PHLPP1

protein-coding

PH domain and leucine rich repeat protein phosphatase 1, the group of Pleckstrin homology domain containing|Protein phosphatases, Mg2+/Mn2+ dependent

Gene summary

This gene encodes a member of the serine/threonine phosphatase family. The encoded protein promotes apoptosis by dephosphorylating and inactivating the serine/threonine kinase Akt, and functions as a tumor suppressor in multiple types of cancer. Increased expression of this gene may also play a role in obesity and type 2 diabetes by interfering with Akt-mediated insulin signaling. [provided by RefSeq, Dec 2011]

Previous symbols:

PLEKHE1
PHLPP

MANE transcript

NM_194449.4

Inheritance

—

ClinVar variants

U:306B:21

Top phenotype

Focal impaired awareness seizure

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr18:62,715,541-62,980,433

External References & Databases

Ensembl (ENSG00000081913)

Transcript & Mutation Effects

hg38 • Region Span ~264.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PHLPP1 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 300

not providedTotal: 21

Focal impaired awareness seizureTotal: 1

Attention deficit hyperactivity disorderTotal: 1

SeizureTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_194449.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	11 clinvar	2 clinvar	17
missense			299 clinvar	8 clinvar		307
nonsense			2 clinvar			2
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	0	0	306	19	2	327

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_194449.4	RefSeq	NP_919431.2	17	MANE Select
ENST00000262719.10	Ensembl	ENSP00000262719.4	17	MANE Select
ENST00000591386.1	Ensembl	ENSP00000467279.1	6	Standard
ENST00000937482.1	Ensembl	ENSP00000607541.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Focal Adhesion-PI3K-Akt-mTOR-signaling pathway
PI3K-Akt Signaling Pathway
Signal Transduction
EGFR1

Biological Process

regulation of T cell anergy
protein dephosphorylation
apoptotic process
entrainment of circadian clock
regulation of apoptotic process

Molecular Function

protein serine/threonine phosphatase activity
protein binding
metal ion binding

Cellular Component

photoreceptor inner segment
cytoplasm
cytosol
nuclear membrane
photoreceptor outer segment membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262719
Coding exons: 17
Length: 264995
Individuals with no LoFs: 124669
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 124683
p: 0.0000561

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.75	691	833	0.829	0.0000469	11022
Missense (PolyPhen)		260	358.41	0.72542		4223
Synonymous	-0.256	369	363	1.02	0.0000230	3642
Loss of Function	5.95	8	56.1	0.143	0.00000304	690

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00017	0.00017	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000046	0.000044	rare
South Asian	0.00010	0.000098	rare
Other	0.00017	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Protein phosphatase involved in regulation of Akt and PKC signaling. Mediates dephosphorylation in the C-terminal domain hydrophobic motif of members of the AGC Ser/Thr protein kinase family; specifically acts on 'Ser-473' of AKT2 and AKT3, 'Ser-660' of PRKCB and 'Ser-657' of PRKCA (PubMed:15808505, PubMed:17386267, PubMed:18162466). Isoform 2 seems to have a major role in regulating Akt signaling in hippocampal neurons (By similarity). Akt regulates the balance between cell survival and apoptosis through a cascade that primarily alters the function of transcription factors that regulate pro- and antiapoptotic genes. Dephosphorylation of 'Ser-473' of Akt triggers apoptosis and suppression of tumor growth. Dephosphorylation of PRKCA and PRKCB leads to their destabilization and degradation (PubMed:18162466). Dephosphorylates STK4 on 'Thr-387' leading to STK4 activation and apoptosis (PubMed:20513427). Dephosphorylates RPS6KB1 and is involved in regulation of cap-dependent translation (PubMed:21986499). Inhibits cancer cell proliferation and may act as a tumor suppressor (PubMed:19079341). Dephosphorylates RAF1 inhibiting its kinase activity (PubMed:24530606). May act as a negative regulator of K-Ras signaling in membrane rafts (By similarity). Involved in the hippocampus-dependent long-term memory formation (By similarity). Involved in circadian control by regulating the consolidation of circadian periodicity after resetting (By similarity). Involved in development and function of regulatory T-cells (By similarity). {ECO:0000250|UniProtKB:Q8CHE4, ECO:0000250|UniProtKB:Q9WTR8, ECO:0000269|PubMed:15808505, ECO:0000269|PubMed:17386267, ECO:0000269|PubMed:18162466, ECO:0000269|PubMed:19079341, ECO:0000269|PubMed:21986499, ECO:0000269|PubMed:24530606}.;

Recessive Scores

pRec: 0.142

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.715

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium