PPP4R4

Summary

PPP4R4 (protein phosphatase 4 regulatory subunit 4, HGNC:23788) is a protein-coding gene on chromosome 14q32.2, encoding Serine/threonine-protein phosphatase 4 regulatory subunit 4 (Q6NUP7). Putative regulatory subunit of serine/threonine-protein phosphatase 4.

The protein encoded by this gene is a HEAT-like repeat-containing protein. The HEAT repeat is a tandemly repeated, 37-47 amino acid long module occurring in a number of cytoplasmic proteins. Arrays of HEAT repeats form a rod-like helical structure and appear to function as protein-protein interaction surfaces. The repeat-containing region of this protein has some similarity to the constant regulatory domain of the protein phosphatase 2A PR65/A subunit. The encoded protein binds protein serine/threonine phosphatase 4c in the cytoplasm.

Source: NCBI Gene 57718 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 113 total
• MANE Select transcript: NM_058237

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23788
Approved symbol	PPP4R4
Name	protein phosphatase 4 regulatory subunit 4
Location	14q32.2
Locus type	gene with protein product
Status	Approved
Aliases	PP4R4, CFAP14
Ensembl gene	ENSG00000119698
Ensembl biotype	protein_coding
OMIM	616790
Entrez	57718

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 9 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000304338, ENST00000328839, ENST00000553661, ENST00000555690, ENST00000556470, ENST00000556884, ENST00000903467, ENST00000924613, ENST00000924614, ENST00000941299

RefSeq mRNA: 6 — MANE Select: NM_058237 NM_001348142, NM_001348143, NM_001348144, NM_001348145, NM_020958, NM_058237

CCDS: CCDS9921, CCDS9922

Canonical transcript exons

ENST00000304338 — 25 exons

Exon	Start	End
ENSE00000808741	94230587	94230734
ENSE00000808742	94231242	94231315
ENSE00000808743	94233653	94233759
ENSE00000808744	94234562	94234669
ENSE00000808745	94237565	94237686
ENSE00000808746	94240673	94240795
ENSE00000808747	94241788	94241957
ENSE00000808748	94242289	94242408
ENSE00000808749	94244635	94244712
ENSE00000808750	94245587	94245670
ENSE00000808751	94246357	94246539
ENSE00000808752	94250172	94250277
ENSE00000808753	94251749	94251896
ENSE00000808754	94256460	94256604
ENSE00000808760	94275374	94275521
ENSE00001011176	94258783	94258824
ENSE00001173806	94265794	94265887
ENSE00001173812	94265387	94265473
ENSE00001229623	94266959	94267029
ENSE00001229735	94264878	94264947
ENSE00001323443	94259295	94259369
ENSE00001378408	94278619	94279734
ENSE00003480019	94176054	94176127
ENSE00003501313	94174322	94174582
ENSE00003650912	94208464	94208566

Expression profiles

Bgee: expression breadth ubiquitous, 125 present calls, max score 87.11.

FANTOM5 (CAGE): breadth broad, TPM avg 4.9089 / max 156.2172, expressed in 900 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
141208	2.3417	704
141209	2.1103	677
141210	0.2073	103
141207	0.0870	42
207345	0.0702	37
207346	0.0606	30
141206	0.0317	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
superior frontal gyrus	UBERON:0002661	87.11	gold quality
prefrontal cortex	UBERON:0000451	84.99	gold quality
anterior cingulate cortex	UBERON:0009835	84.58	gold quality
nucleus accumbens	UBERON:0001882	84.32	gold quality
frontal cortex	UBERON:0001870	83.77	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	82.62	gold quality
cerebral cortex	UBERON:0000956	82.35	gold quality
Brodmann (1909) area 9	UBERON:0013540	81.80	gold quality
right frontal lobe	UBERON:0002810	81.55	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.11	gold quality
caudate nucleus	UBERON:0001873	80.80	gold quality
Ammon’s horn	UBERON:0001954	80.56	gold quality
putamen	UBERON:0001874	80.49	gold quality
temporal lobe	UBERON:0001871	80.32	gold quality
amygdala	UBERON:0001876	80.25	gold quality
brain	UBERON:0000955	78.29	gold quality
testis	UBERON:0000473	77.95	gold quality
left testis	UBERON:0004533	77.69	gold quality
right testis	UBERON:0004534	77.49	gold quality
hypothalamus	UBERON:0001898	76.90	gold quality
left ovary	UBERON:0002119	75.10	gold quality
islet of Langerhans	UBERON:0000006	74.97	gold quality
corpus callosum	UBERON:0002336	74.81	gold quality
ovary	UBERON:0000992	74.67	gold quality
right ovary	UBERON:0002118	72.88	gold quality
substantia nigra	UBERON:0002038	72.73	gold quality
primary visual cortex	UBERON:0002436	72.66	gold quality
right hemisphere of cerebellum	UBERON:0014890	71.67	gold quality
ectocervix	UBERON:0012249	71.64	gold quality
endocervix	UBERON:0000458	71.16	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.87

