PPM1F

Summary

PPM1F (protein phosphatase, Mg2+/Mn2+ dependent 1F, HGNC:19388) is a protein-coding gene on chromosome 22q11.22, encoding Protein phosphatase 1F (P49593). Dephosphorylates and concomitantly deactivates CaM-kinase II activated upon autophosphorylation, and CaM-kinases IV and I activated upon phosphorylation by CaM-kinase kinase.

The protein encoded by this gene is a member of the PP2C family of Ser/Thr protein phosphatases. PP2C family members are known to be negative regulators of cell stress response pathways. This phosphatase can interact with Rho guanine nucleotide exchange factors (PIX), and thus block the effects of p21-activated kinase 1 (PAK), a protein kinase mediating biological effects downstream of Rho GTPases. Calcium/calmodulin-dependent protein kinase II gamma (CAMK2G/CAMK-II) is found to be one of the substrates of this phosphatase. The overexpression of this phosphatase or CAMK2G has been shown to mediate caspase-dependent apoptosis. An alternatively spliced transcript variant has been identified, but its full-length nature has not been determined.

Source: NCBI Gene 9647 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cholestasis (Limited, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 159 total — 1 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes
• MANE Select transcript: NM_014634

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19388
Approved symbol	PPM1F
Name	protein phosphatase, Mg2+/Mn2+ dependent 1F
Location	22q11.22
Locus type	gene with protein product
Status	Approved
Aliases	FEM-2, KIAA0015, POPX2, CaMKPase, CAMKP
Ensembl gene	ENSG00000100034
Ensembl biotype	protein_coding
OMIM	619309
Entrez	9647

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 5 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000263212, ENST00000397495, ENST00000407142, ENST00000424647, ENST00000445205, ENST00000484588, ENST00000486259, ENST00000496143, ENST00000497072, ENST00000623652

RefSeq mRNA: 2 — MANE Select: NM_014634 NM_001410836, NM_014634

CCDS: CCDS13796, CCDS93128

Canonical transcript exons

ENST00000263212 — 8 exons

Exon	Start	End
ENSE00000651114	21931148	21931291
ENSE00000651115	21933391	21933579
ENSE00001135900	21945843	21946108
ENSE00001189657	21919425	21923471
ENSE00001258870	21952792	21952848
ENSE00003496968	21939532	21939680
ENSE00003655517	21925569	21925662
ENSE00003786859	21934024	21934226

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 94.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.5310 / max 587.4937, expressed in 1817 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193259	22.5890	1815
193258	1.5575	563
193257	0.2031	67
193254	0.1814	61

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	94.00	gold quality
mononuclear cell	CL:0000842	93.94	gold quality
leukocyte	CL:0000738	93.77	gold quality
sural nerve	UBERON:0015488	93.32	gold quality
granulocyte	CL:0000094	93.30	gold quality
blood	UBERON:0000178	92.91	gold quality
cervix squamous epithelium	UBERON:0006922	90.45	gold quality
endothelial cell	CL:0000115	90.15	gold quality
periodontal ligament	UBERON:0008266	89.82	gold quality
spleen	UBERON:0002106	89.40	gold quality
tibial nerve	UBERON:0001323	88.93	gold quality
right lung	UBERON:0002167	88.61	gold quality
tendon of biceps brachii	UBERON:0008188	88.56	gold quality
apex of heart	UBERON:0002098	88.39	gold quality
tibia	UBERON:0000979	88.25	gold quality
upper lobe of left lung	UBERON:0008952	87.90	gold quality
upper lobe of lung	UBERON:0008948	87.34	gold quality
body of uterus	UBERON:0009853	87.11	gold quality
olfactory bulb	UBERON:0002264	86.99	silver quality
stromal cell of endometrium	CL:0002255	86.81	gold quality
lower esophagus	UBERON:0013473	86.38	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.37	gold quality
visceral pleura	UBERON:0002401	86.13	gold quality
right adrenal gland	UBERON:0001233	85.96	gold quality
esophagus	UBERON:0001043	85.91	gold quality
lung	UBERON:0002048	85.87	gold quality
myometrium	UBERON:0001296	85.85	gold quality
left adrenal gland cortex	UBERON:0035825	85.72	gold quality
esophagus mucosa	UBERON:0002469	85.71	gold quality
left adrenal gland	UBERON:0001234	85.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.34

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
ARHGDIA	Activation
ITGB1	Activation
SRF	Repression

miRNA regulators (miRDB)

174 targeting PPM1F, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057

Literature-anchored findings (GeneRIF, showing 20)

• The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family. (POPX1; POPX2) (PMID:11864573)
• PPM1F plays a key role in the regulation of CaMKII intracellularly (PMID:15140879)
• The POPX2 phosphatase regulates cancer cell motility and invasiveness. (PMID:20016286)
• Data identify a biochemical pathway through which POPX2 exerts its apparent cellular function: the regulation of activity of glycogen synthase kinase-3, which in turn modulates extracellular signal-regulated kinase and cell motility. (PMID:21656682)
• FHOD1 and PPM1F (direct regulators of the actin cytoskeleton) were identified as novel targets of miR-200c. Expression levels of FHOD1 and PPM1F were inversely correlated with miR-200c level in breast cancer cell lines and breast cancer patient samples. (PMID:22144583)
• hCaMKP activity is reversibly regulated by oxidation/reduction at Cys-359 (PMID:22743349)
• POPX2 might regulate cell motility through its regulation of the MAPK1/3, leading to changes in the cytoskeleton and cell motility. (PMID:23621870)
• POPX2 affects trafficking by determining the phosphorylation status of KIF3A at serine 690. (PMID:24338362)
• Overexpression of PPM1F is associated with metastasis of hepatocellular carcinoma. (PMID:26498692)
• PPM1F could work downstream of alpha9-nAchR to promote nicotine-induced carcinogenic signals. Thus, PPM1F expression could be used for prognostic diagnosis, or inhibited as a potential strategy for cancer prevention and therapy. (PMID:27769050)
• This study, combined with our previous findings, suggests that a single ubiquitously expressed phosphatase POPX2 influences cancer metastasis via modulating multiple biological processes including MAPK signaling and exosome cytokine secretion. (PMID:27976581)
• POPX2 is a negative regulator of TAK1 signaling pathway and modulates apoptosis through the regulation of TAK1 activity. (PMID:28906490)
• PPM1F is involved in stress- and trauma-related manifestation of anxiety and depression. (PMID:29054677)
• PPM1F overexpression suppressed cell proliferation and invasion and counteracted the tumour-promoting role of miR-590, but PPM1F knockdown reversed these effects. (PMID:29473240)
• our findings demonstrated that low expression of miR-490-3p or high expression of PPM1F was positively associated with poor survival and tumor recurrence in patients with HCC, and miR-490-3p suppressed cell proliferation and invasion by targeting PPM1F. (PMID:30470261)
• results extend prior work linking PPM1F to Post Traumatic Stress Disorder and suggest that variants in this gene may have bearing on the neural integrity of the prefrontal cortex. (PMID:31446381)
• Phosphatase POPX2 interferes with cell cycle by interacting with Chk1. (PMID:31944151)
• Circular RNA circPPM1F modulates M1 macrophage activation and pancreatic islet inflammation in type 1 diabetes mellitus. (PMID:33042261)
• PPM1F controls integrin activity via a conserved phospho-switch. (PMID:33119040)
• The BHLHE40-PPM1F-AMPK pathway regulates energy metabolism and is associated with the aggressiveness of endometrial cancer. (PMID:38301894)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppm1f	ENSDARG00000005786
mus_musculus	Ppm1f	ENSMUSG00000026181
rattus_norvegicus	Ppm1f	ENSRNOG00000037909
drosophila_melanogaster	Pdp	FBGN0029958
drosophila_melanogaster	CG10376	FBGN0032702
drosophila_melanogaster	Ppm1	FBGN0035143
drosophila_melanogaster	CG17746	FBGN0035425
drosophila_melanogaster	Nil	FBGN0039421
drosophila_melanogaster	alph	FBGN0086361
caenorhabditis_elegans		WBGENE00006460
caenorhabditis_elegans		WBGENE00018362
caenorhabditis_elegans	pdp-1	WBGENE00022832

Paralogs (16): TAB1 (ENSG00000100324), PPM1A (ENSG00000100614), PPM1H (ENSG00000111110), PPM1G (ENSG00000115241), ILKAP (ENSG00000132323), PPM1B (ENSG00000138032), PPM1J (ENSG00000155367), PPM1L (ENSG00000163590), PPM1K (ENSG00000163644), PPM1M (ENSG00000164088), PDP1 (ENSG00000164951), PPM1D (ENSG00000170836), PDP2 (ENSG00000172840), PPM1E (ENSG00000175175), PP2D1 (ENSG00000183977), PPM1N (ENSG00000213889)

