diff --git a/mypy/expandtype.py b/mypy/expandtype.py
index bff23c53defd..83eec2f7b7c5 100644
--- a/mypy/expandtype.py
+++ b/mypy/expandtype.py
@@ -2,7 +2,7 @@
 
 from typing import Final, Iterable, Mapping, Sequence, TypeVar, cast, overload
 
-from mypy.nodes import ARG_STAR, Var
+from mypy.nodes import ARG_STAR, FakeInfo, Var
 from mypy.state import state
 from mypy.types import (
     ANY_STRATEGY,
@@ -208,6 +208,16 @@ def visit_erased_type(self, t: ErasedType) -> Type:
 
     def visit_instance(self, t: Instance) -> Type:
         args = self.expand_types_with_unpack(list(t.args))
+
+        if isinstance(t.type, FakeInfo):
+            # The type checker expands function definitions and bodies
+            # if they depend on constrained type variables but the body
+            # might contain a tuple type comment (e.g., # type: (int, float)),
+            # in which case 't.type' is not yet available.
+            #
+            # See: https://github.com/python/mypy/issues/16649
+            return t.copy_modified(args=args)
+
         if t.type.fullname == "builtins.tuple":
             # Normalize Tuple[*Tuple[X, ...], ...] -> Tuple[X, ...]
             arg = args[0]
diff --git a/test-data/unit/check-typevar-values.test b/test-data/unit/check-typevar-values.test
index effaf620f1f0..8b961d88d23d 100644
--- a/test-data/unit/check-typevar-values.test
+++ b/test-data/unit/check-typevar-values.test
@@ -706,3 +706,29 @@ Func = Callable[[], T]
 
 class A: ...
 class B: ...
+
+[case testTypeCommentInGenericTypeWithConstrainedTypeVar]
+from typing import Generic, TypeVar
+
+NT = TypeVar("NT", int, float)
+
+class Foo1(Generic[NT]):
+    p = 1  # type: int
+
+class Foo2(Generic[NT]):
+    p, q = 1, 2.0  # type: (int, float)
+
+class Foo3(Generic[NT]):
+    def bar(self) -> None:
+        p = 1  # type: int
+
+class Foo4(Generic[NT]):
+    def bar(self) -> None:
+        p, q = 1, 2.0  # type: (int, float)
+
+def foo3(x: NT) -> None:
+    p = 1  # type: int
+
+def foo4(x: NT) -> None:
+    p, q = 1, 2.0  # type: (int, float)
+[builtins fixtures/tuple.pyi]