PPP2R5D

Summary

PPP2R5D (protein phosphatase 2 regulatory subunit B’delta, HGNC:9312) is a protein-coding gene on chromosome 6p21.1, encoding Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform (Q14738). 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 2A regulatory subunit B family. Protein phosphatase 2A 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 delta isoform of the regulatory subunit B56 subfamily. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 5528 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 620 total — 11 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 77
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_006245

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9312
Approved symbol	PPP2R5D
Name	protein phosphatase 2 regulatory subunit B’delta
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	B56D, B56delta
Ensembl gene	ENSG00000112640
Ensembl biotype	protein_coding
OMIM	601646
Entrez	5528

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 15 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000230402, ENST00000394110, ENST00000461010, ENST00000467447, ENST00000470467, ENST00000472118, ENST00000482315, ENST00000485511, ENST00000486843, ENST00000676174, ENST00000879146, ENST00000879147, ENST00000879148, ENST00000935957, ENST00000935958, ENST00000949508, ENST00000949509, ENST00000949510, ENST00000949511

RefSeq mRNA: 4 — MANE Select: NM_006245 NM_001270476, NM_006245, NM_180976, NM_180977

CCDS: CCDS43464, CCDS4878, CCDS55002

Canonical transcript exons

ENST00000485511 — 16 exons

Exon	Start	End
ENSE00000751499	43006463	43006679
ENSE00000850031	42989611	42989688
ENSE00001810053	43011149	43012342
ENSE00001811231	42984570	42984704
ENSE00003524929	43008693	43008746
ENSE00003525400	43007935	43008065
ENSE00003551290	43010664	43010736
ENSE00003579648	43007414	43007506
ENSE00003581277	43006911	43007110
ENSE00003636386	43010881	43010997
ENSE00003638338	43008367	43008475
ENSE00003644554	43009322	43009449
ENSE00003663198	43009057	43009227
ENSE00003689538	43007196	43007306
ENSE00003690487	43010468	43010569
ENSE00003693118	43008201	43008260

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 96.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.4667 / max 314.0082, expressed in 1820 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67846	43.4667	1820

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory bulb	UBERON:0002264	96.01	silver quality
type B pancreatic cell	CL:0000169	95.85	gold quality
ganglionic eminence	UBERON:0004023	94.43	gold quality
ventricular zone	UBERON:0003053	94.23	gold quality
cortical plate	UBERON:0005343	93.89	gold quality
prefrontal cortex	UBERON:0000451	93.21	gold quality
smooth muscle tissue	UBERON:0001135	93.03	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.90	gold quality
stromal cell of endometrium	CL:0002255	92.77	gold quality
cerebellar hemisphere	UBERON:0002245	92.60	gold quality
cerebellar cortex	UBERON:0002129	92.59	gold quality
right frontal lobe	UBERON:0002810	92.53	gold quality
pancreatic ductal cell	CL:0002079	92.22	gold quality
gastrocnemius	UBERON:0001388	91.81	gold quality
muscle of leg	UBERON:0001383	91.80	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.60	gold quality
cerebellum	UBERON:0002037	91.52	gold quality
frontal cortex	UBERON:0001870	91.24	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.00	gold quality
ileal mucosa	UBERON:0000331	90.81	gold quality
neocortex	UBERON:0001950	90.68	gold quality
ectocervix	UBERON:0012249	90.66	gold quality
nucleus accumbens	UBERON:0001882	90.65	gold quality
descending thoracic aorta	UBERON:0002345	90.61	gold quality
endocervix	UBERON:0000458	90.57	gold quality
small intestine	UBERON:0002108	90.53	gold quality
embryo	UBERON:0000922	90.51	gold quality
right coronary artery	UBERON:0001625	90.51	gold quality
mucosa of stomach	UBERON:0001199	90.30	gold quality
body of uterus	UBERON:0009853	90.24	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.38

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, MYC

miRNA regulators (miRDB)

79 targeting PPP2R5D, 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-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-3191-3P	99.45	63.94	356
HSA-MIR-6871-3P	99.43	68.85	741

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 22)

• Data show that the protein phosphatase 2A subunit B56delta specifically interacts with HAND1 and -2, but not other basic helix-loop-helix proteins. (PMID:14636580)
• Gonadotropin-releasing hormone (GnRH) affects the membrane protein phosphatase 2A-associated apoptosis and the enzyme activity in ovarian cancer cells. (PMID:15809743)
• PP2A ABalphaC and ABdeltaC holoenzymes function as positive regulators of Raf1-MEK1/2-ERK1/2 signaling by targeting Raf1 (PMID:16239230)
• PP2A:B56delta as a key upstream regulator of Cdk1 activity upon exit from mitosis (PMID:18056802)
• these data indicate that the B subunits alpha and delta are essential for the interaction of PP2A with CaMKIV. (PMID:19538941)
• Protein kinase A mediated activation of protein phosphatase 2A is enabled by PPP2R5D phosphorylation, which modulates the affinity of the protein phosphatase 2A holoenzyme to its physiological substrates. (PMID:20423611)
• PP2A-B56delta is the single most significant contributor, of the PP2A holoenzyme subunits, to BubR1 and Bub1 kinetochore localization. (PMID:25246613)
• MiR-9 regulates GR signaling and steroid-resistant airway hyperresponsiveness by reducing protein phosphatase 2A activity. (PMID:25772595)
• Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth (PMID:25972378)
• Mutant B56delta was A and C binding-deficient, while mutant Aalpha subunits bound B56delta well but were unable to bind C (PMID:26168268)
• Mutations in PPP2R5D are genetic cause of intellectual disability. (PMID:26576547)
• a new holoenzyme with PPM1G-B56delta as integral components, in which the regulatory subunit provides accessibility to distinct substrates for the phosphatase by defining its cellular localization, is reported. (PMID:31432583)
• Reduction of protein phosphatase 2A (PP2A) complexity reveals cellular functions and dephosphorylation motifs of the PP2A/B’delta holoenzyme. (PMID:32156701)
• Critical role of PP2A-B56 family protein degradation in HIV-1 Vif mediated G2 cell cycle arrest. (PMID:32446377)
• Early-Onset Parkinsonism Is a Manifestation of the PPP2R5D p.E200K Mutation. (PMID:32743835)
• A disorder-related variant (E420K) of a PP2A-regulatory subunit (PPP2R5D) causes constitutively active AKT-mTOR signaling and uncoordinated cell growth. (PMID:33482199)
• PPP2R5D-Related Neurodevelopmental Disorder or Developmental and Epileptic Encephalopathy?: A Novel Phenotypic Description and Review of Published Cases. (PMID:34448180)
• Co-Occurrence of Fragile X Syndrome with a Second Genetic Condition: Three Independent Cases of Double Diagnosis. (PMID:34946857)
• Rare missense variants in the PPP2R5D gene associated with Parkinson’s disease in the Han Chinese population. (PMID:35257824)
• PPP2R5D promotes hepatitis C virus infection by binding to viral NS5B and enhancing viral RNA replication. (PMID:35836293)
• Clinical, neuroimaging and molecular characteristics of PPP2R5D-related neurodevelopmental disorders: an expanded series with functional characterisation and genotype-phenotype analysis. (PMID:36216457)
• A novel nonsense mutation in PPP2R5D is associated with neurodevelopmental disorders and shows incomplete penetrance in a Chinese pedigree. (PMID:36403339)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppp2r5d	ENSDARG00000014428
mus_musculus	Ppp2r5d	ENSMUSG00000059409
rattus_norvegicus	Ppp2r5d	ENSRNOG00000016849
drosophila_melanogaster	wrd	FBGN0042693
caenorhabditis_elegans		WBGENE00007554
caenorhabditis_elegans		WBGENE00012348

Paralogs (4): PPP2R5A (ENSG00000066027), PPP2R5B (ENSG00000068971), PPP2R5C (ENSG00000078304), PPP2R5E (ENSG00000154001)

Protein

Protein identifiers

Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform — Q14738 (reviewed: Q14738)

Alternative names: PP2A B subunit isoform B’-delta, PP2A B subunit isoform B56-delta, PP2A B subunit isoform PR61-delta, PP2A B subunit isoform R5-delta

All UniProt accessions (5): E9PFR3, Q14738, H0Y8C4, H7C5Q9, H7C5Z1

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.

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 the PP2A A subunit PPP2R1A. Interacts with SGO1. Interacts with ADCY8.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Isoform Delta-2 is widely expressed. Isoform Delta-1 is highly expressed in brain.

Disease relevance. Houge-Janssens syndrome 1 (HJS1) [MIM:616355] An autosomal dominant disorder characterized by global developmental delay, hypotonia, variably impaired intellectual development, poor speech, and dysmorphic facial features. Additional more variable features may include macrocephaly and seizures. The disease is caused by variants affecting the gene represented in this entry.

Induction. By retinoic acid; in neuroblastoma cell lines.

Similarity. Belongs to the phosphatase 2A regulatory subunit B56 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q14738-1	Delta-1	yes
Q14738-2	Delta-2
Q14738-3	Delta-3

RefSeq proteins (4): NP_001257405, NP_006236, NP_851307, NP_851308 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002554	PP2A_B56	Family
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily

Pfam: PF01603

UniProt features (59 total): helix 23, repeat 8, modified residue 6, sequence variant 5, turn 4, strand 4, region of interest 2, short sequence motif 2, compositionally biased region 2, splice variant 2, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8U1X	ELECTRON MICROSCOPY	2.7
8U89	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14738-F1	80.69	0.62

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 (6): 63, 88, 89, 90, 573, 598

Function

Pathways and Gene Ontology

Reactome pathways

95 pathways

ID	Pathway
R-HSA-141444	Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal
R-HSA-163767	PP2A-mediated dephosphorylation of key metabolic factors
R-HSA-180024	DARPP-32 events
R-HSA-195253	Degradation of beta-catenin by the destruction complex
R-HSA-196299	Beta-catenin phosphorylation cascade
R-HSA-198753	ERK/MAPK targets
R-HSA-202670	ERKs are inactivated
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2500257	Resolution of Sister Chromatid Cohesion
R-HSA-389356	Co-stimulation by CD28
R-HSA-389513	Co-inhibition by CTLA4
R-HSA-432142	Platelet sensitization by LDL
R-HSA-4641262	Disassembly of the destruction complex and recruitment of AXIN to the membrane
R-HSA-5339716	Signaling by GSK3beta mutants
R-HSA-5358747	CTNNB1 S33 mutants aren’t phosphorylated
R-HSA-5358749	CTNNB1 S37 mutants aren’t phosphorylated
R-HSA-5358751	CTNNB1 S45 mutants aren’t phosphorylated
R-HSA-5358752	CTNNB1 T41 mutants aren’t phosphorylated
R-HSA-5467337	APC truncation mutants have impaired AXIN binding
R-HSA-5467340	AXIN missense mutants destabilize the destruction complex
R-HSA-5467348	Truncations of AMER1 destabilize the destruction complex
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-5673000	RAF activation
R-HSA-5675221	Negative regulation of MAPK pathway
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-68877	Mitotic Prometaphase
R-HSA-9634600	Regulation of glycolysis by fructose 2,6-bisphosphate metabolism
R-HSA-9648025	EML4 and NUDC in mitotic spindle formation
R-HSA-109582	Hemostasis
R-HSA-111885	Opioid Signalling

MSigDB gene sets: 395 (showing top): GGGACCA_MIR133A_MIR133B, GOBP_CHROMOSOME_ORGANIZATION, MYAATNNNNNNNGGC_UNKNOWN, REACTOME_INNATE_IMMUNE_SYSTEM, CCAWYNNGAAR_UNKNOWN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, RORA1_01, SP3_Q3, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, REACTOME_CO_STIMULATION_BY_CD28, MODULE_503, COUP_01

GO Biological Process (3): signal transduction (GO:0007165), nervous system development (GO:0007399), meiotic sister chromatid cohesion (GO:0051177)

GO Molecular Function (3): protein phosphatase regulator activity (GO:0019888), protein phosphatase activator activity (GO:0072542), protein binding (GO:0005515)

GO Cellular Component (5): protein phosphatase type 2A complex (GO:0000159), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-17 pathways:

Category	Pathways
Signaling by CTNNB1 phospho-site mutants	4
Regulation of T cell activation by CD28 family	2
Amplification of signal from the kinetochores	1
Integration of energy metabolism	1
Opioid Signalling	1
Signaling by WNT	1
Degradation of beta-catenin by the destruction complex	1
Nuclear Events (kinase and transcription factor activation)	1
MAPK targets/ Nuclear events mediated by MAP kinases	1
ERK/MAPK targets	1
Mitotic Anaphase	1
Mitotic Prometaphase	1
Platelet homeostasis	1
TCF dependent signaling in response to WNT	1
Signaling by WNT in cancer	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
phosphoprotein phosphatase activity	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
system development	1
sister chromatid cohesion	1
phosphatase regulator activity	1
protein phosphatase binding	1
phosphatase activator activity	1
protein phosphatase regulator activity	1
binding	1
protein serine/threonine phosphatase complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1777 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPP2R5D	KLHDC3	Q9BQ90	937
PPP2R5D	MEA1	Q16626	931
PPP2R5D	PPP2R1A	P30153	872
PPP2R5D	PPP2R2A	P50409	850
PPP2R5D	PPP2CA	P05323	831
PPP2R5D	PPP2R2D	Q66LE6	744
PPP2R5D	PPP2R3A	Q06190	733
PPP2R5D	AKAP6	Q13023	697
PPP2R5D	PPP2R5C	Q13362	674
PPP2R5D	MINK1	Q8N4C8	668
PPP2R5D	PPP2R3B	Q9Y5P8	625
PPP2R5D	LCMT1	Q9UIC8	539
PPP2R5D	PPP2R1B	P30154	536
PPP2R5D	PPP2R2B	Q00005	535
PPP2R5D	PPP2CB	P11082	520

IntAct

149 interactions, top by confidence:

A	B	Type	Score
PPP2R1A	PPP2R5D	psi-mi:“MI:0915”(physical association)	0.950
PPME1	PPP2R1A	psi-mi:“MI:0914”(association)	0.950
PPP2R1A	STRN	psi-mi:“MI:0914”(association)	0.880
PPP2R1A	STRN	psi-mi:“MI:2364”(proximity)	0.880
PPP2CA	STRN	psi-mi:“MI:0914”(association)	0.840
PPP2CB	STRN	psi-mi:“MI:0914”(association)	0.790
PPP2R5D	SGO1	psi-mi:“MI:0915”(physical association)	0.750
PPP4C	TCP1	psi-mi:“MI:0914”(association)	0.730
PPP2CB	CEP43	psi-mi:“MI:0914”(association)	0.730
PPP2R5D	PPFIA1	psi-mi:“MI:0915”(physical association)	0.720
PPFIA1	PPP2R5D	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PPP2R1B	PPP2R5D	psi-mi:“MI:0915”(physical association)	0.680
PPP2R1A	PPFIA3	psi-mi:“MI:0914”(association)	0.670
PPP4C	SUPT5H	psi-mi:“MI:0914”(association)	0.640
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
PPP2R5D	CDC25C	psi-mi:“MI:0915”(physical association)	0.590
FSD2	PPP2R5D	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (253): USHBP1 (Two-hybrid), FSD2 (Two-hybrid), PPP2R5D (Two-hybrid), PPP2R5D (Two-hybrid), PPP2R5D (Two-hybrid), PPP2R5D (Two-hybrid), PPP2R5D (Two-hybrid), RORC (Two-hybrid), PPP2R5D (Two-hybrid), PPP2R5D (Two-hybrid), PPP2R5D (Two-hybrid), PPP2R5D (Affinity Capture-MS), PPP2R5D (Affinity Capture-MS), PPP2R5D (Affinity Capture-MS), PPP2R5D (Affinity Capture-MS)

ESM2 similar proteins: A0A571BF63, A0JMA8, A1A535, A1A5P5, A1ZBE8, A6H8H2, A8XSV3, B0BF33, B2RS91, E7F187, O17237, O43150, P25054, P30630, Q05B30, Q09263, Q14156, Q14738, Q14D04, Q19317, Q1AAU6, Q21106, Q2KI89, Q5PQS3, Q5R4N9, Q5R629, Q5RAY1, Q5SPP5, Q5U245, Q5VZ89, Q61315, Q61QK6, Q620W3, Q641A2, Q6ZQ18, Q7SIG6, Q7Z3E5, Q7Z401, Q7Z7A4, Q8BG67

Diamond homologs: A4FV68, O04375, O04376, O18178, P38903, P78759, Q10428, Q13362, Q14738, Q15172, Q15173, Q16537, Q28647, Q28651, Q28653, Q28654, Q54VB6, Q60996, Q61151, Q6I621, Q6PD03, Q6PD28, Q80W83, Q8LF36, Q8RW96, Q93YV6, Q9LU89, Q9LVE2, Q9SV41, Q9ZQY6

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
PRKACA	up-regulates	PPP2R5D	phosphorylation
PPP2R5D	“up-regulates activity”	RAF1	binding
PPP2R5D	“form complex”	PP2Ca_R1A_Bd	binding
ATM	“up-regulates activity”	PPP2R5D	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 155 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
Signaling by GSK3beta mutants	5	38.5×	7e-06
CTNNB1 S33 mutants aren’t phosphorylated	5	38.5×	7e-06
CTNNB1 S37 mutants aren’t phosphorylated	5	38.5×	7e-06
CTNNB1 S45 mutants aren’t phosphorylated	5	38.5×	7e-06
CTNNB1 T41 mutants aren’t phosphorylated	5	38.5×	7e-06
Spry regulation of FGF signaling	5	36.0×	8e-06
Beta-catenin phosphorylation cascade	5	33.9×	1e-05
Platelet sensitization by LDL	5	33.9×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	9
Uncertain significance	262
Likely benign	246
Benign	29

Top pathogenic / likely-pathogenic (20)

Variant ID	HGVS	Classification
1218767	NM_006245.4(PPP2R5D):c.757C>G (p.Arg253Gly)	Pathogenic
1395783	NM_006245.4(PPP2R5D):c.621G>T (p.Trp207Cys)	Pathogenic
1686092	NM_006245.4(PPP2R5D):c.434A>T (p.Lys145Met)	Pathogenic
190287	NM_006245.4(PPP2R5D):c.602C>G (p.Pro201Arg)	Pathogenic
217455	NM_006245.4(PPP2R5D):c.157C>T (p.Pro53Ser)	Pathogenic
217457	NM_006245.4(PPP2R5D):c.619T>A (p.Trp207Arg)	Pathogenic
217912	NM_006245.4(PPP2R5D):c.1258G>A (p.Glu420Lys)	Pathogenic
4279007	NM_006245.4(PPP2R5D):c.619T>G (p.Trp207Gly)	Pathogenic
4710742	NM_006245.4(PPP2R5D):c.620G>T (p.Trp207Leu)	Pathogenic
521616	NM_006245.4(PPP2R5D):c.752A>C (p.Asp251Ala)	Pathogenic
984893	NM_006245.4(PPP2R5D):c.253C>T (p.Arg85Ter)	Pathogenic
1172649	NM_006245.4(PPP2R5D):c.592_600del (p.Glu198_Glu200del)	Likely pathogenic
1217871	NM_006245.4(PPP2R5D):c.612_614del (p.Glu204_Ala205delinsAsp)	Likely pathogenic
2626874	NM_006245.4(PPP2R5D):c.649T>C (p.Phe217Leu)	Likely pathogenic
3236570	NM_006245.4(PPP2R5D):c.391T>G (p.Phe131Val)	Likely pathogenic
3237199	NM_006245.4(PPP2R5D):c.608T>C (p.Leu203Pro)	Likely pathogenic
3358934	NM_006245.4(PPP2R5D):c.570_605del (p.Gly191_Thr202del)	Likely pathogenic
4292297	NM_006245.4(PPP2R5D):c.608T>G (p.Leu203Arg)	Likely pathogenic
984889	NM_006245.4(PPP2R5D):c.599_602delinsGGCA (p.Glu200_Pro201delinsGlyHis)	Likely pathogenic
984891	NM_006245.4(PPP2R5D):c.590A>G (p.Glu197Gly)	Likely pathogenic

SpliceAI

2093 predictions. Top by Δscore:

Variant	Effect	Δscore
6:42984701:GAAG:G	donor_gain	1.0000
6:42984702:AAGGT:A	donor_loss	1.0000
6:42984705:G:C	donor_loss	1.0000
6:42989686:G:GT	donor_gain	1.0000
6:43006676:AAAGG:A	donor_loss	1.0000
6:43006677:AAGGT:A	donor_loss	1.0000
6:43006678:AGGT:A	donor_loss	1.0000
6:43006680:G:A	donor_loss	1.0000
6:43006681:T:G	donor_loss	1.0000
6:43007047:G:GT	donor_gain	1.0000
6:43007050:G:GG	donor_gain	1.0000
6:43007122:G:T	donor_gain	1.0000
6:43007123:A:T	donor_gain	1.0000
6:43007194:A:AG	acceptor_gain	1.0000
6:43007195:G:GA	acceptor_gain	1.0000
6:43007195:GT:G	acceptor_gain	1.0000
6:43007195:GTT:G	acceptor_gain	1.0000
6:43007283:G:GT	donor_gain	1.0000
6:43007303:CCAG:C	donor_loss	1.0000
6:43007306:GGTAC:G	donor_loss	1.0000
6:43007307:G:C	donor_loss	1.0000
6:43007412:A:AG	acceptor_gain	1.0000
6:43007413:G:GG	acceptor_gain	1.0000
6:43007413:GCTC:G	acceptor_gain	1.0000
6:43007502:TTGCT:T	donor_gain	1.0000
6:43007504:GCT:G	donor_gain	1.0000
6:43007507:G:GG	donor_gain	1.0000
6:43007924:T:A	acceptor_gain	1.0000
6:43007927:A:AG	acceptor_gain	1.0000
6:43007928:C:G	acceptor_gain	1.0000

AlphaMissense

3984 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:43006953:T:C	L122P	1.000
6:43006979:T:C	F131L	1.000
6:43006981:C:A	F131L	1.000
6:43006981:C:G	F131L	1.000
6:43007012:A:G	K142E	1.000
6:43007014:G:C	K142N	1.000
6:43007014:G:T	K142N	1.000
6:43007023:G:C	K145N	1.000
6:43007023:G:T	K145N	1.000
6:43007025:G:C	R146P	1.000
6:43007034:T:A	L149H	1.000
6:43007034:T:C	L149P	1.000
6:43007207:C:A	N178K	1.000
6:43007207:C:G	N178K	1.000
6:43007253:T:C	F194L	1.000
6:43007255:T:A	F194L	1.000
6:43007255:T:G	F194L	1.000
6:43007257:A:G	D195G	1.000
6:43007268:G:C	D199H	1.000
6:43007275:C:A	P201H	1.000
6:43007292:T:A	W207R	1.000
6:43007292:T:C	W207R	1.000
6:43007294:G:C	W207C	1.000
6:43007294:G:T	W207C	1.000
6:43007302:T:C	L210P	1.000
6:43007472:C:A	A231D	1.000
6:43007959:G:C	D251H	1.000
6:43007971:C:T	R255W	1.000
6:43007972:G:C	R255P	1.000
6:43007981:T:C	L258P	1.000

dbSNP variants (sampled 300 via entrez): RS1000188261 (6:42989296 A>C), RS1000230169 (6:42995339 C>G,T), RS1000340519 (6:43002084 C>T), RS1000415362 (6:42987150 G>A,C), RS1000531502 (6:42982929 T>C), RS1000591118 (6:43006855 C>T), RS1000620573 (6:43006548 C>G,T), RS1000621141 (6:43000885 G>A,T), RS1000705108 (6:42993710 G>A), RS1000835168 (6:42993518 C>T), RS1000886256 (6:43006629 G>A,C), RS1000895803 (6:43000085 G>A), RS1001235202 (6:43007056 C>A,T), RS1001256017 (6:43003706 G>C), RS1001505351 (6:42990236 G>A,C)

Disease associations

OMIM: gene MIM:601646 | disease phenotypes: MIM:214100, MIM:616355, MIM:308350

GenCC curated gene-disease

Disease	Classification	Inheritance
Houge-Janssens syndrome 1	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (5): peroxisome biogenesis disorder (MONDO:0019234), Houge-Janssens syndrome 1 (MONDO:0014602), intellectual disability (MONDO:0001071), genetic developmental and epileptic encephalopathy (MONDO:0100062), neurodevelopmental disorder (MONDO:0700092)

Orphanet (3): Peroxisome biogenesis disorder (Orphanet:79189), Intellectual disability-macrocephaly-hypotonia-behavioral abnormalities syndrome (Orphanet:457279), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

77 total (30 of 77 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000176	Submucous cleft hard palate
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000238	Hydrocephalus
HP:0000256	Macrocephaly
HP:0000260	Wide anterior fontanel
HP:0000268	Dolichocephaly
HP:0000276	Long face
HP:0000297	Facial hypotonia
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000325	Triangular face
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000369	Low-set ears
HP:0000478	Abnormality of the eye
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000545	Myopia
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000744	Low frustration tolerance
HP:0000750	Delayed speech and language development
HP:0001137	Alternating esotropia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002337_128	Amyotrophic lateral sclerosis (sporadic)	8.000000e-06
GCST007876_88	Estimated glomerular filtration rate	3.000000e-28

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C536664	Peroxisome biogenesis disorders (supp.)
C531857	Zellweger leukodystrophy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067334 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs3805945	Toxicity	3	cyclophosphamide;epirubicin;fluorouracil	Breast Neoplasms;Neutropenia

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
Particulate Matter	increases expression, decreases expression, increases abundance	2
FR900359	affects phosphorylation	1
echimidine	decreases expression, increases metabolic processing	1
2,4,6-tribromophenol	decreases expression	1
lasiocarpine	decreases expression, increases metabolic processing	1
pirinixic acid	affects binding, decreases expression, increases activity	1
decabromobiphenyl ether	decreases expression	1
tetrabromobisphenol A	decreases expression	1
coumarin	decreases phosphorylation	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	increases expression	1
Bortezomib	decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Vehicle Emissions	increases abundance, increases expression	1
Caffeine	affects phosphorylation	1
Chelating Agents	affects binding, decreases expression	1
Copper	affects binding, decreases expression	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Ribonucleotides	affects binding	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652098	Binding	Binding affinity to human PPP2R5D incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1CL	Abcam A-431 PPP2R5D KO	Cancer cell line	Female
CVCL_D9P7	Ubigene HEK293 PPP2R5D KO	Transformed cell line	Female
CVCL_TG11	HAP1 PPP2R5D (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT01838941	PHASE3	COMPLETED	Betaine and Peroxisome Biogenesis Disorders
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT03856866	PHASE2	COMPLETED	Hydroxychloroquine Administration for Reduction of Pexophagy
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT01668186	Not specified	RECRUITING	Longitudinal Natural History Study of Patients With Peroxisome Biogenesis Disorders (PBD)
NCT03440905	Not specified	COMPLETED	Proxy-Reported Symptoms and Quality of Life Survey in Zellweger Spectrum Disorders
NCT06190626	Not specified	RECRUITING	Longitudinal Prospective Natural History Study of Retinopathy in Zellweger Spectrum Disorder
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)