Cowden disease: genes and variants
Explore variant evidence for Cowden disease across 4 analyzed proteins (PTEN, PIK3CA, SDHD, AKT1). Linked ClinVar records include 78 pathogenic or likely pathogenic variants, 514 variants of uncertain significance and 52 with conflicting classifications.
Coverage includes proteins already analyzed in CATVariant, not every gene involved in this condition. Database links are associations, not an assessment of clinical gene–disease validity. Computable evidence prioritizes variants for expert review and does not reclassify them. Source labels are pooled across this disease family.
Data updated 2026-10-10. Automated aggregation, not a clinical review date.
Download variant evidence (CSV)
Genes linked to Cowden disease
PTEN: Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN
A lipid and protein phosphatase that removes phosphate groups from signaling molecules, especially PIP3. By opposing the PI3K-AKT pathway, it limits cell growth and survival signals, and PTEN variants are associated with Cowden syndrome and multiple cancers.
41 ClinVar pathogenic / likely pathogenic and 34 uncertain variants in PTEN have source records linked to Cowden disease. Association strength is not clinical gene validity.
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.
23 ClinVar pathogenic / likely pathogenic and 216 uncertain variants in PIK3CA have source records linked to Cowden disease. Association strength is not clinical gene validity.
SDHD: Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial
It provides a membrane-anchoring component of succinate dehydrogenase and is required for normal complex II electron transfer. Germline loss-of-function variants, often showing a parent-of-origin effect, strongly predispose to head-and-neck paragangliomas and pheochromocytomas.
11 ClinVar pathogenic / likely pathogenic and 156 uncertain variants in SDHD have source records linked to Cowden disease. Association strength is not clinical gene validity.
AKT1: RAC-alpha serine/threonine-protein kinase
It integrates PI3K-dependent growth-factor signals to promote cell survival, proliferation, glucose metabolism, and protein synthesis. Somatic activating variants occur in multiple cancers, while mosaic activation, especially E17K, causes Proteus syndrome.
3 ClinVar pathogenic / likely pathogenic and 157 uncertain variants in AKT1 have source records linked to Cowden disease. Association strength is not clinical gene validity.
Weakly linked (only a few uncertain records): SDHB.
Where Cowden disease variants cluster
- PTEN Phosphatase tensin-type (positions 14–185): 37 of 41 ClinVar pathogenic / likely pathogenic variants, 2.1× more than its size predicts.
- SDHD Transmembrane (positions 91–111): 7 of 11 ClinVar pathogenic / likely pathogenic variants, 4.8× more than its size predicts.
- PIK3CA PI3K-ABD (positions 16–105): 3 of 23 ClinVar pathogenic / likely pathogenic variants, 1.6× more than its size predicts.
ClinVar pathogenic and likely pathogenic variants linked to Cowden disease
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| PTEN G129R | 129 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN S170R | 170 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| SDHD H102N | 102 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| SDHD H102Y | 102 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| SDHD H102L | 102 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| SDHD H102P | 102 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| PTEN D24G | 24 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN D24V | 24 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN D24Y | 24 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN P96Q | 96 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN P96R | 96 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN C124W | 124 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN C124S | 124 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN G129E | 129 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN G129V | 129 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN C136R | 136 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN C136F | 136 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| SDHD D92Y | 92 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| PTEN F90S | 90 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN D92G | 92 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN I101T | 101 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN G127R | 127 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN M134T | 134 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN G165R | 165 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PIK3CA E545D | 545 | PIK helical | Pathogenic / likely pathogenic (★★) |
| PIK3CA Y1021H | 1021 | PI3K/PI4K catalytic | Pathogenic / likely pathogenic (★★) |
| PTEN M35T | 35 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN N48K | 48 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN N48S | 48 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN H93Y | 93 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN H123Y | 123 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN A126P | 126 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN G132S | 132 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN D162E | 162 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN S170N | 170 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| SDHD L107R | 107 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| AKT1 E17K | 17 | PH | Pathogenic / likely pathogenic (★★) |
| PIK3CA H1047Y | 1047 | PI3K/PI4K catalytic | Pathogenic / likely pathogenic (★★) |
| SDHD G138R | 138 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| PIK3CA C378Y | 378 | C2 PI3K-type | Pathogenic / likely pathogenic (★★) |
| PIK3CA M1043I | 1043 | PI3K/PI4K catalytic | Pathogenic / likely pathogenic (★★) |
| PIK3CA N1044S | 1044 | PI3K/PI4K catalytic | Pathogenic / likely pathogenic (★★) |
| PTEN K13E | 13 | Pathogenic / likely pathogenic (★★) | |
| PTEN R15S | 15 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN G44D | 44 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN C105R | 105 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN L112R | 112 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN H141L | 141 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN Y155S | 155 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN R159G | 159 | Phosphatase tensin-type | Pathogenic / likely pathogenic (★★) |
| PTEN D252V | 252 | C2 tensin-type | Pathogenic / likely pathogenic (★★) |
| SDHD M1V | 1 | Pathogenic / likely pathogenic (★★) | |
| PIK3CA E81K | 81 | PI3K-ABD | Pathogenic / likely pathogenic (★★) |
| PIK3CA R88Q | 88 | PI3K-ABD | Pathogenic / likely pathogenic (★★) |
| PIK3CA P104L | 104 | PI3K-ABD | Pathogenic / likely pathogenic (★★) |
| PIK3CA G118D | 118 | Pathogenic / likely pathogenic (★★) | |
| PIK3CA V344M | 344 | C2 PI3K-type | Pathogenic / likely pathogenic (★★) |
| PIK3CA E365K | 365 | C2 PI3K-type | Pathogenic / likely pathogenic (★★) |
| PIK3CA C420R | 420 | C2 PI3K-type | Pathogenic / likely pathogenic (★★) |
| PIK3CA E970K | 970 | PI3K/PI4K catalytic | Pathogenic / likely pathogenic (★★) |
Showing 60 of 78.
Uncertain variants prioritized for review in Cowden disease
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| PTEN G165E | 165 | Phosphatase tensin-type | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; G165R at the same position is pathogenic; REVEL 0.960 |
Which prediction tools work for Cowden disease
Observed separation of ClinVar pathogenic / likely pathogenic from benign / likely benign variants (AUROC × 100). This benchmark is not a clinical recommendation.
- ESM1b (LLR): 99 out of 100
- AlphaMissense: 98 out of 100
- PolyPhen-2: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- SIFT: 96 out of 100
- CADD: 94 out of 100
- CATVariant: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- REVEL: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- MetaLR: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- phyloP: 70 out of 100
- DMS / MaveDB: 54 out of 100
Same protein, different disease
- PTEN hamartoma tumor syndrome also has ClinVar records linked to PTEN variants; they fall partly in the same places as the Cowden disease variants (147 pathogenic / likely pathogenic).
- Macrocephaly-autism syndrome also has ClinVar records linked to PTEN variants; they fall partly in the same places as the Cowden disease variants (13 pathogenic / likely pathogenic).
- Glioma susceptibility 1 also has ClinVar records linked to PTEN variants; they fall in the same places as the Cowden disease variants (5 pathogenic / likely pathogenic).
- PIK3CA related overgrowth syndrome also has ClinVar records linked to PIK3CA variants; they fall partly in the same places as the Cowden disease variants (30 pathogenic / likely pathogenic).
- Megalencephaly-capillary malformation-polymicrogyria syndrome also has ClinVar records linked to PIK3CA variants; they fall partly in the same places as the Cowden disease variants (22 pathogenic / likely pathogenic).
- Ovarian neoplasm also has ClinVar records linked to PIK3CA variants; they fall in the same places as the Cowden disease variants (5 pathogenic / likely pathogenic).
- Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes also has ClinVar records linked to PIK3CA variants; they fall partly in the same places as the Cowden disease variants (4 pathogenic / likely pathogenic).
- Pheochromocytoma also has ClinVar records linked to SDHD variants; they fall in the same places as the Cowden disease variants (14 pathogenic / likely pathogenic).
- Paragangliomas with sensorineural hearing loss also has ClinVar records linked to SDHD variants; they fall in the same places as the Cowden disease variants (13 pathogenic / likely pathogenic).
- Carney-Stratakis syndrome also has ClinVar records linked to SDHD variants; they fall in the same places as the Cowden disease variants (11 pathogenic / likely pathogenic).
- Pheochromocytoma/paraganglioma syndrome 5 also has ClinVar records linked to SDHD variants; they fall in the same places as the Cowden disease variants (4 pathogenic / likely pathogenic).
Diseases related to Cowden disease
- Hereditary breast cancer, also linked to AKT1, PIK3CA and PTEN
- Ovarian cancer, also linked to AKT1 and PIK3CA
- Endometrial carcinoma, also linked to PIK3CA and PTEN
- Head and neck squamous cell carcinoma, also linked to PIK3CA and PTEN
- Noonan syndrome, also linked to PIK3CA
- PTEN hamartoma tumor syndrome, also linked to PTEN
- Pheochromocytoma/paraganglioma syndrome 5, also linked to SDHD
- Pheochromocytoma, also linked to SDHD
- PIK3CA related overgrowth syndrome, also linked to PIK3CA
- Megalencephaly-capillary malformation-polymicrogyria syndrome, also linked to PIK3CA
- Carney-Stratakis syndrome, also linked to SDHD
- Colorectal cancer, also linked to PIK3CA
Frequently asked questions
Which genes have records linked to Cowden disease?
This view contains 4 analyzed proteins: PTEN, PIK3CA, SDHD, AKT1. Links come from clinical records and association databases. They do not imply that every listed gene is a validated cause, and missing genes may not yet be analyzed.
What do the clinical classifications mean?
Linked records include 78 pathogenic or likely pathogenic variants, 514 variants of uncertain significance and 52 with conflicting classifications. Labels summarize source records; multi-condition records may not make a separate assertion for this disease. Check the original record and review status.
Does the evidence score change a VUS classification?
No. 1 VUS or conflicting variants reach the likely-pathogenic points range on the computable criteria available here. This is a research prioritization signal, not a clinical classification. Patient, family and other required evidence may be missing.
Can I download the variant evidence?
Download the CSV for all 687 variants in the selected disease scope, including clinical labels, review status, evidence criteria, predictor scores, functional measurements and population frequency where available.
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from eligible public CATVariant analyses 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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