PPP1R14D

Summary

PPP1R14D (protein phosphatase 1 regulatory inhibitor subunit 14D, HGNC:14953) is a protein-coding gene on chromosome 15q15.1, encoding Protein phosphatase 1 regulatory subunit 14D (Q9NXH3). Inhibitor of PPP1CA.

Protein phosphatase-1 (PP1; see MIM 176875) is a major cellular phosphatase that reverses serine/threonine protein phosphorylation. PPP1R14D is a PP1 inhibitor that itself is regulated by phosphorylation (Liu et al., 2004 [PubMed 12974676]).

Source: NCBI Gene 54866 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 37 total
• MANE Select transcript: NM_017726

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14953
Approved symbol	PPP1R14D
Name	protein phosphatase 1 regulatory inhibitor subunit 14D
Location	15q15.1
Locus type	gene with protein product
Status	Approved
Aliases	CPI17-like, FLJ20251, GBPI-1, MGC119014, MGC119016
Ensembl gene	ENSG00000166143
Ensembl biotype	protein_coding
OMIM	613256
Entrez	54866

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000299174, ENST00000427255, ENST00000921612, ENST00000921613

RefSeq mRNA: 2 — MANE Select: NM_017726 NM_001130143, NM_017726

CCDS: CCDS10066, CCDS45230

Canonical transcript exons

ENST00000299174 — 4 exons

Exon	Start	End
ENSE00000000285	40828387	40828708
ENSE00002585437	40815451	40815761
ENSE00003503334	40816170	40816253
ENSE00003601694	40815962	40815994

Expression profiles

Bgee: expression breadth ubiquitous, 125 present calls, max score 98.84.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3619 / max 148.7065, expressed in 29 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149508	0.2286	23
149509	0.1333	16

Top tissues by expression

253 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	98.84	gold quality
rectum	UBERON:0001052	97.01	gold quality
ileal mucosa	UBERON:0000331	95.78	gold quality
duodenum	UBERON:0002114	92.07	gold quality
jejunal mucosa	UBERON:0000399	90.11	gold quality
pancreatic ductal cell	CL:0002079	88.74	gold quality
colonic mucosa	UBERON:0000317	88.42	gold quality
transverse colon	UBERON:0001157	87.47	gold quality
mucosa of sigmoid colon	UBERON:0004993	86.39	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.41	gold quality
small intestine	UBERON:0002108	84.47	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.25	gold quality
gall bladder	UBERON:0002110	83.19	gold quality
intestine	UBERON:0000160	77.32	gold quality
vermiform appendix	UBERON:0001154	76.94	gold quality
colonic epithelium	UBERON:0000397	75.86	gold quality
large intestine	UBERON:0000059	75.18	gold quality
colon	UBERON:0001155	74.52	gold quality
caecum	UBERON:0001153	74.24	gold quality
tibialis anterior	UBERON:0001385	69.72	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	69.59	gold quality
jejunum	UBERON:0002115	67.88	gold quality
adult mammalian kidney	UBERON:0000082	66.45	gold quality
islet of Langerhans	UBERON:0000006	65.54	gold quality
buccal mucosa cell	CL:0002336	60.93	gold quality
metanephros cortex	UBERON:0010533	60.10	gold quality
lower esophagus mucosa	UBERON:0035834	60.09	gold quality
kidney	UBERON:0002113	58.10	gold quality
skin of hip	UBERON:0001554	57.99	silver quality
metanephros	UBERON:0000081	56.82	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-8410	yes	14.80
E-ANND-3	yes	5.57

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

23 targeting PPP1R14D, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-12135	98.99	70.26	1814
HSA-MIR-647	97.73	67.79	927
HSA-MIR-3139	96.68	66.77	652
HSA-MIR-6858-3P	96.37	64.41	771
HSA-MIR-3657	96.33	66.29	608
HSA-MIR-28-5P	96.16	66.12	579
HSA-MIR-708-5P	96.16	66.12	576
HSA-MIR-604	93.13	64.42	299

Literature-anchored findings (GeneRIF, showing 2)

• A gastrointestinal- and brain-specific PP1 inhibitory protein (GBPI-1)is activated by PKC phosphorylation. A longer GBPI-2 splice variant mRNA is found in testes. (PMID:12974676)
• PPP1R14D promotes the proliferation, migration and invasion of lung adenocarcinoma via the PKCalpha/BRAF/MEK/ERK signaling pathway. (PMID:36263632)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppp1r14d	ENSDARG00000110496
mus_musculus	Ppp1r14d	ENSMUSG00000027317
rattus_norvegicus	Ppp1r14d	ENSRNOG00000012648
drosophila_melanogaster	CG17124	FBGN0032297
caenorhabditis_elegans		WBGENE00010109

Paralogs (3): PPP1R14A (ENSG00000167641), PPP1R14B (ENSG00000173457), PPP1R14C (ENSG00000198729)

Protein

Protein identifiers

Protein phosphatase 1 regulatory subunit 14D — Q9NXH3 (reviewed: Q9NXH3)

Alternative names: Gastrointestinal and brain-specific PP1-inhibitory protein 1

All UniProt accessions (2): E9PAT1, Q9NXH3

UniProt curated annotations — full annotation on UniProt →

Function. Inhibitor of PPP1CA. Has inhibitory activity only when phosphorylated, creating a molecular switch for regulating the phosphorylation status of PPP1CA substrates and smooth muscle contraction.

Subcellular location. Cytoplasm.

Tissue specificity. Detected in colon, intestine, kidney and brain cortex.

Post-translational modifications. Phosphorylated on several residues.

Similarity. Belongs to the PP1 inhibitor family.

RefSeq proteins (2): NP_001123615, NP_060196* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008025	CPI-17	Family
IPR036658	CPI-17_sf	Homologous_superfamily

Pfam: PF05361

UniProt features (10 total): compositionally biased region 3, mutagenesis site 3, region of interest 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NXH3-F1	74.48	0.29

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 58

Mutagenesis-validated functional residues (3):

Position	Phenotype
21–22	reduces inhibitory activity by 57%.
25	reduces inhibitory activity by 13%.
58	reduces inhibitory activity by 16%. reduces phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 68 (showing top): MODULE_255, XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN, MODULE_317, COUP_01, SOX9_B1, HNF4_DR1_Q3, HNF4_01, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_UP, SHEN_SMARCA2_TARGETS_DN, MODULE_69, GOMF_PHOSPHATASE_INHIBITOR_ACTIVITY, GOMF_PROTEIN_SERINE_THREONINE_PHOSPHATASE_INHIBITOR_ACTIVITY, COUP_DR1_Q6, GOMF_ENZYME_INHIBITOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY

GO Biological Process (1): regulation of phosphorylation (GO:0042325)

GO Molecular Function (2): protein serine/threonine phosphatase inhibitor activity (GO:0004865), protein phosphatase inhibitor activity (GO:0004864)

GO Cellular Component (2): cytoplasm (GO:0005737), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
phosphorylation	1
regulation of metabolic process	1
protein serine/threonine phosphatase activity	1
protein phosphatase inhibitor activity	1
phosphoprotein phosphatase activity	1
phosphatase inhibitor activity	1
protein phosphatase regulator activity	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

404 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPP1R14D	PPP1R14C	Q8TAE6	924
PPP1R14D	PPP1R14B	Q96C90	882
PPP1R14D	PPP1R14A	Q96A00	859
PPP1R14D	PPP1CA	P08129	660
PPP1R14D	PPP2CA	P05323	549
PPP1R14D	LRRC42	Q9Y546	519
PPP1R14D	TRARG1	Q8IXB3	458
PPP1R14D	PPP1R8	Q12972	433
PPP1R14D	ZNF550	Q7Z398	428
PPP1R14D	MYOZ2	Q9NPC6	407
PPP1R14D	ZBTB21	Q9ULJ3	405
PPP1R14D	ZFPM1	Q8IX07	387
PPP1R14D	SNAP47	Q5SQN1	383
PPP1R14D	MEX3A	A1L020	364
PPP1R14D	PPP1R1C	Q8WVI7	359

IntAct

2 interactions, top by confidence:

A	B	Type	Score
PPP1R14D	MAPK9	psi-mi:“MI:0914”(association)	0.350

BioGRID (4): PPP1CC (Affinity Capture-MS), MAPK9 (Affinity Capture-MS), PNMA2 (Affinity Capture-MS), LANCL2 (Affinity Capture-MS)

ESM2 similar proteins: A0A8M9QN10, B2RYN2, D3YWQ0, D4A929, F1MAB7, O08576, O43147, O73916, O75064, O75912, O93307, O95475, O95996, Q08AE8, Q0VDN7, Q2KHT9, Q2KIL7, Q3TQF0, Q3U1Y4, Q4VBF2, Q58D79, Q5EB20, Q5REG4, Q5T124, Q5U3H9, Q5U464, Q6DGF9, Q6ZUJ8, Q7TT52, Q80U12, Q80V91, Q8BPQ7, Q8K1S6, Q8K3F4, Q8N9I9, Q8R4R9, Q8R512, Q8TAE6, Q8TDY4, Q8WWL2

Diamond homologs: O18734, Q62084, Q7TT52, Q8K3F3, Q8K3F4, Q8MIK9, Q8R4R9, Q8R4S0, Q8TAE6, Q91VC7, Q96A00, Q96C90, Q99MC0, Q9NXH3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

37 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

490 predictions. Top by Δscore:

Variant	Effect	Δscore
15:40815991:TGGCC:T	acceptor_loss	1.0000
15:40815992:GGCC:G	acceptor_loss	1.0000
15:40815993:GCCTA:G	acceptor_loss	1.0000
15:40815994:CCT:C	acceptor_loss	1.0000
15:40815995:CT:C	acceptor_loss	1.0000
15:40815996:T:G	acceptor_loss	1.0000
15:40816165:CCTA:C	donor_loss	1.0000
15:40816171:T:TA	donor_gain	1.0000
15:40828383:CTA:C	donor_loss	1.0000
15:40828384:TAC:T	donor_loss	1.0000
15:40828385:A:AC	donor_gain	1.0000
15:40828386:C:CC	donor_gain	1.0000
15:40828386:C:CG	donor_loss	1.0000
15:40815757:AAAGC:A	acceptor_gain	0.9900
15:40815758:AAGC:A	acceptor_gain	0.9900
15:40815760:GC:G	acceptor_gain	0.9900
15:40815760:GCC:G	acceptor_loss	0.9900
15:40815761:CC:C	acceptor_gain	0.9900
15:40815761:CCT:C	acceptor_loss	0.9900
15:40815762:C:CC	acceptor_gain	0.9900
15:40815762:C:T	acceptor_gain	0.9900
15:40815762:CT:C	acceptor_loss	0.9900
15:40815763:T:C	acceptor_loss	0.9900
15:40815956:CCTTA:C	donor_loss	0.9900
15:40815960:AC:A	donor_loss	0.9900
15:40815961:CCTC:C	donor_loss	0.9900
15:40815991:TGGC:T	acceptor_gain	0.9900
15:40815995:C:CC	acceptor_gain	0.9900
15:40816252:TC:T	acceptor_gain	0.9900
15:40816253:CC:C	acceptor_gain	0.9900

AlphaMissense

937 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:40815756:A:C	F126L	0.990
15:40815756:A:T	F126L	0.990
15:40815758:A:G	F126L	0.990
15:40828461:A:G	Y61H	0.990
15:40815745:A:G	L130P	0.988
15:40815733:A:G	L134P	0.986
15:40816174:A:G	L112P	0.985
15:40816210:A:G	L100P	0.984
15:40828417:C:A	W75C	0.983
15:40828417:C:G	W75C	0.983
15:40828460:T:C	Y61C	0.982
15:40828460:T:G	Y61S	0.982
15:40815757:A:G	F126S	0.979
15:40828445:A:G	L66P	0.975
15:40816185:C:A	Q108H	0.973
15:40816185:C:G	Q108H	0.973
15:40816186:T:G	Q108P	0.973
15:40828461:A:C	Y61D	0.973
15:40828469:G:A	T58I	0.969
15:40816174:A:T	L112Q	0.968
15:40828394:A:G	L83P	0.968
15:40828462:C:A	K60N	0.968
15:40828462:C:G	K60N	0.968
15:40816225:A:C	I95S	0.967
15:40816210:A:T	L100H	0.966
15:40828433:A:G	L70P	0.966
15:40828435:C:A	W69C	0.963
15:40828435:C:G	W69C	0.963
15:40828461:A:T	Y61N	0.963
15:40815733:A:T	L134H	0.960

dbSNP variants (sampled 300 via entrez): RS1000100673 (15:40817893 G>A), RS1000135567 (15:40819032 C>A,G), RS1000235691 (15:40827897 G>A), RS1000378083 (15:40815497 G>A,T), RS1000797439 (15:40821808 A>C,G), RS1000910737 (15:40825875 T>A,C), RS1001004284 (15:40819611 C>T), RS1001527278 (15:40822378 G>T), RS1001559873 (15:40822107 T>C), RS1001859132 (15:40828841 C>A), RS1001861996 (15:40827859 G>A), RS1002602267 (15:40815905 G>A,C,T), RS1002860438 (15:40829334 A>G), RS1003107881 (15:40822405 T>C), RS1003232434 (15:40823433 T>A,C)

Disease associations

OMIM: gene MIM:613256 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST010725_23	Malaria	2.000000e-06
GCST010725_38	Malaria	3.000000e-06
GCST010725_80	Malaria	7.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation	1
abrine	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.