {% endif %}
                 {% if route.gateway %}
                   <gatewayId>{{ route.gateway.id }}</gatewayId>
                   <origin>CreateRoute</origin>
diff --git a/tests/terraform-tests.success.txt b/tests/terraform-tests.success.txt
index 9d90ca3ed..9fd5a291b 100644
--- a/tests/terraform-tests.success.txt
+++ b/tests/terraform-tests.success.txt
@@ -94,7 +94,6 @@ TestAccAWSUserGroupMembership
 TestAccAWSUserPolicyAttachment
 TestAccAWSUserSSHKey
 TestAccAWSVpc_
-TestAccAWSRouteTable_disappears
 TestAccAWSAPIGatewayStage_basic
 TestAccAWSAPIGatewayStage_accessLogSettings_kinesis
 TestAccAWSAPIGatewayStage_accessLogSettings
@@ -111,6 +110,8 @@ TestAccAWSRouteTable_IPv6_To_EgressOnlyInternetGateway
 TestAccAWSRouteTable_IPv6_To_NetworkInterface_Unattached
 TestAccAWSRouteTable_disappears
 TestAccAWSRouteTable_basic
+TestAccAWSRouteTable_MultipleRoutes
+TestAccAWSRouteTable_PrefixList_To_InternetGateway
 TestAccAWSSsmDocumentDataSource
 TestAccAwsEc2ManagedPrefixList
 TestAccAWSEgressOnlyInternetGateway
diff --git a/tests/test_ec2/test_route_tables.py b/tests/test_ec2/test_route_tables.py
index 7c195235d..8b92b4b4d 100644
--- a/tests/test_ec2/test_route_tables.py
+++ b/tests/test_ec2/test_route_tables.py
@@ -752,9 +752,7 @@ def test_create_route_with_egress_only_igw():
     )
 
     route_table.reload()
-    eigw_route = [r for r in route_table.routes if r.destination_cidr_block == "None"][
-        0
-    ]
+    eigw_route = [r for r in route_table.routes if r.destination_cidr_block == ""][0]
     eigw_route.egress_only_internet_gateway_id.should.equal(eigw_id)
     eigw_route.state.should.equal("active")