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

86 targeting PPP4R4, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-10395-5P	99.86	67.35	676

Literature-anchored findings (GeneRIF, showing 1)

• PP4R4 forms a novel cytosolic complex with PP4c, independent from the complexes containing PP4R1, PP4R2.PP4R3, and alpha4, and the regulatory subunits of PP4c have evolved different modes of interaction with the catalytic subunit (PMID:18715871)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppp4r4	ENSDARG00000010407
mus_musculus	Ppp4r4	ENSMUSG00000021209
rattus_norvegicus	Ppp4r4	ENSRNOG00000054052
caenorhabditis_elegans		WBGENE00009781

Protein

Protein identifiers

Serine/threonine-protein phosphatase 4 regulatory subunit 4 — Q6NUP7 (reviewed: Q6NUP7)

All UniProt accessions (4): Q6NUP7, G3V422, G3V431, G3V516

UniProt curated annotations — full annotation on UniProt →

Function. Putative regulatory subunit of serine/threonine-protein phosphatase 4.

Subunit / interactions. Serine/threonine-protein phosphatase 4 (PP4) occurs in different assemblies of the catalytic and one or more regulatory subunits. Component of the PP4 complex PPP4C-PPP4R4.

Subcellular location. Cytoplasm.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6NUP7-1	1	yes
Q6NUP7-2	2

RefSeq proteins (6): NP_001335071, NP_001335072, NP_001335073, NP_001335074, NP_066009, NP_478144* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR021133	HEAT_type_2	Repeat
IPR039918	PPP4R4	Family

UniProt features (18 total): compositionally biased region 4, repeat 3, mutagenesis site 3, modified residue 2, splice variant 2, region of interest 2, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6NUP7-F1	79.13	0.65

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 (2): 775, 797

Mutagenesis-validated functional residues (3):

Position	Phenotype
501	abolishes interaction with ppp4c.
618	diminishes interaction with ppp4c.
618	abolishes interaction with ppp4c.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 108 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, TGCGCANK_UNKNOWN, GCANCTGNY_MYOD_Q6, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, GOBP_BLASTOCYST_DEVELOPMENT, NRF2_Q4, MYB_Q3, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, TAATGTG_MIR323, GOBP_EMBRYO_DEVELOPMENT, GTATGAT_MIR154_MIR487, chr14q32, MYB_Q5_01, TGGAAA_NFAT_Q4_01, YGCGYRCGC_UNKNOWN

GO Biological Process (1): blastocyst hatching (GO:0001835)

GO Molecular Function (4): protein phosphatase inhibitor activity (GO:0004864), protein serine/threonine phosphatase inhibitor activity (GO:0004865), protein phosphatase regulator activity (GO:0019888), protein binding (GO:0005515)

GO Cellular Component (5): cytoplasm (GO:0005737), cytosol (GO:0005829), cilium (GO:0005929), protein serine/threonine phosphatase complex (GO:0008287), ciliary basal body (GO:0036064)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphoprotein phosphatase activity	2
cellular anatomical structure	2
blastocyst development	1
hatching	1
phosphatase inhibitor activity	1
protein phosphatase regulator activity	1
protein serine/threonine phosphatase activity	1
protein phosphatase inhibitor activity	1
phosphatase regulator activity	1
protein phosphatase binding	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
phosphatase complex	1
microtubule organizing center	1
cilium	1

