PIN1

protein-coding

peptidylprolyl cis/trans isomerase, NIMA-interacting 1, the group of Parvulins

Gene summary

Peptidyl-prolyl cis/trans isomerases (PPIases) catalyze the cis/trans isomerization of peptidyl-prolyl peptide bonds. This gene encodes one of the PPIases, which specifically binds to phosphorylated ser/thr-pro motifs to catalytically regulate the post-phosphorylation conformation of its substrates. The conformational regulation catalyzed by this PPIase has a profound impact on key proteins involved in the regulation of cell growth, genotoxic and other stress responses, the immune response, induction and maintenance of pluripotency, germ cell development, neuronal differentiation, and survival. This enzyme also plays a key role in the pathogenesis of Alzheimer's disease and many cancers. Multiple alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jun 2011]

MANE transcript

NM_006221.4

Inheritance

—

ClinVar variants

U:15B:1

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr19:9,835,257-9,849,689

External References & Databases

Ensembl (ENSG00000127445)

Transcript & Mutation Effects

hg38 • Region Span ~14.4 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 PIN1 variants in ClinVar

1 Conditions Cataloged

not specifiedTotal: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006221.4. 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				1 clinvar		1
missense			14 clinvar			14
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	15	1	0	16

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006221.4	RefSeq	NP_006212.1	4	MANE Select
ENST00000247970.9	Ensembl	ENSP00000247970.5	4	MANE Select
ENST00000586352.5	Ensembl	ENSP00000467197.1	3	Standard
ENST00000587625.5	Ensembl	ENSP00000466656.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pin1	Danio rerio	Structure: apoptotic process Quality: increased occurrence abnormal

Gene / Model

Organism

Observed Phenotype

pin1

Danio rerio

Structure: apoptotic process

Quality: increased occurrence

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

RIG-I-like receptor signaling pathway - Homo sapiens (human)
RIG-I-like Receptor Signaling
Gene expression (Transcription)
how progesterone initiates the oocyte maturation
Generic Transcription Pathway

Biological Process

protein peptidyl-prolyl isomerization
regulation of protein phosphorylation
positive regulation of protein phosphorylation
cell cycle
regulation of mitotic nuclear division

Molecular Function

peptidyl-prolyl cis-trans isomerase activity
motor activity
protein binding
beta-catenin binding
mitogen-activated protein kinase kinase binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
mitochondrion
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000247970
Coding exons: 4
Length: 14426
Individuals with no LoFs: 125247
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125249
p: 0.00000798

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.35	66	105	0.629	0.00000701	1045
Missense (PolyPhen)		19	44.177	0.43009		384
Synonymous	0.407	41	44.5	0.922	0.00000331	300
Loss of Function	2.43	1	8.78	0.114	4.60e-7	97

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000093	0.0000088	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Peptidyl-prolyl cis/trans isomerase (PPIase) that binds to and isomerizes specific phosphorylated Ser/Thr-Pro (pSer/Thr- Pro) motifs. By inducing conformational changes in a subset of phosphorylated proteins, acts as a molecular switch in multiple cellular processes (PubMed:21497122, PubMed:22033920, Ref. 21). Displays a preference for acidic residues located N-terminally to the proline bond to be isomerized. Regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Down-regulates kinase activity of BTK (PubMed:16644721). Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation (PubMed:15664191). Binds and targets PML and BCL6 for degradation in a phosphorylation-dependent manner (PubMed:17828269). Acts as a regulator of JNK cascade by binding to phosphorylated FBXW7, disrupting FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation: degradation of FBXW7 leads to subsequent stabilization of JUN (PubMed:22608923). May facilitate the ubiquitination and proteasomal degradation of RBBP8/CtIP through CUL3/KLHL15 E3 ubiquitin-protein ligase complex, hence favors DNA double-strand repair through error-prone non-homologous end joining (NHEJ) over error-free, RBBP8-mediated homologous recombination (HR) (PubMed:23623683, PubMed:27561354). {ECO:0000269|PubMed:15664191, ECO:0000269|PubMed:16644721, ECO:0000269|PubMed:17828269, ECO:0000269|PubMed:21497122, ECO:0000269|PubMed:22033920, ECO:0000269|PubMed:22608923, ECO:0000269|PubMed:23623683, ECO:0000269|PubMed:27561354}.;

Recessive Scores

pRec: 0.400

Intolerance Scores

LoFtool: 0.508
RVIS EVS: -0.03
RVIS percentile EVS: 51.4

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.676

Gene Damage Prediction

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