diff --git a/mypy/checkexpr.py b/mypy/checkexpr.py
index 44855f49afaf9..699bd73bfc550 100644
--- a/mypy/checkexpr.py
+++ b/mypy/checkexpr.py
@@ -3770,6 +3770,7 @@ def visit_comparison_expr(self, e: ComparisonExpr) -> Type:
                         pass
                     elif (
                         container_errors.has_new_errors()
+                        and not has_operator(item_type, "__contains__")
                         and
                         # is_valid_var_arg is True for any Iterable
                         self.is_valid_var_arg(item_type)
@@ -3800,21 +3801,17 @@ def visit_comparison_expr(self, e: ComparisonExpr) -> Type:
                         failed_out = True
 
                 if not encountered_partial_type and not failed_out:
-                    iterable_type = UnionType.make_union(iterable_types)
-                    if not is_subtype(left_type, iterable_type):
-                        if not container_types:
-                            self.msg.unsupported_operand_types("in", left_type, right_type, e)
-                        else:
-                            container_type = UnionType.make_union(container_types)
-                            if not self.chk.can_skip_diagnostics and self.dangerous_comparison(
-                                left_type,
-                                container_type,
-                                original_container=right_type,
-                                prefer_literal=False,
-                            ):
-                                self.msg.dangerous_comparison(
-                                    left_type, container_type, "container", e
-                                )
+                    all_item_types = container_types + iterable_types
+                    if all_item_types:
+                        combined_type = UnionType.make_union(all_item_types)
+                        if not self.chk.can_skip_diagnostics and self.dangerous_comparison(
+                            left_type,
+                            combined_type,
+                            original_container=right_type,
+                            prefer_literal=False,
+                        ):
+                            kind = "container" if container_types else "iterable"
+                            self.msg.dangerous_comparison(left_type, combined_type, kind, e)
 
             elif operator in operators.op_methods:
                 method = operators.op_methods[operator]
diff --git a/test-data/unit/check-expressions.test b/test-data/unit/check-expressions.test
index 7123285e5eca1..b8dcd63973039 100644
--- a/test-data/unit/check-expressions.test
+++ b/test-data/unit/check-expressions.test
@@ -395,7 +395,7 @@ if int():
 if int():
     c = a in b  # E: Unsupported right operand type for in ("B")
 if int():
-    c = b in d  # E: Unsupported operand types for in ("B" and "D")
+    c = b in d
 if int():
     c = b in a
 if int():
@@ -2814,3 +2814,18 @@ class A:
 
 A().f(fobar=1) # E: Unexpected keyword argument "fobar" for overloaded function "f" of "A"; did you mean "foobar"?
 [builtins fixtures/list.pyi]
+[case testInOperatorGeneratorOverlap_issue21601]
+from typing import Generator
+class Signals(int): pass
+def f(gen: Generator[Signals, None, None]) -> None:
+    # This shouldn't be an error since Signals and int overlap.
+    1 in gen
+    # This shouldn't be an error since float and int overlap.
+    1.5 in gen
+
+[case testInOperatorIterableUnion_issue21595]
+from typing import Union, List
+def f(var: Union[List[int], str]) -> None:
+    # 2 in str throws TypeError at runtime, so mypy MUST catch this
+    # and not silence it just because list[int] accepts it.
+    2 in var  # E: Unsupported right operand type for in ("list[int] | str")