PTEN

Chr 10AD

phosphatase and tensin homolog

NCBI Gene: 5728 ENSG00000171862 UniProt: P60484

Dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins (PubMed:9187108, PubMed:9256433, PubMed:9616126). Also functions as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring of PtdIns(3,4,5)P3/phosphatidylinositol 3,4,5-trisphosphate, PtdIns(3,4)P2/phosphatidylinositol 3,4-diphosphate and PtdIns3P/phosphatidylinositol 3-phosphate with a preference for PtdIns(3,4,5)P3 (PubMed:16824732, PubMed:26504226, PubMed:9593664, PubMed:9811831). Furthermore, this enzyme can also act as a cytosolic inositol 3-phosphatase acting on Ins(1,3,4,5,6)P5/inositol 1,3,4,5,6 pentakisphosphate and possibly Ins(1,3,4,5)P4/1D-myo-inositol 1,3,4,5-tetrakisphosphate (PubMed:11418101, PubMed:15979280). Antagonizes the PI3K-AKT/PKB signaling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival (PubMed:31492966, PubMed:37279284). The unphosphorylated form cooperates with MAGI2 to suppress AKT1 activation (PubMed:11707428). In motile cells, suppresses the formation of lateral pseudopods and thereby promotes cell polarization and directed movement (PubMed:22279049). Dephosphorylates tyrosine-phosphorylated focal adhesion kinase and inhibits cell migration and integrin-mediated cell spreading and focal adhesion formation (PubMed:22279049). Required for growth factor-induced epithelial cell migration; growth factor stimulation induces PTEN phosphorylation which changes its binding preference from the p85 regulatory subunit of the PI3K kinase complex to DLC1 and results in translocation of the PTEN-DLC1 complex to the posterior of migrating cells to promote RHOA activation (PubMed:26166433). Meanwhile, TNS3 switches binding preference from DLC1 to p85 and the TNS3-p85 complex translocates to the leading edge of migrating cells to activate RAC1 activation (PubMed:26166433). Plays a role as a key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (By similarity). Involved in the regulation of synaptic function in excitatory hippocampal synapses. Recruited to the postsynaptic membrane upon NMDA receptor activation, is required for the modulation of synaptic activity during plasticity. Enhancement of lipid phosphatase activity is able to drive depression of AMPA receptor-mediated synaptic responses, activity required for NMDA receptor-dependent long-term depression (LTD) (By similarity). May be a negative regulator of insulin signaling and glucose metabolism in adipose tissue. The nuclear monoubiquitinated form possesses greater apoptotic potential, whereas the cytoplasmic nonubiquitinated form induces less tumor suppressive ability (PubMed:10468583, PubMed:18716620)

Primary Disease Associations & Inheritance

{Glioma susceptibility 2}MIM #613028

{Meningioma}MIM #607174

Cowden syndrome 1MIM #158350

Lhermitte-Duclos diseaseMIM #158350

Macrocephaly/autism syndromeMIM #605309

Prostate cancer, somaticMIM #176807

UniProtSquamous cell carcinoma of the head and neck

UniProtEndometrial cancer

UniProtGlioma 2

571

ClinVar variants

139

Pathogenic / LP

0.26

pLI score

Active trials

Clinical Summary— PTEN

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Gene-Disease Validity (ClinGen)

PTEN hamartoma tumor syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

139 Pathogenic / Likely Pathogenic· 224 VUS of 571 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.51LOEUF

pLI 0.257

Z-score 3.20

OE 0.24 (0.13–0.51)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

3.49Z-score

OE missense 0.33 (0.27–0.41)

72 obs / 216.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.24 (0.13–0.51)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.33 (0.27–0.41)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.02

0≤1.21.6

LoF obs/exp: 5 / 20.8Missense obs/exp: 72 / 216.4Syn Z: -0.12

ClinVar Variant Classifications

571 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic99

Likely Pathogenic40

VUS224

Likely Benign157

Benign43

Conflicting8

Pathogenic

Likely Pathogenic

224

VUS

157

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	74	4	21	0	99
Likely Pathogenic	16	9	15	0	40
VUS	7	169	43	5	224
Likely Benign	0	1	101	55	157
Benign	0	0	12	31	43
Conflicting	—				8
Total	97	183	192	91	571

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PTEN · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PTEN-related hamartoma tumour syndrome (Cowden syndrome)

definitive

ADLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure

Dev. DisordersCancer

G2P ↗

splice region variantframeshift variantstop gainedmissense variantregulatory region variantwhole partial gene deletion

PTEN-related Proteus syndrome

definitive

ADLoss Of FunctionAbsent Gene Product

Dev. DisordersSkinSkeletal

G2P ↗

PTEN-related Lhermitte-Duclos disease

definitive

ADLoss Of FunctionAbsent Gene Product

EyeSkin

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

PHOSPHATASE AND TENSIN HOMOLOG; PTEN

MIM #601728 · *

{Glioma susceptibility 2}

MIM #613028