PPP2R2B

Summary

PPP2R2B (protein phosphatase 2 regulatory subunit Bbeta, HGNC:9305) is a protein-coding gene on chromosome 5q32, encoding Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform (Q00005). The B regulatory subunit might modulate substrate selectivity and catalytic activity, and might also direct the localization of the catalytic enzyme to a particular subcellular compartment.

The product of this gene belongs to the phosphatase 2 regulatory subunit B family. Protein phosphatase 2 is one of the four major Ser/Thr phosphatases, and it is implicated in the negative control of cell growth and division. It consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits. The B regulatory subunit might modulate substrate selectivity and catalytic activity. This gene encodes a beta isoform of the regulatory subunit B55 subfamily. Defects in this gene cause autosomal dominant spinocerebellar ataxia 12 (SCA12), a disease caused by degeneration of the cerebellum, sometimes involving the brainstem and spinal cord, and in resulting in poor coordination of speech and body movements. Multiple alternatively spliced variants, which encode different isoforms, have been identified for this gene. The 5’ UTR of some of these variants includes a CAG trinucleotide repeat sequence (7-28 copies) that can be expanded to 55-78 copies in cases of SCA12.

Source: NCBI Gene 5521 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spinocerebellar ataxia type 12 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 76 total
• Phenotypes (HPO): 34
• MANE Select transcript: NM_181675

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9305
Approved symbol	PPP2R2B
Name	protein phosphatase 2 regulatory subunit Bbeta
Location	5q32
Locus type	gene with protein product
Status	Approved
Aliases	PR55-BETA, PR52B, B55beta
Ensembl gene	ENSG00000156475
Ensembl biotype	protein_coding
OMIM	604325
Entrez	5521

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 22 protein_coding, 6 nonsense_mediated_decay, 5 protein_coding_CDS_not_defined

ENST00000336640, ENST00000394409, ENST00000394411, ENST00000394413, ENST00000394414, ENST00000453001, ENST00000502876, ENST00000504198, ENST00000504565, ENST00000508267, ENST00000508545, ENST00000509721, ENST00000512011, ENST00000512639, ENST00000512984, ENST00000515880, ENST00000520231, ENST00000522831, ENST00000528601, ENST00000530902, ENST00000532154, ENST00000885029, ENST00000885030, ENST00000885031, ENST00000885032, ENST00000885033, ENST00000885034, ENST00000928166, ENST00000928167, ENST00000946776, ENST00000946777, ENST00000946778, ENST00000946779

RefSeq mRNA: 10 — MANE Select: NM_181675 NM_001271899, NM_001271900, NM_001271948, NM_001428277, NM_001428279, NM_181674, NM_181675, NM_181676, NM_181677, NM_181678

CCDS: CCDS4283, CCDS4284, CCDS43380, CCDS64281, CCDS64282, CCDS93800

Canonical transcript exons

ENST00000394411 — 10 exons

Exon	Start	End
ENSE00001518391	146878591	146878757
ENSE00002153895	146580742	146590226
ENSE00003484771	146701045	146701142
ENSE00003538929	146592971	146593062
ENSE00003583811	146697979	146698144
ENSE00003608172	146650547	146650724
ENSE00003609462	146878002	146878195
ENSE00003618402	146638251	146638415
ENSE00003634281	146691128	146691240
ENSE00003682537	146600291	146600460

Expression profiles

Bgee: expression breadth ubiquitous, 244 present calls, max score 98.70.

FANTOM5 (CAGE): breadth broad, TPM avg 15.3153 / max 861.2169, expressed in 666 samples.

FANTOM5 promoters (25 alternative TSS)

Promoter ID	TPM avg	Samples expressed
64005	5.4224	578
64017	3.7849	151
64011	0.9234	112
64019	0.8359	99
64016	0.7087	97
63996	0.6521	145
63997	0.5136	126
64010	0.3997	95
64020	0.3113	77
64003	0.3018	131

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	98.70	gold quality
cortical plate	UBERON:0005343	98.69	gold quality
ganglionic eminence	UBERON:0004023	98.57	gold quality
prefrontal cortex	UBERON:0000451	97.71	gold quality
caudate nucleus	UBERON:0001873	97.55	gold quality
nucleus accumbens	UBERON:0001882	97.53	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.50	gold quality
putamen	UBERON:0001874	97.49	gold quality
endothelial cell	CL:0000115	97.36	gold quality
primary visual cortex	UBERON:0002436	97.36	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.27	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.22	gold quality
frontal cortex	UBERON:0001870	97.14	gold quality
entorhinal cortex	UBERON:0002728	97.13	gold quality
neocortex	UBERON:0001950	97.06	gold quality
telencephalon	UBERON:0001893	97.04	gold quality
amygdala	UBERON:0001876	97.00	gold quality
temporal lobe	UBERON:0001871	96.98	gold quality
cerebral cortex	UBERON:0000956	96.94	gold quality
anterior cingulate cortex	UBERON:0009835	96.90	gold quality
cingulate cortex	UBERON:0003027	96.86	gold quality
superior frontal gyrus	UBERON:0002661	96.81	gold quality
middle temporal gyrus	UBERON:0002771	96.81	gold quality
occipital lobe	UBERON:0002021	96.64	gold quality
right frontal lobe	UBERON:0002810	96.62	gold quality
medial globus pallidus	UBERON:0002477	96.45	gold quality
postcentral gyrus	UBERON:0002581	96.39	gold quality
substantia nigra	UBERON:0002038	96.36	gold quality
parietal lobe	UBERON:0001872	96.34	gold quality
substantia nigra pars compacta	UBERON:0001965	96.32	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	8798.85
E-HCAD-25	yes	4540.80
E-HCAD-5	yes	48.16
E-GEOD-81608	yes	14.50
E-ANND-3	yes	7.09
E-GEOD-180759	no	4680.78
E-MTAB-9154	no	915.79
E-GEOD-83139	no	210.57
E-ENAD-27	no	8.16

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, FOXC1, MYC, SP1, TFAP4

miRNA regulators (miRDB)

56 targeting PPP2R2B, 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-126-5P	100.00	72.71	3180
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-3923	99.52	69.21	446
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-653-5P	99.46	67.35	1300
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-892C-5P	99.16	70.56	2116

Literature-anchored findings (GeneRIF, showing 40)

• a novel ATM-dependent mechanism is regulating association of B55 subunits with nuclear PP2A in response to IR (PMID:11723136)
• cyclin G2 also associates with various PP2A B’ regulatory subunits, as previously shown for cyclin G1 (PMID:11956189)
• Cyclin G recruits PP2A in order to modulate the phosphorylation of Mdm2 and thereby to regulate both Mdm2 and p53. (PMID:11983168)
• Phosphorylation of bestrophin is regulated by PP2A. (PMID:12058047)
• SCA12 triplet expansion rate in Italian ataxia patients (PMID:12140678)
• Analysis of CTA/CTG and CAG polymorphism in a Polish control group. (PMID:14960773)
• phospholipase D suppresses protein phosphatase 2A and is involved in the mTOR survival pathway in the transformation of human cells (PMID:16109716)
• PP2A plays a positive rather than a negative role in the regulation of IKKbeta (PMID:16126728)
• analysis of a founder for SCA12 in the Indian population (PMID:16138911)
• We therefore propose that PP2A plays a crucial role in the maintenance of cell-cell adhesion through recruitment of IQGAP1 to the Rac-bound E-cadherin-catenins complex. (PMID:16245300)
• The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. (PMID:16286244)
• PP2A-mediated dephosphorylation of HSP27 and tau correlated with PP2A-induced preservation of endothelial cell cytoskeleton (PMID:16475161)
• Cyclin G2 may modulate the cell cycle and cellular division processes through modulation of PP2A and centrosomal associated activities. (PMID:17123511)
• The small t antigen (ST) of DNA tumor virus SV40 inhibits PP2A phosphatase activity through its N-terminal J domain. (PMID:17529992)
• results suggest that the PPP2R2B gene CAG repeat polymorphism may be functional and may, in part, play a role in conferring susceptibility to Alzheimer disease and essential tremor in Taiwan (PMID:18484086)
• Adenovirus E4orf4 protein downregulates MYC expression through interaction with the PP2A-B55 subunit (PMID:18653458)
• Results suggest that Parkinsonism (PD) and multiple system atrophy (MSA) are not associated with spinocerebellar ataxia 12 (SCA12) and it is not necessary to screen SCA12 in PD and MSA patients. (PMID:18973067)
• Cells with ectopically expressed PPP2R2B were shown predisposed to autophagy and oxidative stress induced cell death. (PMID:20017961)
• Quantitative methylation analysis identified ABCB1, FOXC1, PPP2R2B and PTEN as novel genes to be methylated in ductal carcinoma in situ. (PMID:20056007)
• We investigated methylation patterns in the promoter regions of ABCB1, ATM, BRCA1, CDH3, CDKN2A, CXCR4, ESR1, FBXW7, FOXC1, GSTP1, IGF2, HMLH1, PPP2R2B, and PTEN75 in well-described pre-treatment samples from locally advanced breast cancer (PMID:20338046)
• The CAG repeat in SCA12 functions as a cis element to up-regulate PPP2R2B expression. (PMID:20533062)
• results indicate that the A variant of the rs319217 SNP of the PPP2R2B gene is a marker of better prognosis in breast cancer (PMID:20669227)
• Autosomal dominant cerebellar ataxia mapping to 5q31-q33.1 has no CAG repeat expansion or other mutations of the PPP2R2B gene. (PMID:20937954)
• CAG repeat lengths in the PPP2R2B gene may be potential genetic markers for Alzheimer disease susceptibility in the Japanese population. (PMID:21029765)
• PPP2R2B, encoding the B55beta regulatory subunit of the PP2A complex, is epigenetically inactivated by DNA hypermethylation in colorectal cancer. (PMID:21075311)
• oxidative stress induced by mitochondrial dysfunction causes elevated expression of ppp2r2b and plays a causal role in SCA12; and reduction of ROS is a potential therapeutic intervention for this neuropathy (PMID:21471219)
• defective production of PP2A Bbeta upon IL-2 deprivation results in apoptosis resistance and longer survival of autoreactive T cells, in a subset of SLE patients (PMID:21746932)
• This study suggested that PPP2R2B CAG expansion mutation might lead increase induction of Spinocerebellar ataxia type 12. (PMID:21827912)
• Data indicate that PPP2R2B gene product PP2A/Bbeta2 activates the mitochondrial fission enzyme dynamin-related protein 1 (Drp1) by dephosphorylating Ser656. (PMID:22583914)
• Single nucleotide polymorphisms in PPP2R2B is associated with drug response in breast cancer. (PMID:23034890)
• Differential autophagic neuronal cell death under stress is determined by the cytoplasmic and mitochondrial-specific PPP2R2B isoforms. (PMID:23381641)
• Bod1 regulates protein phosphatase 2A at mitotic kinetochores. (PMID:24157919)
• Identification of the adenovirus E4orf4 protein binding site on the B55alpha and Cdc55 regulatory subunits of PP2A: Implications for PP2A (PMID:24244166)
• We demonstrate that PP2A/B55 is required for Gwl dephosphorylation at the essential Cdk site Thr194. Ensa/ARPP19 dephosphorylation is mediated by the RNA (PMID:24391510)
• PP2A-B55beta promotes cyclin E1 overexpression by antagonizing its degradation and its inhibition could represent a therapeutic mechanism for abrogating cyclin E1 function in cancers (PMID:24509904)
• Inactivation of protein-phosphatase 2A causing hyperphosphorylation of paraprotein targets in monoclonal gammopathy of undetermined significance, multiple myeloma and Waldenstrom’s macroglobulinemia is due to an exchange of its regulatory subunits (PMID:24676687)
• Bcl-2 phosphorylation at Ser70 by selective tyrosine nitration of PP2A-B56delta stabilizes its antiapoptotic activity (PMID:25082878)
• investigated CAG copies within PPP2R2B in 29 patients with spinocerebellar ataxia who are excluded from the most common subtypes; 3 patients carried 53, 46 and 54 CAG repeats respectively, while the other 26 cases harbored CAG repeats less than 30 (PMID:25634432)
• IER5 functions as a positive feedback regulator of HSF1 and that this process involves PP2A/B55 and HSF1 dephosphorylation. (PMID:25816751)
• Thus, Fcp1 coordinates Cdk1 and Gwl inactivation to derepress PP2A-B55, generating a dephosphorylation switch that drives mitosis progression. (PMID:26653855)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ppp2r2b	ENSMUSG00000024500
rattus_norvegicus	Ppp2r2b	ENSRNOG00000018851
caenorhabditis_elegans	sur-6	WBGENE00006352

Paralogs (3): PPP2R2C (ENSG00000074211), PPP2R2D (ENSG00000175470), PPP2R2A (ENSG00000221914)

Protein

Protein identifiers

Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform — Q00005 (reviewed: Q00005)

Alternative names: PP2A subunit B isoform B55-beta, PP2A subunit B isoform PR55-beta, PP2A subunit B isoform R2-beta, PP2A subunit B isoform beta

All UniProt accessions (7): Q00005, D6RB57, D6RF04, D6RGF9, E5RFC4, E9PCT7, H0YA16

UniProt curated annotations — full annotation on UniProt →

Function. The B regulatory subunit might modulate substrate selectivity and catalytic activity, and might also direct the localization of the catalytic enzyme to a particular subcellular compartment. Within the PP2A holoenzyme complex, isoform 2 is required to promote proapoptotic activity. Isoform 2 regulates neuronal survival through the mitochondrial fission and fusion balance.

Subunit / interactions. PP2A consists of a common heterodimeric core enzyme, composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B’’/PR72/PR130/PR59 and R5/B’/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules. Interacts with TOMM22. Interacts with IER5 (via N- and C-terminal regions).

Subcellular location. Cytoplasm. Cytoskeleton. Membrane Cytoplasm. Mitochondrion. Mitochondrion outer membrane.

Tissue specificity. Brain.

Disease relevance. Spinocerebellar ataxia 12 (SCA12) [MIM:604326] Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA12 is an autosomal dominant cerebellar ataxia (ADCA). The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminal 26 residues of isoform 2 constitute a cryptic mitochondrial matrix import signal with critical basic and hydrophobic residues, that is necessary and sufficient for targeting the PP2A holoenzyme to the outer mitochondrial membrane (OMM) and does not affect holoenzyme formation or catalytic activity. The last WD repeat of isoform 2 constitutes a mitochondrial stop-transfer domain that confers resistance to the unfolding step process required for import and therefore prevents PPP2R2B matrix translocation and signal sequence cleavage.

Miscellaneous. Conserved additional ATG codons are found 5’ of the putative initiator codon in transcripts supporting isoform 1. They may initiate the translation of upstream short open reading frames altering the expression of that isoform as described in PubMed:1849734. Contains a cryptic mitochondrial transit peptide at positions 1-26.

Similarity. Belongs to the phosphatase 2A regulatory subunit B family.

Isoforms (7)

UniProt ID	Names	Canonical?
Q00005-1	1, Bbeta, Bbeta1	yes
Q00005-2	2, Bbeta2
Q00005-3	3
Q00005-4	4
Q00005-5	5
Q00005-6	6
Q00005-7	7

RefSeq proteins (10): NP_001258828, NP_001258829, NP_001258877, NP_001415206, NP_001415208, NP_858060, NP_858061, NP_858062, NP_858063, NP_858064 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000009	PP2A_PR55	Family
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR018067	PP2A_PR55_CS	Conserved_site
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily

UniProt features (25 total): repeat 7, splice variant 6, sequence conflict 6, modified residue 3, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q00005-F1	90.37	0.78

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 (3): 298, 275, 295

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 251 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, RNGTGGGC_UNKNOWN, FXR_IR1_Q6, FREAC2_01, KEGG_TIGHT_JUNCTION, HNF1_Q6, LHX3_01, GGGTGGRR_PAX4_03, SENESE_HDAC1_AND_HDAC2_TARGETS_DN, PAX8_B, SOX9_B1, FREAC3_01, TGCTGAY_UNKNOWN, OCT1_03, GATA1_01

GO Biological Process (1): apoptotic process (GO:0006915)

GO Molecular Function (2): protein phosphatase regulator activity (GO:0019888), protein binding (GO:0005515)

GO Cellular Component (7): protein phosphatase type 2A complex (GO:0000159), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), cytosol (GO:0005829), cytoskeleton (GO:0005856), cytoplasm (GO:0005737), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
phosphoprotein phosphatase activity	1
phosphatase regulator activity	1
protein phosphatase binding	1
binding	1
protein serine/threonine phosphatase complex	1
intracellular membrane-bounded organelle	1
mitochondrial membrane	1
organelle outer membrane	1
intracellular membraneless organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2584 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPP2R2B	ATXN7	O15265	923
PPP2R2B	CACNA1A	P78510	922
PPP2R2B	ATXN10	Q9UBB4	796
PPP2R2B	PPP2CA	P05323	776
PPP2R2B	PPP2R1A	P30153	764
PPP2R2B	PPP2R3C	Q969Q6	757
PPP2R2B	FXN	Q16595	751
PPP2R2B	PPP2R3A	Q06190	741
PPP2R2B	PPP2R1B	P30154	736
PPP2R2B	PRKCG	P05129	726
PPP2R2B	PPP2R5B	Q15173	716
PPP2R2B	ATXN3	P54252	706
PPP2R2B	ATXN2	Q99700	695
PPP2R2B	ATXN1	P54253	694
PPP2R2B	TTBK2	Q6IQ55	684

IntAct

48 interactions, top by confidence:

A	B	Type	Score
PPP2R1A	PPP2CA	psi-mi:“MI:0915”(physical association)	0.990
PPP2R1A	PPP2CA	psi-mi:“MI:0414”(enzymatic reaction)	0.990
PPP2R1A	PPP2CA	psi-mi:“MI:0914”(association)	0.990
PPP2R1A	PPP2R2B	psi-mi:“MI:0915”(physical association)	0.910
PPP2R2C	PPP2R1A	psi-mi:“MI:0914”(association)	0.730
PPP2R2D	YEATS4	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PPP2R2B	MYO9A	psi-mi:“MI:0914”(association)	0.640
PPP2R2C	TCP1	psi-mi:“MI:0914”(association)	0.640
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
PPP2R2D	ENSA	psi-mi:“MI:0914”(association)	0.570
APP	PPP2R2B	psi-mi:“MI:0915”(physical association)	0.560
PPP2R2B	PDPK1	psi-mi:“MI:0915”(physical association)	0.520
PDPK1	PPP2R2B	psi-mi:“MI:0915”(physical association)	0.520
PPP2R2B	RPS6KB1	psi-mi:“MI:0914”(association)	0.500
PPP2R2B	RPS6KB1	psi-mi:“MI:0915”(physical association)	0.500
PPP2R2B	DDX3X	psi-mi:“MI:0914”(association)	0.460
AHI1	OFD1	psi-mi:“MI:2364”(proximity)	0.420

BioGRID (316): PPP2R2B (Affinity Capture-MS), PPP2CB (Co-fractionation), PPP2R1A (Co-fractionation), PPP2R2B (Proximity Label-MS), PPP2R2B (Affinity Capture-MS), PPP2R2B (Affinity Capture-MS), PPP2R2B (Affinity Capture-MS), PPP2R2B (Affinity Capture-Western), SYNM (Affinity Capture-Western), PPP2R2B (Affinity Capture-MS), PPP2R2B (Affinity Capture-MS), PPP2R2B (Affinity Capture-RNA), PPP2R2B (Affinity Capture-MS), PPP2R2B (Affinity Capture-MS), MYO9A (Affinity Capture-MS)

ESM2 similar proteins: A1L3L9, A2X2K3, B0R0D7, B6VA23, O35142, O55029, P35606, P36876, P36877, P50410, P54614, P56932, P63150, P63151, P97888, Q00005, Q00006, Q0D2F4, Q0E2P1, Q29090, Q38821, Q39247, Q4R4I8, Q4R7Z4, Q4R8L3, Q5E9Q7, Q5R4A2, Q5R664, Q5Z8Z7, Q5ZIY5, Q66LE6, Q6AY57, Q6DIY3, Q6NY64, Q6P1F6, Q6QEF8, Q6ZWR4, Q7ZWU5, Q7ZX64, Q80W47

Diamond homologs: A1L3L9, A2X2K3, B6VA23, G5EDR3, P36872, P36876, P36877, P50410, P53031, P54614, P56932, P63150, P63151, P97888, Q00005, Q00006, Q00362, Q0D2F4, Q0E2P1, Q12702, Q29090, Q38821, Q39247, Q4R7Z4, Q4R8L3, Q54Q99, Q5E9Q7, Q5R4A2, Q5Z8Z7, Q5ZIY5, Q66LE6, Q6DIY3, Q6NY64, Q6P1F6, Q6ZWR4, Q7ZX64, Q8BG02, Q925E7, Q95LP0, Q9Y2T4

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PPP2R2B	“form complex”	PP2Ca_R1A_Bd	binding
PPP2R2B	“down-regulates activity”	PDPK1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 41 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.

GO biological processes:

GO term	Partners	Fold	FDR
mitotic cell cycle	5	18.1×	1e-03
negative regulation of apoptotic process	7	6.6×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	13
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3081 predictions. Top by Δscore:

Variant	Effect	Δscore
5:146600456:AAAAA:A	acceptor_gain	1.0000
5:146600457:AAAA:A	acceptor_gain	1.0000
5:146600458:AAA:A	acceptor_gain	1.0000
5:146600459:AA:A	acceptor_gain	1.0000
5:146600460:ACTG:A	acceptor_loss	1.0000
5:146600461:C:CC	acceptor_gain	1.0000
5:146600461:C:G	acceptor_loss	1.0000
5:146600469:C:CT	acceptor_gain	1.0000
5:146638249:A:AC	donor_gain	1.0000
5:146638250:C:CC	donor_gain	1.0000
5:146691121:CACT:C	donor_loss	1.0000
5:146691122:ACTC:A	donor_loss	1.0000
5:146691123:CTCA:C	donor_loss	1.0000
5:146691124:T:TA	donor_loss	1.0000
5:146691125:CA:C	donor_loss	1.0000
5:146691127:C:A	donor_loss	1.0000
5:146691127:CCCG:C	donor_gain	1.0000
5:146697974:CCTA:C	donor_loss	1.0000
5:146697975:CTACC:C	donor_loss	1.0000
5:146697976:TAC:T	donor_loss	1.0000
5:146697977:A:AC	donor_gain	1.0000
5:146697977:ACCA:A	donor_loss	1.0000
5:146697978:C:CC	donor_gain	1.0000
5:146698140:TTACT:T	acceptor_gain	1.0000
5:146698141:TACT:T	acceptor_gain	1.0000
5:146698143:CT:C	acceptor_gain	1.0000
5:146698145:C:CC	acceptor_gain	1.0000
5:146600287:ATAC:A	donor_loss	0.9900
5:146600289:ACCTG:A	donor_loss	0.9900
5:146600290:C:G	donor_loss	0.9900

AlphaMissense

3000 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:146589973:A:C	Y436D	1.000
5:146589975:A:G	L435P	1.000
5:146589975:A:T	L435Q	1.000
5:146589990:G:T	A430E	1.000
5:146589996:G:T	A428E	1.000
5:146589997:C:G	A428P	1.000
5:146590021:A:G	W420R	1.000
5:146590021:A:T	W420R	1.000
5:146590149:G:T	A377D	1.000
5:146590155:A:G	L375P	1.000
5:146590207:A:C	Y358D	1.000
5:146590207:A:G	Y358H	1.000
5:146590210:A:G	S357P	1.000
5:146590212:C:A	G356V	1.000
5:146590212:C:T	G356D	1.000
5:146590213:C:A	G356C	1.000
5:146590213:C:G	G356R	1.000
5:146590215:G:A	T355I	1.000
5:146590215:G:C	T355R	1.000
5:146590215:G:T	T355K	1.000
5:146592987:A:G	W346R	1.000
5:146592987:A:T	W346R	1.000
5:146592997:A:C	F342L	1.000
5:146592997:A:T	F342L	1.000
5:146592998:A:C	F342C	1.000
5:146592998:A:G	F342S	1.000
5:146592999:A:C	F342V	1.000
5:146592999:A:G	F342L	1.000
5:146592999:A:T	F342I	1.000
5:146593001:T:A	K341I	1.000

dbSNP variants (sampled 300 via entrez): RS1000005508 (5:146910092 T>C), RS1000007102 (5:146748911 A>G), RS1000010093 (5:146821887 G>A), RS1000014168 (5:146780297 A>T), RS1000015416 (5:146692427 C>G,T), RS1000023041 (5:146588767 T>C), RS1000023440 (5:146635027 A>G), RS1000029034 (5:146913204 C>G), RS1000031291 (5:146738163 G>A), RS1000032039 (5:146990016 A>G), RS1000046964 (5:146830022 A>G), RS1000060075 (5:147047415 T>C), RS1000065910 (5:147075730 T>G), RS1000072617 (5:146956715 C>G), RS1000074068 (5:146908964 A>G)

Disease associations

OMIM: gene MIM:604325 | disease phenotypes: MIM:604326

GenCC curated gene-disease

Disease	Classification	Inheritance
spinocerebellar ataxia type 12	Strong	Autosomal dominant
neurodevelopmental disorder	Moderate	Autosomal dominant

Mondo (2): spinocerebellar ataxia type 12 (MONDO:0011439), neurodevelopmental disorder (MONDO:0700092)

Orphanet (1): Spinocerebellar ataxia type 12 (Orphanet:98762)

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000317	Facial myokymia
HP:0000496	Abnormality of eye movement
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000726	Dementia
HP:0000739	Anxiety
HP:0000746	Delusion
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001300	Parkinsonism
HP:0001310	Dysmetria
HP:0001317	Abnormal cerebellum morphology
HP:0001347	Hyperreflexia
HP:0002059	Cerebral atrophy
HP:0002067	Bradykinesia
HP:0002073	Progressive cerebellar ataxia
HP:0002075	Dysdiadochokinesis
HP:0002080	Intention tremor
HP:0002120	Cerebral cortical atrophy
HP:0002174	Postural tremor
HP:0002317	Unsteady gait
HP:0002345	Action tremor
HP:0002346	Head tremor
HP:0002375	Hypokinesia
HP:0002406	Limb dysmetria
HP:0002530	Axial dystonia
HP:0007010	Poor fine motor coordination

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST000432_4	Alcohol dependence	3.000000e-06
GCST001877_19	Autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia (combined)	2.000000e-06
GCST002830_4	Urate levels in lean individuals	4.000000e-06
GCST003542_162	Night sleep phenotypes	7.000000e-06
GCST007201_56	Schizophrenia	5.000000e-06
GCST008359_7	Response to cognitive-behavioural therapy in anxiety disorder	4.000000e-06
GCST009600_28	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	4.000000e-08
GCST011624_1	Tau burden	1.000000e-08
GCST011934_1	Takayasu arteritis	6.000000e-07
GCST011939_11	Takayasu arteritis	6.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0007820	cognitive behavioural therapy
EFO:0004760	t-tau measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
C565790	Spinocerebellar Ataxia 12 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	decreases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	3
Valproic Acid	increases expression	3
Aflatoxin B1	affects methylation, decreases expression, decreases methylation	3
trichostatin A	affects cotreatment, decreases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
mercuric bromide	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Arsenic	decreases expression, increases abundance, increases expression, affects cotreatment	2
Cisplatin	affects expression, increases expression	2
Copper	affects binding, increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Tretinoin	increases expression	2
p-Chloromercuribenzoic Acid	decreases expression, affects cotreatment	2
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, affects methylation, increases methylation	1
sodium arsenate	increases abundance, increases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sulforaphane	decreases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
butyraldehyde	increases expression	1
zinc chromate	decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
bleomycetin	increases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	increases expression	1
aflatoxin B2	increases methylation	1

Cellosaurus cell lines

8 cell lines: 5 induced pluripotent stem cell, 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8HK	JHUi003-A	Induced pluripotent stem cell	Female
CVCL_D5AE	IGIBi011-A	Induced pluripotent stem cell	Male
CVCL_E0LI	Ubigene HeLa PPP2R2B KO	Cancer cell line	Female
CVCL_TF95	HAP1 PPP2R2B (-) 1	Cancer cell line	Male
CVCL_TF96	HAP1 PPP2R2B (-) 2	Cancer cell line	Male
CVCL_VN63	IGIBi002-A [2018]	Induced pluripotent stem cell	Male
CVCL_VN64	IGIBi003-A	Induced pluripotent stem cell	Female
CVCL_VN65	IGIBi004-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge