CLOVES syndrome: genes and variants

Genes linked to CLOVES syndrome

• PIK3CA: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform

  Its p110-alpha catalytic activity generates PIP3 and activates AKT-dependent growth, survival, and metabolic signaling downstream of many receptors. Activating variants are frequent cancer drivers and, when present mosaically during development, can cause PIK3CA-related overgrowth spectrum.

  1 disease-causing and 3 uncertain variants in PIK3CA are linked to CLOVES syndrome.

• PIK3R1: Phosphatidylinositol 3-kinase regulatory subunit alpha

  Its p85-family products stabilize and regulate class IA PI3K catalytic subunits and couple receptors to PI3K activation. Pathogenic variants can cause activated PI3K-delta syndrome type 2 or SHORT syndrome depending on how they alter pathway output.

  1 disease-causing and 0 uncertain variants in PIK3R1 are linked to CLOVES syndrome.

Weakly linked (only a few uncertain records): GNA11.

Known disease-causing variants in CLOVES syndrome

Same protein, different disease

• PIK3CA related overgrowth syndrome is also caused by PIK3CA variants; they fall mostly in different places as the CLOVES syndrome variants (30 disease-causing).
• Cowden syndrome is also caused by PIK3CA variants; they fall mostly in different places as the CLOVES syndrome variants (23 disease-causing).
• Megalencephaly-capillary malformation-polymicrogyria syndrome is also caused by PIK3CA variants; they fall mostly in different places as the CLOVES syndrome variants (22 disease-causing).
• Ovarian neoplasm is also caused by PIK3CA variants; they fall mostly in different places as the CLOVES syndrome variants (5 disease-causing).
• PIK3CA constitutional syndrome is also caused by PIK3CA variants; they fall mostly in different places as the CLOVES syndrome variants (4 disease-causing).

Diseases related to CLOVES syndrome

• Noonan syndrome, also linked to PIK3CA
• Cowden syndrome, also linked to PIK3CA
• Ovarian cancer, also linked to PIK3CA
• PIK3CA related overgrowth syndrome, also linked to PIK3CA
• Familial cancer of breast, also linked to PIK3CA
• Megalencephaly-capillary malformation-polymicrogyria syndrome, also linked to PIK3CA
• Colorectal cancer, also linked to PIK3CA
• Gastric cancer, also linked to PIK3CA
• Malignant tumor of urinary bladder, also linked to PIK3CA
• Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, also linked to PIK3CA
• Non-small cell lung carcinoma, also linked to PIK3CA
• Vascular malformation, also linked to PIK3R1

Frequently asked questions

Which genes are linked to CLOVES syndrome?

In CATVariant, CLOVES syndrome is linked to 2 analyzed proteins: PIK3CA (Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform) and PIK3R1 (Phosphatidylinositol 3-kinase regulatory subunit alpha).

How many genetic variants are linked to CLOVES syndrome?

13 variants: 2 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 3 are of uncertain significance or have conflicting reports.

Which uncertain variants in CLOVES syndrome look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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