PPEF2

Summary

PPEF2 (protein phosphatase with EF-hand domain 2, HGNC:9244) is a protein-coding gene on chromosome 4q21.1, encoding Serine/threonine-protein phosphatase with EF-hands 2 (O14830). May play a role in phototransduction.

This gene encodes a member of the serine/threonine protein phosphatase with EF-hand motif family. The protein contains a protein phosphatase catalytic domain, and at least two EF-hand calcium-binding motifs in its C terminus. Although its substrate(s) is unknown, the encoded protein, which is expressed specifically in photoreceptors and the pineal, has been suggested to play a role in the visual system. This gene shares high sequence similarity with the Drosophila retinal degeneration C (rdgC) gene.

Source: NCBI Gene 5470 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 125 total
• MANE Select transcript: NM_006239

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9244
Approved symbol	PPEF2
Name	protein phosphatase with EF-hand domain 2
Location	4q21.1
Locus type	gene with protein product
Status	Approved
Aliases	PPP7CB
Ensembl gene	ENSG00000156194
Ensembl biotype	protein_coding
OMIM	602256
Entrez	5470

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 2 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000286719, ENST00000503352, ENST00000510607, ENST00000511880, ENST00000513324, ENST00000515552, ENST00000652700

RefSeq mRNA: 1 — MANE Select: NM_006239 NM_006239

CCDS: CCDS34013

Canonical transcript exons

ENST00000286719 — 17 exons

Exon	Start	End
ENSE00001025119	75891648	75891705
ENSE00001193388	75889957	75890132
ENSE00001193392	75866189	75866352
ENSE00001193396	75891851	75891978
ENSE00001330815	75888214	75888328
ENSE00001360417	75902230	75902452
ENSE00001360424	75896271	75896383
ENSE00001426219	75859867	75860920
ENSE00003493433	75883166	75883202
ENSE00003521699	75867313	75867419
ENSE00003533787	75884594	75884760
ENSE00003580500	75886852	75886898
ENSE00003580808	75873127	75873312
ENSE00003598564	75872025	75872167
ENSE00003606158	75882926	75883075
ENSE00003618825	75876287	75876673
ENSE00003686435	75864440	75864527

Expression profiles

Bgee: expression breadth ubiquitous, 154 present calls, max score 77.50.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1666 / max 174.7443, expressed in 7 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52604	0.1011	6
52605	0.0276	4
52606	0.0245	5
52603	0.0134	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.50	gold quality
gastrocnemius	UBERON:0001388	76.53	gold quality
muscle of leg	UBERON:0001383	71.70	gold quality
right uterine tube	UBERON:0001302	70.36	gold quality
skeletal muscle organ	UBERON:0014892	66.77	gold quality
right hemisphere of cerebellum	UBERON:0014890	66.03	gold quality
cerebellar hemisphere	UBERON:0002245	65.97	gold quality
cerebellar cortex	UBERON:0002129	65.73	gold quality
cerebellum	UBERON:0002037	63.81	gold quality
mucosa of transverse colon	UBERON:0004991	62.85	gold quality
left uterine tube	UBERON:0001303	60.66	gold quality
endometrium epithelium	UBERON:0004811	59.42	gold quality
descending thoracic aorta	UBERON:0002345	59.39	gold quality
left ovary	UBERON:0002119	59.26	gold quality
metanephros cortex	UBERON:0010533	59.04	gold quality
body of uterus	UBERON:0009853	58.24	gold quality
cortical plate	UBERON:0005343	57.50	gold quality
monocyte	CL:0000576	57.46	gold quality
apex of heart	UBERON:0002098	57.31	gold quality
leukocyte	CL:0000738	56.50	gold quality
spleen	UBERON:0002106	56.48	gold quality
metanephric glomerulus	UBERON:0004736	55.97	gold quality
buccal mucosa cell	CL:0002336	55.62	gold quality
tibial nerve	UBERON:0001323	55.47	gold quality
right coronary artery	UBERON:0001625	55.29	gold quality
right testis	UBERON:0004534	55.09	gold quality
granulocyte	CL:0000094	54.81	gold quality
right ovary	UBERON:0002118	54.57	gold quality
endocervix	UBERON:0000458	54.47	gold quality
muscle layer of sigmoid colon	UBERON:0035805	54.13	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	1406.06
E-MTAB-3929	yes	829.45
E-GEOD-98556	yes	779.06
E-ANND-3	yes	6.04
E-GEOD-93593	no	84.73
E-CURD-97	no	61.64
E-MTAB-6142	no	1.25

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

68 targeting PPEF2, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 2)

• Data suggest that, despite structural divergence, PPEF and PP5 phosphatases may share common interacting partners and functions. (PMID:20674765)
• Exome sequencing reveals PPEF2 variant associated with high myopia. (PMID:38110044)

Cross-species orthologs

33 orthologs

Organism	Symbol	Gene ID
danio_rerio	PPEF2	ENSDARG00000104980
mus_musculus	Ppef2	ENSMUSG00000029410
rattus_norvegicus	Ppef2	ENSRNOG00000052061
drosophila_melanogaster	PpD5	FBGN0005778
drosophila_melanogaster	Pp1-Y1	FBGN0261399
drosophila_melanogaster	rdgC	FBGN0265959
caenorhabditis_elegans		WBGENE00001748
caenorhabditis_elegans		WBGENE00003969
caenorhabditis_elegans		WBGENE00007354
caenorhabditis_elegans		WBGENE00007699
caenorhabditis_elegans		WBGENE00007700
caenorhabditis_elegans		WBGENE00007763
caenorhabditis_elegans		WBGENE00008124
caenorhabditis_elegans	F22D6.9	WBGENE00009054
caenorhabditis_elegans		WBGENE00009079
caenorhabditis_elegans		WBGENE00009101
caenorhabditis_elegans		WBGENE00009893
caenorhabditis_elegans		WBGENE00010265
caenorhabditis_elegans		WBGENE00011133
caenorhabditis_elegans		WBGENE00012008
caenorhabditis_elegans		WBGENE00012741
caenorhabditis_elegans		WBGENE00013476
caenorhabditis_elegans		WBGENE00014158
caenorhabditis_elegans		WBGENE00016010
caenorhabditis_elegans		WBGENE00016081
caenorhabditis_elegans	F26B1.5	WBGENE00017817
caenorhabditis_elegans		WBGENE00018359
caenorhabditis_elegans		WBGENE00018410
caenorhabditis_elegans		WBGENE00019951
caenorhabditis_elegans	W03D8.2	WBGENE00020985
caenorhabditis_elegans		WBGENE00022617
caenorhabditis_elegans		WBGENE00022710
caenorhabditis_elegans	Y71G12B.30	WBGENE00044347

Paralogs (12): PPP5C (ENSG00000011485), PPEF1 (ENSG00000086717), PPP2CB (ENSG00000104695), PPP3CB (ENSG00000107758), PPP2CA (ENSG00000113575), PPP6C (ENSG00000119414), PPP3CC (ENSG00000120910), PPP3CA (ENSG00000138814), PPP4C (ENSG00000149923), PPP1CA (ENSG00000172531), PPP1CC (ENSG00000186298), PPP1CB (ENSG00000213639)

Protein

Protein identifiers

Serine/threonine-protein phosphatase with EF-hands 2 — O14830 (reviewed: O14830)

All UniProt accessions (3): O14830, A0A494C0J1, E7EPQ9

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in phototransduction. May dephosphorylate photoactivated rhodopsin. May function as a calcium sensing regulator of ionic currents, energy production or synaptic transmission.

Subcellular location. Cytoplasm. Cell projection. Cilium. Photoreceptor outer segment. Photoreceptor inner segment.

Tissue specificity. Retinal specific.

Activity regulation. Activated by calcium.

Cofactor. Binds 2 manganese ions per subunit.

Similarity. Belongs to the PPP phosphatase family.

Isoforms (2)

UniProt ID	Names	Canonical?
O14830-1	PPEF-2(L)	yes
O14830-2	PPEF-2(S)

RefSeq proteins (1): NP_006230* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR004843	Calcineurin-like_PHP	Domain
IPR006186	Ser/Thr-sp_prot-phosphatase	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR012008	Ser/Thr-Pase_EF-hand_contain	Family
IPR013235	PPP_dom	Domain
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR029052	Metallo-depent_PP-like	Homologous_superfamily
IPR051134	PPP_phosphatase	Family

Pfam: PF00149, PF08321, PF13499

Catalyzed reactions (Rhea), 2 shown:

• O-phospho-L-seryl-[protein] + H2O = L-seryl-[protein] + phosphate (RHEA:20629)
• O-phospho-L-threonyl-[protein] + H2O = L-threonyl-[protein] + phosphate (RHEA:47004)

UniProt features (39 total): binding site 16, sequence variant 6, domain 4, compositionally biased region 4, region of interest 4, splice variant 2, chain 1, active site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14830-F1	75.93	0.46

Functional residue map

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

Catalytic / active sites (1): 241 (proton donor)

Ligand- & substrate-binding residues (16): 179; 181; 208; 208; 240; 292; 488; 665; 667; 669; 676; 705 …

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 134 (showing top): GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_APOPTOTIC_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_HYDROGEN_PEROXIDE, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, TGCTGAY_UNKNOWN, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, BROWN_MYELOID_CELL_DEVELOPMENT_DN, GOBP_DETECTION_OF_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_APOPTOTIC_SIGNALING_PATHWAY, GOBP_SENSORY_PERCEPTION, GOBP_DEPHOSPHORYLATION, GOBP_PROTEIN_DEPHOSPHORYLATION, GOCC_NEURON_PROJECTION

GO Biological Process (6): protein dephosphorylation (GO:0006470), visual perception (GO:0007601), negative regulation of MAPK cascade (GO:0043409), detection of stimulus involved in sensory perception (GO:0050906), cellular response to hydrogen peroxide (GO:0070301), negative regulation of apoptotic signaling pathway (GO:2001234)

GO Molecular Function (11): protein serine/threonine phosphatase activity (GO:0004722), iron ion binding (GO:0005506), calcium ion binding (GO:0005509), manganese ion binding (GO:0030145), protein serine/threonine kinase inhibitor activity (GO:0030291), Hsp70 protein binding (GO:0030544), mitogen-activated protein kinase kinase kinase binding (GO:0031435), Hsp90 protein binding (GO:0051879), phosphoprotein phosphatase activity (GO:0004721), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (7): photoreceptor outer segment (GO:0001750), photoreceptor inner segment (GO:0001917), nucleus (GO:0005634), cytosol (GO:0005829), cytoplasm (GO:0005737), cilium (GO:0005929), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
transition metal ion binding	2
heat shock protein binding	2
dephosphorylation	1
protein modification process	1
sensory perception of light stimulus	1
MAPK cascade	1
regulation of MAPK cascade	1
negative regulation of intracellular signal transduction	1
sensory perception	1
detection of stimulus	1
cellular response to reactive oxygen species	1
response to hydrogen peroxide	1
negative regulation of signal transduction	1
negative regulation of apoptotic process	1
apoptotic signaling pathway	1
regulation of apoptotic signaling pathway	1
phosphoprotein phosphatase activity	1
metal ion binding	1
protein serine/threonine kinase activity	1
protein kinase inhibitor activity	1
protein-folding chaperone binding	1
protein kinase binding	1
phosphatase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cation binding	1
photoreceptor cell cilium	1
intracellular membrane-bounded organelle	1
cytoplasm	1
intracellular anatomical structure	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

2799 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPEF2	RHO	P08100	707
PPEF2	LRIT2	A6NDA9	570
PPEF2	DRC8	Q5VUJ9	501
PPEF2	CCDC158	Q5M9N0	447
PPEF2	LRIT1	Q9P2V4	447
PPEF2	EFHC1	Q5JVL4	435
PPEF2	SPAG6	O75602	423
PPEF2	OR10S1	Q8NGN2	423
PPEF2	OR3A2	P47893	420
PPEF2	PRKAG3	Q9UGI9	419
PPEF2	PPM1M	Q96MI6	417
PPEF2	GABRD	O14764	410
PPEF2	PSME2	Q9UL46	406
PPEF2	MYLK2	Q9H1R3	406
PPEF2	CILK1	Q9UPZ9	406

IntAct

6 interactions, top by confidence:

A	B	Type	Score
Calm1	PPEF2	psi-mi:“MI:0915”(physical association)	0.510
PPEF2	UNC119	psi-mi:“MI:0915”(physical association)	0.400
PPEF2	HAX1	psi-mi:“MI:0914”(association)	0.350
PPEF2	URI1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (27): AKAP8L (Affinity Capture-MS), ATP2A2 (Affinity Capture-MS), CALM2 (Affinity Capture-MS), HAX1 (Affinity Capture-MS), KRT8 (Affinity Capture-MS), RCN1 (Affinity Capture-MS), RCN2 (Affinity Capture-MS), SDF4 (Affinity Capture-MS), SPAG9 (Affinity Capture-MS), TUBB6 (Affinity Capture-MS), YWHAG (Affinity Capture-MS), CACYBP (Proximity Label-MS), KIAA1524 (Proximity Label-MS), WDR92 (Proximity Label-MS), PIH1D1 (Proximity Label-MS)

ESM2 similar proteins: A0A0G2JXT6, A0JMF6, A0JMK5, A2ALK8, A2BGG1, A6QLT4, A7MB43, G5ED68, O13819, O14830, P26045, P33402, P51432, Q09M05, Q13496, Q13613, Q15111, Q3USB7, Q4KWH5, Q4R6N0, Q4U2V3, Q52KU6, Q5EB32, Q5F452, Q5R6F6, Q5R9S3, Q5U581, Q62688, Q6AXQ4, Q6NU08, Q6TEL0, Q6XPS3, Q7TPM9, Q7ZXF1, Q8K394, Q8NCE2, Q8VE11, Q8VEL2, Q96EF0, Q96MI9

