diff --git a/src/coreclr/jit/optcse.cpp b/src/coreclr/jit/optcse.cpp
index f633a5e3272bb5..0d67ffd7a956a5 100644
--- a/src/coreclr/jit/optcse.cpp
+++ b/src/coreclr/jit/optcse.cpp
@@ -536,7 +536,15 @@ unsigned Compiler::optValnumCSE_Index(GenTree* tree, Statement* stmt)
     // than the one from its op2.  For this case we want to create two different
     // CSE candidates. This allows us to CSE the GT_COMMA separately from its value.
     //
-    if (tree->OperGet() == GT_COMMA)
+    // Even this exception has an exception: for struct typed GT_COMMAs we
+    // cannot allow the comma and op2 to be separate candidates as, if we
+    // decide to CSE both the comma and its op2, then creating the store with
+    // the comma will sink it into the op2, potentially breaking the op2 CSE
+    // definition if it itself is another comma. This restriction is related to
+    // the fact that we do not have af first class representation for struct
+    // temporaries in our IR.
+    //
+    if (tree->OperIs(GT_COMMA) && !varTypeIsStruct(tree))
     {
         // op2 is the value produced by a GT_COMMA
         GenTree* op2      = tree->AsOp()->gtOp2;
@@ -588,7 +596,7 @@ unsigned Compiler::optValnumCSE_Index(GenTree* tree, Statement* stmt)
             key = vnLibNorm;
         }
     }
-    else // Not a GT_COMMA or a GT_CNS_INT
+    else // Not a primitive GT_COMMA or a GT_CNS_INT
     {
         key = vnLibNorm;
     }
diff --git a/src/tests/JIT/Regression/JitBlue/Runtime_106380/Runtime_106380.cs b/src/tests/JIT/Regression/JitBlue/Runtime_106380/Runtime_106380.cs
new file mode 100644
index 00000000000000..5853038fc1df6c
--- /dev/null
+++ b/src/tests/JIT/Regression/JitBlue/Runtime_106380/Runtime_106380.cs
@@ -0,0 +1,40 @@
+// Licensed to the .NET Foundation under one or more agreements.
+// The .NET Foundation licenses this file to you under the MIT license.
+
+// Found by Antigen
+// Reduced from 24.98 KB to 779 B.
+using System.Runtime.Intrinsics;
+using System.Runtime.Intrinsics.Arm;
+using Xunit;
+
+public class Runtime_106380
+{
+    static Vector64<uint> s_v64_uint_23 = Vector64<uint>.AllBitsSet;
+    Vector64<uint> v64_uint_74 = Vector64.Create((uint)2, 2);
+    private void Method0()
+    {
+        unchecked
+        {
+            AdvSimd.MaxPairwise(v64_uint_74 += Vector64.ConditionalSelect(Vector64<uint>.Zero, s_v64_uint_23, s_v64_uint_23) & v64_uint_74, v64_uint_74 += (s_v64_uint_23 ^ v64_uint_74)& (s_v64_uint_23 = v64_uint_74));
+            return;
+        }
+    }
+    [Fact]
+    public static void TestEntryPoint()
+    {
+        if (AdvSimd.IsSupported)
+        {
+            new Runtime_106380().Method0();
+        }
+    }
+}
+
+/*
+Environment:
+
+set DOTNET_TieredCompilation=0
+
+Assert failure(PID 13404 [0x0000345c], Thread: 5136 [0x1410]): Assertion failed 'type != TYP_VOID' in 'TestClass:Method0():this' during 'Optimize Valnum CSEs' (IL size 111; hash 0x46e9aa75; FullOpts)
+    File: C:\wk\runtime\src\coreclr\jit\gentree.cpp:8388
+    Image: C:\aman\Core_Root\corerun.exe
+*/
diff --git a/src/tests/JIT/Regression/JitBlue/Runtime_106380/Runtime_106380.csproj b/src/tests/JIT/Regression/JitBlue/Runtime_106380/Runtime_106380.csproj
new file mode 100644
index 00000000000000..15edd99711a1a4
--- /dev/null
+++ b/src/tests/JIT/Regression/JitBlue/Runtime_106380/Runtime_106380.csproj
@@ -0,0 +1,8 @@
+<Project Sdk="Microsoft.NET.Sdk">
+  <PropertyGroup>
+    <Optimize>True</Optimize>
+  </PropertyGroup>
+  <ItemGroup>
+    <Compile Include="$(MSBuildProjectName).cs" />
+  </ItemGroup>
+</Project>
\ No newline at end of file