Working on issue #1762: Brought

  ./python.exe -m timeit -s 'from fractions import Fraction; f = Fraction(3, 2)' 'isinstance(3, Fraction); isinstance(f, Fraction)'
from 12.3 usec/loop to 3.44 usec/loop and
  ./python.exe -m timeit -s 'from fractions import Fraction' 'Fraction(3, 2)'
from 48.8 usec to 23.6 usec by avoiding genexps and sets in __instancecheck__
and inlining the common case from __subclasscheck__.

Lib/abc.py

@@ -163,8 +163,20 @@ class ABCMeta(type):
 
     def __instancecheck__(cls, instance):
         """Override for isinstance(instance, cls)."""
-        return any(cls.__subclasscheck__(c)
-                   for c in set([instance.__class__, type(instance)]))
+        # Inline the cache checking for new-style classes.
+        subclass = instance.__class__
+        if subclass in cls._abc_cache:
+            return True
+        subtype = type(instance)
+        if subtype is subclass:
+            if (cls._abc_negative_cache_version ==
+                ABCMeta._abc_invalidation_counter and
+                subclass in cls._abc_negative_cache):
+                return False
+            # Fall back to the subclass check.
+            return cls.__subclasscheck__(subclass)
+        return (cls.__subclasscheck__(subclass) or
+                cls.__subclasscheck__(subtype))
 
     def __subclasscheck__(cls, subclass):
         """Override for issubclass(subclass, cls)."""

Lib/test/test_abc.py

@@ -83,6 +83,16 @@ class TestABC(unittest.TestCase):
         self.assertEqual(issubclass(C, A), True)
         self.assertEqual(isinstance(c, A), True)
 
+    def test_isinstance_invalidation(self):
+        class A:
+            __metaclass__ = abc.ABCMeta
+        class B(object):
+            pass
+        b = B()
+        self.assertEqual(isinstance(b, A), False)
+        A.register(B)
+        self.assertEqual(isinstance(b, A), True)
+
     def test_registration_builtins(self):
         class A:
             __metaclass__ = abc.ABCMeta