Diamond homologs: A0CNL9, A0DJ90, G5EBX9, G5EGK8, O04857, O14829, O14830, O15757, O35385, O35655, O43049, O76932, O82733, O82734, P11493, P11611, P11612, P12982, P13681, P20654, P22198, P23594, P23595, P23733, P23734, P23777, P23880, P30366, P32598, P33329, P36873, P36874, P40421, P48461, P48462, P48463, P48480, P48481, P48482, P48483

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	112
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2821 predictions. Top by Δscore:

Variant	Effect	Δscore
4:75860920:CCT:C	acceptor_gain	1.0000
4:75860922:T:C	acceptor_gain	1.0000
4:75860926:C:CT	acceptor_gain	1.0000
4:75860927:A:T	acceptor_gain	1.0000
4:75867307:TCTTA:T	donor_loss	1.0000
4:75867308:CTTA:C	donor_loss	1.0000
4:75867309:TTA:T	donor_loss	1.0000
4:75867310:TACC:T	donor_loss	1.0000
4:75867311:A:AC	donor_gain	1.0000
4:75867311:A:AT	donor_loss	1.0000
4:75867312:C:CC	donor_gain	1.0000
4:75867312:C:T	donor_loss	1.0000
4:75867312:CCGA:C	donor_gain	1.0000
4:75867418:TC:T	acceptor_gain	1.0000
4:75867419:CC:C	acceptor_gain	1.0000
4:75883000:T:A	donor_gain	1.0000
4:75883005:T:C	donor_gain	1.0000
4:75884574:A:AC	donor_gain	1.0000
4:75884574:AAG:A	donor_gain	1.0000
4:75884575:A:C	donor_gain	1.0000
4:75884608:ATGGT:A	donor_gain	1.0000
4:75884756:CCATT:C	acceptor_gain	1.0000
4:75884757:CATTC:C	acceptor_gain	1.0000
4:75884759:TT:T	acceptor_gain	1.0000
4:75884767:A:T	acceptor_gain	1.0000
4:75884769:C:CT	acceptor_gain	1.0000
4:75884770:A:T	acceptor_gain	1.0000
4:75884777:CCAG:C	acceptor_gain	1.0000
4:75884778:C:T	acceptor_gain	1.0000
4:75884778:CAG:C	acceptor_gain	1.0000

AlphaMissense

4987 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:75884717:T:A	D208V	0.999
4:75884720:C:A	G207V	0.999
4:75872153:A:C	F507L	0.998
4:75872153:A:T	F507L	0.998
4:75872155:A:G	F507L	0.998
4:75873232:A:C	F467L	0.998
4:75873232:A:T	F467L	0.998
4:75873234:A:G	F467L	0.998
4:75884624:C:A	G239V	0.998
4:75884626:T:A	R238S	0.998
4:75884626:T:G	R238S	0.998
4:75884627:C:G	R238T	0.998
4:75884716:G:C	D208E	0.998
4:75884716:G:T	D208E	0.998
4:75884717:T:C	D208G	0.998
4:75884717:T:G	D208A	0.998
4:75884720:C:T	G207D	0.998
4:75884722:G:C	N206K	0.998
4:75884722:G:T	N206K	0.998
4:75872106:A:T	V523D	0.997
4:75873297:A:G	W446R	0.997
4:75873297:A:T	W446R	0.997
4:75883026:A:G	L278P	0.997
4:75884627:C:A	R238I	0.997
4:75884629:G:C	N237K	0.997
4:75884629:G:T	N237K	0.997
4:75884721:C:G	G207R	0.997
4:75884726:A:G	F205S	0.997
4:75873169:A:C	H488Q	0.996
4:75873169:A:T	H488Q	0.996

dbSNP variants (sampled 300 via entrez): RS1000052006 (4:75884962 A>C,G), RS1000120356 (4:75867955 C>T), RS1000144067 (4:75871358 C>A,G,T), RS1000194249 (4:75869432 A>T), RS1000335634 (4:75886783 T>C), RS1000350173 (4:75865574 C>A,T), RS1000537515 (4:75885293 A>T), RS1000548872 (4:75873054 C>T), RS1000564626 (4:75890656 A>G), RS10007472 (4:75896068 T>C), RS1000770947 (4:75865228 C>T), RS1000829378 (4:75879196 T>C), RS1000857986 (4:75859906 T>G), RS1000893434 (4:75880334 A>G), RS1000923863 (4:75861052 A>C)

Disease associations

OMIM: gene MIM:602256 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007009_3	Hippocampal volume	7.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005035	hippocampal volume

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
aristolochic acid I	increases expression	1
vanadyl sulfate	increases expression	1
CGP 52608	affects binding, increases reaction	1
theaflavin-3,3’-digallate	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Copper	affects cotreatment, decreases expression	1
Niclosamide	decreases expression	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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