diff --git a/Makefile b/Makefile
index 0bbb078d6..1bdeb4338 100644
--- a/Makefile
+++ b/Makefile
@@ -328,13 +328,18 @@ config.h:
 	if [ "x$(HTS_BUILD_AVX512)" != "x" ] ; then \
 	    echo '#define HAVE_AVX512 1' >> $@ ; \
 	fi
+	echo '#if defined __x86_64__ && (defined HAVE_SSSE3 || defined HAVE_AVX2 || defined HAVE_AVX512)' >> $@
+	echo '#define HAVE_X86INTRIN_H 1' >> $@
+	echo '#endif' >> $@
 	echo '#if defined __x86_64__ || defined __arm__ || defined __aarch64__' >> $@
 	echo '#define HAVE_ATTRIBUTE_CONSTRUCTOR 1' >> $@
 	echo '#endif' >> $@
-	echo '#if (defined(__x86_64__) || defined(_M_X64))' >> $@
-	echo '#define HAVE_ATTRIBUTE_TARGET_SSSE3 1' >> $@
-	echo '#define HAVE_BUILTIN_CPU_SUPPORT_SSSE3 1' >> $@
-	echo '#endif' >> $@
+	if [ "x$(HTS_HAVE_SSSE3_BUILTINS)" != "x" ]; then \
+	    echo '#if (defined(__x86_64__) || defined(_M_X64))' >> $@ ; \
+	    echo '#define HAVE_ATTRIBUTE_TARGET_SSSE3 1' >> $@ ; \
+	    echo '#define HAVE_BUILTIN_CPU_SUPPORT_SSSE3 1' >> $@ ; \
+	    echo '#endif' >> $@ ; \
+	fi
 	echo '#if defined __linux__' >> $@
 	echo '#define HAVE_GETAUXVAL' >> $@
 	echo '#elif defined __FreeBSD__' >> $@
diff --git a/configure.ac b/configure.ac
index 9fb221216..c50635968 100644
--- a/configure.ac
+++ b/configure.ac
@@ -83,14 +83,16 @@ AC_CHECK_DECL([_XOPEN_SOURCE], [],
   [AC_DEFINE([_XOPEN_SOURCE], [700], [Specify X/Open requirements])],
   [])
 
-dnl Check that we have cpuid, and if so run the x86 SIMD checks
+dnl Check that we have cpuid and x86intrin.h, and if so run the x86 SIMD checks
 AC_CHECK_DECLS([__get_cpuid_max, __cpuid_count], [
    hts_have_cpuid=yes
 ], [
    hts_have_cpuid=no
 ], [[#include <cpuid.h>]])
 
-AS_IF(test "x$hts_have_cpuid" = "xyes", [
+AC_CHECK_HEADERS([x86intrin.h])
+
+AS_IF([test "x$hts_have_cpuid" = "xyes" && test "x$ac_cv_header_x86intrin_h" = "xyes"], [
 dnl Options for rANS32x16 sse4.1 version - sse4.1
 HTS_CHECK_COMPILE_FLAGS_NEEDED([sse4.1], [-msse4.1 -mssse3 -mpopcnt],
  [AC_LANG_PROGRAM([[
@@ -666,6 +668,33 @@ Linux, FreeBSD, MacOS, and other BSD derivatives])
     ])
   ])
 
+# Check for a working fstatat interface
+AS_IF([test "$ref_cache" = enabled],[
+  AC_MSG_CHECKING([for fstatat])
+  AC_LINK_IFELSE([
+    AC_LANG_PROGRAM([
+      #include <fcntl.h>
+      #include <sys/stat.h>
+    ],[
+      struct stat statbuf;
+      return fstatat(AT_FDCWD, "/", &statbuf, AT_SYMLINK_NOFOLLOW);
+    ])
+  ], [
+    AC_MSG_RESULT([yes])
+  ], [
+    AC_MSG_RESULT([no])
+    ref_cache="disabled"
+    AS_IF([test "x$enable_ref_cache" = xcheck], [
+      AC_MSG_WARN([ref-cache not enabled: missing fstatat()])
+    ],[
+      MSG_ERROR([ref-cache not enabled
+
+ref-cache is not supported on this configuration, as the fstatat() interface
+cannot be found.])
+    ])
+  ])
+])
+
 # Check how to get a working cmsg interface
 AS_IF([test "$ref_cache" = enabled],[
   AC_MSG_CHECKING([for CMSG_LEN])
diff --git a/hts_probe_cc.sh b/hts_probe_cc.sh
index c9fc0a821..b7401dfff 100755
--- a/hts_probe_cc.sh
+++ b/hts_probe_cc.sh
@@ -60,9 +60,11 @@ run_test ()
     rm -f conftest conftest.err conftest.c
     cat - > conftest.c
     if run_compiler ; then
-        echo "$2 ="
+        if test "x$2" != x ; then
+            echo "$2 ="
+        fi
         echo "$3 = 1"
-    elif run_compiler "$1" ; then
+    elif test "x$1" != x && run_compiler "$1" ; then
         echo "$2 = $1"
         echo "$3 = 1"
     else
@@ -140,4 +142,29 @@ int main(int argc, char **argv) { return 0; }
 #endif
 EOF
 
+# Check for __builtin_cpu_supports("ssse3") and __attribute__((target("ssse3")))
+
+run_test '' '' HTS_HAVE_SSSE3_BUILTINS <<'EOF'
+#ifdef __x86_64__
+#include "x86intrin.h"
+__attribute__((target("ssse3")))
+static void shuffle(char *aptr, char *bptr) {
+    if (__builtin_cpu_supports("ssse3")) {
+        __m128i a = _mm_lddqu_si128((__m128i *)aptr);
+        __m128i b = _mm_shuffle_epi8(a, a);
+        _mm_storeu_si128((__m128i *)bptr, b);
+    }
+}
+
+int main(int argc, char **argv) {
+    char in[sizeof(__m128i)] = { 0 }, out[sizeof(__m128i)] = { 0 };
+    in[0] = argv[0][0];
+    shuffle(in, out);
+    return out[0];
+}
+#else
+int main(int argc, char **argv) { return 0; }
+#endif
+EOF
+
 rm -f conftest.c
diff --git a/sam_internal.h b/sam_internal.h
index 135b881b1..161782aa3 100644
--- a/sam_internal.h
+++ b/sam_internal.h
@@ -100,7 +100,10 @@ static inline void nibble2base_default(uint8_t *nib, char *seq, int len) {
 }
 
 #if defined HAVE_ATTRIBUTE_CONSTRUCTOR && \
-    ((defined __x86_64__ && defined HAVE_ATTRIBUTE_TARGET_SSSE3 && defined HAVE_BUILTIN_CPU_SUPPORT_SSSE3) || \
+    ((defined __x86_64__ && \
+      defined HAVE_X86INTRIN_H && HAVE_X86INTRIN_H && \
+      defined HAVE_ATTRIBUTE_TARGET_SSSE3 && \
+      defined HAVE_BUILTIN_CPU_SUPPORT_SSSE3) || \
      (defined __ARM_NEON))
 #define BUILDING_SIMD_NIBBLE2BASE
 #endif
diff --git a/simd.c b/simd.c
index 014a370d6..62a2e7766 100644
--- a/simd.c
+++ b/simd.c
@@ -34,8 +34,8 @@ DEALINGS IN THE SOFTWARE.  */
 #include "htslib/sam.h"
 #include "sam_internal.h"
 
-#if defined __x86_64__
-#include <immintrin.h>
+#if defined __x86_64__ && defined HAVE_X86INTRIN_H && HAVE_X86INTRIN_H
+#include <x86intrin.h>
 #elif defined __ARM_NEON
 #include <arm_neon.h>
 #endif