Protein interactions and networks

STRING

988 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPP4R4	PPP4C	P33172	939
PPP4R4	PPP4R1	Q8TF05	795
PPP4R4	PPP4R2	Q9NY27	774
PPP4R4	PPP4R3A	Q6IN85	633
PPP4R4	PPP4R3B	Q5MIZ7	533
PPP4R4	PPP6R1	Q9UPN7	518
PPP4R4	PPP6C	O00743	511
PPP4R4	SERPINA10	Q9UK55	484
PPP4R4	SLC35F1	Q5T1Q4	475
PPP4R4	RFLNA	Q6ZTI6	442
PPP4R4	PPP6R2	O75170	428
PPP4R4	PM20D2	Q8IYS1	425
PPP4R4	BPHL	Q86WA6	414
PPP4R4	GPR149	Q86SP6	413
PPP4R4	STRN	O43815	399

IntAct

24 interactions, top by confidence:

A	B	Type	Score
PPP4R4	PPP4C	psi-mi:“MI:0915”(physical association)	0.830
PPP4C	PPP4R4	psi-mi:“MI:0915”(physical association)	0.830
PPP4C	TCP1	psi-mi:“MI:0914”(association)	0.730
PPP4C	SUPT5H	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
PARP2	PPP4R4	psi-mi:“MI:0557”(adp ribosylation reaction)	0.440
YWHAQ	MCRIP1	psi-mi:“MI:0914”(association)	0.350
PPP4C	MID1	psi-mi:“MI:0914”(association)	0.350
PPP4C	ISG15	psi-mi:“MI:0914”(association)	0.350
HSPA5	HNRNPDL	psi-mi:“MI:0914”(association)	0.350
SFN	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
YWHAE	PLEKHG3	psi-mi:“MI:2364”(proximity)	0.270
YWHAQ	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (27): PPP4R4 (Affinity Capture-MS), PPP4R4 (Affinity Capture-MS), PPP4C (Affinity Capture-MS), PPP4R4 (Affinity Capture-RNA), PPP4R4 (Negative Genetic), PPP4R4 (Positive Genetic), PPP4R4 (Affinity Capture-MS), PPP4R4 (Affinity Capture-Western), PPP4C (Affinity Capture-Western), PPP4C (Reconstituted Complex), PPP4R4 (Proximity Label-MS), PPP4R4 (Affinity Capture-MS), PPP4R4 (Affinity Capture-MS), PPP4R4 (Affinity Capture-MS), PPP4R4 (Affinity Capture-MS)

ESM2 similar proteins: A0A3Q1LSX9, A1A5G0, A1A5K2, A2A5R2, A2APV2, A2VE70, D3ZYR1, O00203, O04376, O35643, O60308, O75122, P52303, Q05397, Q08AM6, Q08DS7, Q0JRZ9, Q10567, Q13367, Q28FH2, Q32PG1, Q3UQN2, Q4U0G1, Q561M0, Q5R807, Q5ZIW5, Q6NUP7, Q6NXC0, Q6NYW6, Q6ZPF4, Q7TSU1, Q7YRF1, Q7Z460, Q80TV8, Q8BRT1, Q8C0Y0, Q8IVF7, Q8LF36, Q8N7B6, Q8RW96

Diamond homologs: Q6NUP7, Q8C0Y0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 17 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	6	268.7×	2e-12
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	237.1×	2e-12
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	237.1×	2e-12
Activation of BH3-only proteins	6	175.2×	2e-11
RHO GTPases activate PKNs	6	112.0×	2e-10
Intrinsic Pathway for Apoptosis	6	103.3×	4e-10
SARS-CoV-1-host interactions	6	62.0×	7e-09
Apoptosis	6	59.3×	8e-09

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	6	36.9×	1e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	98
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

4189 predictions. Top by Δscore:

Variant	Effect	Δscore
14:94208461:A:AG	acceptor_gain	1.0000
14:94208461:AAGT:A	acceptor_gain	1.0000
14:94208462:A:AG	acceptor_gain	1.0000
14:94208463:G:GG	acceptor_gain	1.0000
14:94208565:GA:G	donor_gain	1.0000
14:94208567:G:GG	donor_gain	1.0000
14:94230656:G:GT	donor_gain	1.0000
14:94231237:A:G	acceptor_gain	1.0000
14:94231241:GGT:G	acceptor_gain	1.0000
14:94232476:A:AG	donor_gain	1.0000
14:94233760:G:GG	donor_gain	1.0000
14:94234554:A:AG	acceptor_gain	1.0000
14:94234555:C:G	acceptor_gain	1.0000
14:94234558:TCA:T	acceptor_loss	1.0000
14:94234559:CAGC:C	acceptor_loss	1.0000
14:94234560:A:AG	acceptor_gain	1.0000
14:94234560:AGC:A	acceptor_loss	1.0000
14:94234561:G:GA	acceptor_gain	1.0000
14:94234561:GC:G	acceptor_gain	1.0000
14:94234561:GCATT:G	acceptor_gain	1.0000
14:94234670:G:C	donor_loss	1.0000
14:94241784:TTA:T	acceptor_loss	1.0000
14:94241785:TA:T	acceptor_loss	1.0000
14:94241786:A:AC	acceptor_loss	1.0000
14:94241787:G:GT	acceptor_loss	1.0000
14:94241787:GGA:G	acceptor_gain	1.0000
14:94241928:G:GG	donor_gain	1.0000
14:94241933:G:GT	donor_gain	1.0000
14:94242260:A:AG	acceptor_gain	1.0000
14:94242261:C:G	acceptor_gain	1.0000

AlphaMissense

5727 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:94176111:G:C	A59P	1.000
14:94176121:T:C	L62P	1.000
14:94231256:T:A	W153R	1.000
14:94231256:T:C	W153R	1.000
14:94237609:T:C	L259P	1.000
14:94246426:T:A	W500R	1.000
14:94246426:T:C	W500R	1.000
14:94246427:G:C	W500S	1.000
14:94246428:G:C	W500C	1.000
14:94246428:G:T	W500C	1.000
14:94250185:T:A	V542D	1.000
14:94251778:A:G	R583G	1.000
14:94251779:G:C	R583T	1.000
14:94251779:G:T	R583I	1.000
14:94251780:A:C	R583S	1.000
14:94251780:A:T	R583S	1.000
14:94251896:G:C	R622T	1.000
14:94256460:A:C	R622S	1.000
14:94256460:A:T	R622S	1.000
14:94256585:T:A	V664D	1.000
14:94176082:T:A	V49D	0.999
14:94176094:T:C	L53P	0.999
14:94176110:G:C	R58S	0.999
14:94176110:G:T	R58S	0.999
14:94176112:C:A	A59D	0.999
14:94176124:T:C	L63P	0.999
14:94208505:T:C	L78P	0.999
14:94230626:G:C	A112P	0.999
14:94230627:C:A	A112D	0.999
14:94231269:T:C	L157P	0.999

dbSNP variants (sampled 300 via entrez): RS1000010355 (14:94219748 T>C), RS1000018469 (14:94194417 C>T), RS1000022746 (14:94226749 T>C), RS1000031417 (14:94243038 G>A,T), RS1000043175 (14:94250902 A>G), RS1000066085 (14:94267129 T>G), RS1000077212 (14:94212460 G>A), RS1000099438 (14:94245149 A>T), RS1000113022 (14:94191556 C>A,T), RS1000127730 (14:94223309 G>T), RS1000162767 (14:94271562 G>A), RS1000208645 (14:94247211 T>A), RS1000223079 (14:94223044 G>A,C), RS1000244534 (14:94174513 C>T), RS1000270404 (14:94191813 T>A)

Disease associations

OMIM: gene MIM:616790 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003262_268	Post bronchodilator FEV1	3.000000e-07
GCST003264_394	Post bronchodilator FEV1/FVC ratio	9.000000e-11
GCST003264_905	Post bronchodilator FEV1/FVC ratio	1.000000e-06
GCST004147_21	Chronic obstructive pulmonary disease	4.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

42 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	affects methylation, increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	increases expression	1
propionaldehyde	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentanal	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
belinostat	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
(+)-JQ1 compound	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Vorinostat	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Aldehydes	increases expression	1
Benzo(a)pyrene	increases expression	1
Copper	affects cotreatment, decreases expression	1
Drugs, Chinese Herbal	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TG26	HAP1 PPP4R4 (-) 1	Cancer cell line	Male
CVCL_TG27	HAP1 PPP4R4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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