Protein

Protein identifiers

Protein phosphatase 1F — P49593 (reviewed: P49593)

Alternative names: Ca(2+)/calmodulin-dependent protein kinase phosphatase, Partner of PIX 2, Protein fem-2 homolog

All UniProt accessions (5): P49593, A8MX49, B5MCT7, C9J2F3, C9JL74

UniProt curated annotations — full annotation on UniProt →

Function. Dephosphorylates and concomitantly deactivates CaM-kinase II activated upon autophosphorylation, and CaM-kinases IV and I activated upon phosphorylation by CaM-kinase kinase. Promotes apoptosis.

Subunit / interactions. Associates with FEM1B.

Disease relevance. Defects in PPM1F may be a cause of sclerosing cholangitis, short stature, hypothyroidism, and abnormal tongue pigmentation.

Cofactor. Binds 2 magnesium or manganese ions per subunit.

Similarity. Belongs to the PP2C family.

Isoforms (2)

UniProt ID	Names	Canonical?
P49593-1	1	yes
P49593-2	2

RefSeq proteins (2): NP_001397765, NP_055449* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000222	PP2C_BS	Binding_site
IPR001932	PPM-type_phosphatase-like_dom	Domain
IPR015655	PP2C	Family
IPR036457	PPM-type-like_dom_sf	Homologous_superfamily

Pfam: PF00481

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 (19 total): sequence variant 5, binding site 5, splice variant 2, region of interest 2, chain 1, domain 1, modified residue 1, sequence conflict 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49593-F1	87.70	0.76

Functional residue map

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

Ligand- & substrate-binding residues (5): 198; 198; 199; 360; 404

Post-translational modifications (1): 454

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9617324	Negative regulation of NMDA receptor-mediated neuronal transmission

MSigDB gene sets: 269 (showing top): GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_REGULATION_OF_CELL_CELL_ADHESION_MEDIATED_BY_CADHERIN, GOBP_FOCAL_ADHESION_ASSEMBLY, GOBP_REGULATION_OF_EPITHELIAL_CELL_MIGRATION, GOBP_GROWTH, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_AMEBOIDAL_TYPE_CELL_MIGRATION, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION

GO Biological Process (17): apoptotic process (GO:0006915), signal transduction (GO:0007165), positive regulation of gene expression (GO:0010628), positive regulation of epithelial cell migration (GO:0010634), positive regulation of cell-substrate adhesion (GO:0010811), positive regulation of cell migration (GO:0030335), regulation of protein localization (GO:0032880), intracellular signal transduction (GO:0035556), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of growth (GO:0045927), positive regulation of chemotaxis (GO:0050921), negative regulation of protein transport (GO:0051224), positive regulation of stress fiber assembly (GO:0051496), positive regulation of focal adhesion assembly (GO:0051894), cellular response to xenobiotic stimulus (GO:0071466), negative regulation of cell-cell adhesion mediated by cadherin (GO:2000048), protein dephosphorylation (GO:0006470)

GO Molecular Function (8): protein serine/threonine phosphatase activity (GO:0004722), protein tyrosine/serine/threonine phosphatase activity (GO:0008138), calmodulin-dependent protein phosphatase activity (GO:0033192), metal ion binding (GO:0046872), phosphoprotein phosphatase activity (GO:0004721), protein binding (GO:0005515), hydrolase activity (GO:0016787), cation binding (GO:0043169)

GO Cellular Component (4): nucleus (GO:0005634), cytosol (GO:0005829), protein-containing complex (GO:0032991), perinuclear region of cytoplasm (GO:0048471)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Activation of NMDA receptors and postsynaptic events	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphoprotein phosphatase activity	2
cytoplasm	2
cellular anatomical structure	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
epithelial cell migration	1
regulation of epithelial cell migration	1
positive regulation of cell migration	1
regulation of cell-substrate adhesion	1
cell-substrate adhesion	1
positive regulation of cell adhesion	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
intracellular protein localization	1
regulation of localization	1
intracellular anatomical structure	1
signal transduction	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
growth	1
regulation of growth	1
positive regulation of biological process	1
chemotaxis	1
positive regulation of response to external stimulus	1
positive regulation of locomotion	1
regulation of chemotaxis	1
protein transport	1
negative regulation of transport	1
regulation of protein transport	1

Protein interactions and networks

STRING

1752 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPM1F	CUL2	Q13617	756
PPM1F	FHOD1	Q9Y613	604
PPM1F	PPM1M	Q96MI6	598
PPM1F	SNW1	Q13573	543
PPM1F	CAMK2G	Q13555	531
PPM1F	ARHGEF6	Q15052	529
PPM1F	TRA2A	Q13595	515
PPM1F	PPTC7	Q8NI37	500
PPM1F	FEM1B	Q9UK73	500
PPM1F	DGCR2	P98153	491
PPM1F	DIAPH1	O60610	475
PPM1F	RBX1	P62877	447
PPM1F	ZNF830	Q96NB3	436
PPM1F	MED15	Q96RN5	426
PPM1F	ASCC2	Q9H1I8	425

IntAct

52 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
DIAPH1	PPM1F	psi-mi:“MI:0915”(physical association)	0.540
DIAPH1	PPM1F	psi-mi:“MI:0407”(direct interaction)	0.540
FEM1B	PPM1F	psi-mi:“MI:0407”(direct interaction)	0.540
PPM1F	FEM1B	psi-mi:“MI:0915”(physical association)	0.540
PPM1F	CAMK2A	psi-mi:“MI:0203”(dephosphorylation reaction)	0.440
CPT1C	PPM1F	psi-mi:“MI:0915”(physical association)	0.400
PPM1F	KCTD6	psi-mi:“MI:0915”(physical association)	0.400
PPM1F	Camkk2	psi-mi:“MI:0915”(physical association)	0.400
PPM1F	LMTK2	psi-mi:“MI:0915”(physical association)	0.370
PPM1F	AATK	psi-mi:“MI:0915”(physical association)	0.370
PPM1F	ERBB4	psi-mi:“MI:0915”(physical association)	0.370
PPM1F	ERBB2	psi-mi:“MI:0915”(physical association)	0.370
PPM1F	ERBB3	psi-mi:“MI:0915”(physical association)	0.370
PPM1F	ROR1	psi-mi:“MI:0915”(physical association)	0.370
PPM1F	ROR2	psi-mi:“MI:0915”(physical association)	0.370
PPM1F	PTK7	psi-mi:“MI:0915”(physical association)	0.370
MUC20	RAD51B	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
SLC16A11	ESYT2	psi-mi:“MI:0914”(association)	0.350
CDC25B	PPM1F	psi-mi:“MI:0914”(association)	0.350
SLF1	CD8A	psi-mi:“MI:0914”(association)	0.350
KLK15	APAF1	psi-mi:“MI:0914”(association)	0.350
BBS1	PCYT1A	psi-mi:“MI:0914”(association)	0.350
LYPD1	ADAM10	psi-mi:“MI:0914”(association)	0.350
SLC2A2	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC7A11	PSMD9	psi-mi:“MI:0914”(association)	0.350

BioGRID (84): PRKAA2 (Affinity Capture-Western), PRKAA1 (Affinity Capture-Western), PPM1F (Affinity Capture-Western), PPM1F (Affinity Capture-Western), PRKAA1 (Biochemical Activity), PPM1F (Co-fractionation), PPM1F (Affinity Capture-MS), CAMK2A (Biochemical Activity), PPM1F (Proximity Label-MS), PPM1F (Affinity Capture-Western), PPM1F (Affinity Capture-Western), PPM1F (Affinity Capture-Western), PPM1F (Affinity Capture-MS), PPM1F (Affinity Capture-MS), PPM1F (Two-hybrid)

ESM2 similar proteins: A2AI05, O00587, O08760, O15527, O55240, O70249, P21139, P49593, P50336, P56602, Q1JP61, Q1JPJ0, Q2TBI8, Q32PI0, Q3T0A0, Q501J2, Q5E9V4, Q5H879, Q5IS64, Q5SUV1, Q5T440, Q60HD5, Q6AYG0, Q6AYR8, Q6P9U1, Q8BNV1, Q8BZG5, Q8IZ69, Q8K4Q6, Q8N371, Q8N9H8, Q8R2H9, Q8VCA8, Q91W89, Q923W9, Q969S8, Q96AZ1, Q96FB5, Q96FI4, Q96FV2

Diamond homologs: A0A7U2MSD6, A0BLX0, A0BQL0, A0CUB5, A0DSB3, A0DTY1, A3A8Q4, A3A8W2, A3A8W6, A5PJZ2, F1LNI5, G0RT93, O04719, O15355, O15743, O62829, O62830, O75688, O80871, O81716, P20650, P34221, P35813, P35814, P35815, P36993, P38089, P39966, P40371, P49443, P49444, P49593, P49595, P49596, P49597, P49598, P79126, P93006, Q09172, Q09173

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
PPM1F	down-regulates	CAMK2A	dephosphorylation
PPM1F	down-regulates	PAK1	dephosphorylation
PPM1F	down-regulates	PAK2	dephosphorylation
PPM1F	down-regulates	PAK	dephosphorylation
PPM1F	“down-regulates activity”	CHEK1	dephosphorylation
PPM1F	“down-regulates activity”	LATS1	dephosphorylation
PPM1F	“down-regulates activity”	MAP3K7	dephosphorylation
PPM1F	“down-regulates activity”	CAMK1	dephosphorylation
PPM1F	“down-regulates activity”	CAMK4	dephosphorylation
PPM1F	“down-regulates activity”	PAK1	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 60 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
cell surface receptor protein tyrosine kinase signaling pathway	6	18.6×	4e-04
mRNA processing	6	8.4×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	92
Likely benign	30
Benign	19

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
694456	GRCh37/hg19 22q11.22(chr22:22320654-22566334)x1	Likely pathogenic

SpliceAI

1731 predictions. Top by Δscore:

Variant	Effect	Δscore
22:21923226:C:CT	donor_gain	1.0000
22:21923348:T:TA	donor_gain	1.0000
22:21923468:TCCC:T	acceptor_gain	1.0000
22:21923469:CCC:C	acceptor_gain	1.0000
22:21923469:CCCC:C	acceptor_gain	1.0000
22:21923470:CC:C	acceptor_gain	1.0000
22:21923470:CCC:C	acceptor_gain	1.0000
22:21923471:CC:C	acceptor_gain	1.0000
22:21923471:CCT:C	acceptor_loss	1.0000
22:21923472:C:CC	acceptor_gain	1.0000
22:21925567:A:AC	donor_gain	1.0000
22:21925568:C:CC	donor_gain	1.0000
22:21933405:T:A	donor_gain	1.0000
22:21933543:C:CT	acceptor_gain	1.0000
22:21933546:C:CT	acceptor_gain	1.0000
22:21934022:A:AC	donor_gain	1.0000
22:21934023:C:CC	donor_gain	1.0000
22:21934023:CAGA:C	donor_gain	1.0000
22:21939530:A:AC	donor_gain	1.0000
22:21939531:C:CC	donor_gain	1.0000
22:21939531:CAGGT:C	donor_gain	1.0000
22:21952790:ACC:A	donor_gain	1.0000
22:21952791:CCC:C	donor_gain	1.0000
22:21923095:G:C	donor_gain	0.9900
22:21923180:C:CA	donor_gain	0.9900
22:21923227:C:CT	donor_gain	0.9900
22:21923467:ATCCC:A	acceptor_gain	0.9900
22:21923477:C:CT	acceptor_gain	0.9900
22:21923481:C:CT	acceptor_gain	0.9900
22:21925524:T:TA	donor_gain	0.9900

AlphaMissense

2951 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:21923242:G:C	N405K	0.998
22:21923242:G:T	N405K	0.998
22:21925577:C:A	R326I	0.998
22:21923246:T:A	D404V	0.997
22:21923378:T:A	D360V	0.997
22:21923381:C:T	C359Y	0.997
22:21925577:C:G	R326T	0.997
22:21925580:G:A	S325F	0.997
22:21933542:C:T	G199D	0.997
22:21933545:T:A	D198V	0.997
22:21923471:C:T	G329E	0.996
22:21925603:T:A	R317S	0.996
22:21925603:T:G	R317S	0.996
22:21933544:A:C	D198E	0.996
22:21933544:A:T	D198E	0.996
22:21934070:T:G	D171A	0.996
22:21934071:C:G	D171H	0.996
22:21923243:T:A	N405I	0.995
22:21923246:T:G	D404A	0.995
22:21923380:A:C	C359W	0.995
22:21925575:C:G	A327P	0.995
22:21925576:T:A	R326S	0.995
22:21925576:T:G	R326S	0.995
22:21925580:G:T	S325Y	0.995
22:21931221:C:A	G273V	0.995
22:21933542:C:A	G199V	0.995
22:21934073:T:A	E170V	0.995
22:21923237:G:T	T407K	0.994
22:21925604:C:G	R317T	0.994
22:21931215:G:A	S275F	0.994

dbSNP variants (sampled 300 via entrez): RS1000031883 (22:21934353 A>G), RS1000126366 (22:21951982 G>C), RS1000198697 (22:21920589 G>C), RS1000254217 (22:21920359 G>A), RS1000408467 (22:21925753 T>C), RS1000501721 (22:21938267 G>A,T), RS1000536118 (22:21919462 G>A), RS1000550830 (22:21944262 T>C), RS1000588333 (22:21919228 C>A), RS1000759467 (22:21925992 C>T), RS1000895411 (22:21929791 G>A,C), RS1000912558 (22:21927609 T>G), RS1000932207 (22:21927185 A>G), RS1000959516 (22:21938493 T>G), RS1001044099 (22:21933317 G>A,T)

Disease associations

OMIM: gene MIM:619309 | disease phenotypes: MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
cholestasis	Limited	Autosomal recessive

Mondo (2): autism (MONDO:0005260), cholestasis (MONDO:0001751)

Orphanet (0):

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000717	Autism

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000246_26	Attention deficit hyperactivity disorder	6.000000e-06
GCST007324_32	Adventurousness	3.000000e-08
GCST008103_64	Bipolar disorder	6.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008579	risk-taking behaviour

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D002779	Cholestasis	C06.130.120.135

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066265 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	3
bisphenol F	increases expression, affects cotreatment, increases methylation, decreases methylation	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression, decreases reaction	2
Silicon Dioxide	increases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
chlorophyllin	decreases reaction, increases expression	1
nickel chloride	decreases expression	1
cupric chloride	increases expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	increases expression, increases reaction	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Bortezomib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	decreases expression, increases abundance, affects cotreatment	1
Benztropine	decreases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	increases expression, increases reaction	1
Cuprizone	affects cotreatment, decreases expression	1
Diazinon	decreases methylation	1
Estradiol	affects expression	1
Haloperidol	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Ozone	affects expression, increases abundance	1
Polychlorinated Biphenyls	affects expression	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
CHEMBL5652088	Binding	Binding affinity to human PPM1F 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_B3EG	Abcam HEK293T PPM1F KO	Transformed cell line	Female
CVCL_TF40	HAP1 PPM1F (-) 1	Cancer cell line	Male
CVCL_TF41	HAP1 PPM1F (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01373918	PHASE4	TERMINATED	Low Dose Fat for the Prevention of Liver Disease in Babies With Gastrointestinal Disorders
NCT01585935	PHASE4	COMPLETED	Preventing Cholestasis Using SMOFLipid®
NCT01998620	PHASE4	UNKNOWN	Efficacy and Safety of S-adenosyl-L-methionine in Treatment of Chronic Hepatitis B Patients With Cholestasis
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT00007020	PHASE3	COMPLETED	Compassionate Treatment of Patients With Inborn Errors of Bile Acid Metabolism With Cholic Acid
NCT00058890	PHASE3	COMPLETED	Gabapentin to Treat Itch in Patients With Liver Disease
NCT01194063	PHASE3	COMPLETED	Use of Omegaven Fish Oil Emulsion for Parenteral Nutrition Associated Liver Disease in Infants and Children
NCT02357576	PHASE3	COMPLETED	Standard Lipid Therapy vs IVFE Minimization for Prevention of PNALD
NCT02663453	PHASE3	COMPLETED	Effectiveness of Multicomponent Lipid Emulsion in Preterm Infants Requiring Parenteral Nutrition
NCT03662282	PHASE3	COMPLETED	Omegaven as Alternative Parenteral Fat Nutrition
NCT04167358	PHASE3	ACTIVE_NOT_RECRUITING	Linerixibat Long-term Safety, and Tolerability Study
NCT04309773	PHASE3	UNKNOWN	Efficacy of 24 Month of Bezafibrate in Primary Sclerosing Cholangitis With Persistent Cholestasis Despite Ursodeoxycholic Acid Therapy