PPIH

Summary

PPIH (peptidylprolyl isomerase H, HGNC:14651) is a protein-coding gene on chromosome 1p34.2, encoding Peptidyl-prolyl cis-trans isomerase H (O43447). PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding. It is a selective cancer dependency (DepMap: 42.8% of cell lines).

The protein encoded by this gene is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins. This protein is a specific component of the complex that includes pre-mRNA processing factors PRPF3, PRPF4, and PRPF18, as well as U4/U5/U6 tri-snRNP. This protein has been shown to possess PPIase activity and may act as a protein chaperone that mediates the interactions between different proteins inside the spliceosome.

Source: NCBI Gene 10465 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 24 total — 1 pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 42.8% of screened cell lines
• MANE Select transcript: NM_006347

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14651
Approved symbol	PPIH
Name	peptidylprolyl isomerase H
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Aliases	USA-CYP, CYP-20, SnuCyp-20, CYPH, MGC5016
Ensembl gene	ENSG00000171960
Ensembl biotype	protein_coding
OMIM	606095
Entrez	10465

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 27 protein_coding, 6 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000304979, ENST00000372549, ENST00000372550, ENST00000436387, ENST00000440068, ENST00000461351, ENST00000676675, ENST00000677219, ENST00000677307, ENST00000677312, ENST00000677356, ENST00000677900, ENST00000677926, ENST00000678038, ENST00000678076, ENST00000678193, ENST00000678308, ENST00000678333, ENST00000678803, ENST00000679245, ENST00000910630, ENST00000910631, ENST00000910632, ENST00000910633, ENST00000910634, ENST00000924397, ENST00000924398, ENST00000924399, ENST00000924400, ENST00000924401, ENST00000924402, ENST00000924403, ENST00000947098, ENST00000947099, ENST00000947100

RefSeq mRNA: 2 — MANE Select: NM_006347 NM_001330510, NM_006347

CCDS: CCDS469

Canonical transcript exons

ENST00000304979 — 10 exons

Exon	Start	End
ENSE00001144169	42666547	42666587
ENSE00001144176	42665980	42666067
ENSE00001144183	42664863	42664955
ENSE00001144190	42660862	42660904
ENSE00001144198	42659522	42659566
ENSE00001144207	42659228	42659251
ENSE00001146489	42667351	42667440
ENSE00001830638	42658423	42658512
ENSE00001847781	42676584	42676758
ENSE00003525208	42658844	42658908

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 94.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.0082 / max 699.4472, expressed in 1817 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2459	34.0082	1817

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
embryo	UBERON:0000922	94.81	gold quality
ventricular zone	UBERON:0003053	94.81	gold quality
ganglionic eminence	UBERON:0004023	94.35	gold quality
mucosa of transverse colon	UBERON:0004991	94.14	gold quality
granulocyte	CL:0000094	93.60	gold quality
secondary oocyte	CL:0000655	93.49	gold quality
rectum	UBERON:0001052	93.42	gold quality
tongue squamous epithelium	UBERON:0006919	93.11	gold quality
oocyte	CL:0000023	92.28	gold quality
esophagus mucosa	UBERON:0002469	92.27	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.25	gold quality
lymph node	UBERON:0000029	92.24	gold quality
colonic epithelium	UBERON:0000397	92.15	gold quality
esophagus squamous epithelium	UBERON:0006920	91.83	gold quality
left lobe of thyroid gland	UBERON:0001120	91.73	gold quality
monocyte	CL:0000576	91.46	gold quality
islet of Langerhans	UBERON:0000006	91.37	gold quality
spleen	UBERON:0002106	91.32	gold quality
leukocyte	CL:0000738	91.29	gold quality
right lobe of thyroid gland	UBERON:0001119	91.20	gold quality
mononuclear cell	CL:0000842	91.14	gold quality
epithelium of esophagus	UBERON:0001976	91.05	gold quality
right ovary	UBERON:0002118	91.03	gold quality
ectocervix	UBERON:0012249	90.96	gold quality
skin of abdomen	UBERON:0001416	90.86	gold quality
left ovary	UBERON:0002119	90.84	gold quality
thyroid gland	UBERON:0002046	90.78	gold quality
esophagus	UBERON:0001043	90.70	gold quality
transverse colon	UBERON:0001157	90.69	gold quality
parietal pleura	UBERON:0002400	90.68	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.57
E-ENAD-17	no	1887.98
E-CURD-112	no	3.60

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

17 targeting PPIH, 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-5582-3P	99.86	72.48	4221
HSA-MIR-200A-5P	99.76	69.10	949
HSA-MIR-200B-5P	99.76	69.05	948
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-6848-3P	99.64	66.49	885
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-6843-3P	99.26	66.42	915
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-3921	97.81	67.45	1431
HSA-MIR-5187-3P	97.28	67.10	1037
HSA-MIR-4653-5P	97.22	67.72	1429
HSA-MIR-6730-3P	97.03	67.54	889
HSA-MIR-301A-5P	96.88	68.07	931
HSA-MIR-301B-5P	96.88	67.75	946
HSA-MIR-550B-3P	95.43	67.73	599

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 42.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 2)

• Free and complexed cyclophilin H have virtually identical conformations suggesting that the U4/U6-60K binding site is pre-shaped and the peptidyl-prolyl-cis/trans isomerase activity is unaffected by complex formation (PMID:12875835)
• PPIH gene regulation system and its prognostic significance in hepatocellular carcinoma: a comprehensive analysis. (PMID:37874737)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppih	ENSDARG00000041530
mus_musculus	Ppih	ENSMUSG00000060288
rattus_norvegicus	Ppih	ENSRNOG00000008489
drosophila_melanogaster	CG17266	FBGN0033089
caenorhabditis_elegans		WBGENE00000887

Paralogs (22): PPIE (ENSG00000084072), PPIL2 (ENSG00000100023), PPIF (ENSG00000108179), PPWD1 (ENSG00000113593), NKTR (ENSG00000114857), PPIL4 (ENSG00000131013), PPIL1 (ENSG00000137168), PPIG (ENSG00000138398), CWC27 (ENSG00000153015), PPIB (ENSG00000166794), PPIC (ENSG00000168938), PPID (ENSG00000171497), PPIL6 (ENSG00000185250), PPIA (ENSG00000196262), PPIAL4G (ENSG00000236334), PPIL3 (ENSG00000240344), PPIAL4A (ENSG00000263353), PPIAL4H (ENSG00000270339), PPIAL4E (ENSG00000271567), PPIAL4F (ENSG00000279782), PPIAL4C (ENSG00000288867), PPIAL4D (ENSG00000289549)

Protein

Protein identifiers

Peptidyl-prolyl cis-trans isomerase H — O43447 (reviewed: O43447)

Alternative names: Rotamase H, Small nuclear ribonucleoprotein particle-specific cyclophilin H, U-snRNP-associated cyclophilin SnuCyp-20

All UniProt accessions (8): O43447, A0A7I2V2H6, A0A7I2V343, A0A7I2V5V0, A0A7I2YQS4, C9JQD4, H0YEL5, Q6FH36

UniProt curated annotations — full annotation on UniProt →

Function. PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding. Participates in pre-mRNA splicing. May play a role in the assembly of the U4/U5/U6 tri-snRNP complex, one of the building blocks of the spliceosome. May act as a chaperone.

Subunit / interactions. Interacts directly with PRPF4. Part of a heteromeric complex containing PPIH, PRPF3 and PRPF4 that is stable in the absence of RNA. Component of the U4/U6-U5 tri-snRNP complex composed of the U4, U6 and U5 snRNAs and at least PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, SNRNP200, TXNL4A, SNRNP40, DDX23, CD2BP2, PPIH, SNU13, EFTUD2, SART1 and USP39. Heterodimer with PRPF18.

Subcellular location. Nucleus speckle. Cytoplasm.

Activity regulation. Inhibited by cyclosporin A.

Similarity. Belongs to the cyclophilin-type PPIase family. PPIase H subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
O43447-1	1	yes
O43447-2	2

RefSeq proteins (2): NP_001317439, NP_006338* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002130	Cyclophilin-type_PPIase_dom	Domain
IPR020892	Cyclophilin-type_PPIase_CS	Conserved_site
IPR024936	Cyclophilin-type_PPIase	Family
IPR029000	Cyclophilin-like_dom_sf	Homologous_superfamily

Pfam: PF00160

Enzyme classification (BRENDA):

• EC 5.2.1.8 — peptidylprolyl isomerase (BRENDA: 69 organisms, 374 substrates, 222 inhibitors, 24 Km, 30 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
N-SUCCINYL-ALA-GLU-(TRANS)-PRO-PHE-4-NITROANILID	0.17–0.7	5
N-SUCCINYL-ALA-ALA-(CIS)-PRO-PHE-4-NITROANILIDE	0.104–0.814	2
RNASE T1	0.0004–0.0006	2
SUCCINYL-ALA-ALA-PRO-PHE 4-NITROANILIDE	0.451–1.247	2
SUCCINYL-ALA-LYS-PRO-PHE-4-NITROANILIDE	0.585–0.788	2
ALA-GLY-PSI[CS-N]-PRO-PHE-4-NITROANILIDE	0.53	1
N-SUCCINYL-ALA-LEU-(CIS)-PRO-PHE-4-NITROANILIDE	0.059	1
SUCCINYL-ALA-GLU-PRO-PHE-7-AMIDO-4-METHYLCOUMARI	0.12	1
TRYWNAKMK-(CIS)-PFIFGA	2	1
SUCCINYL-ALA-ALA-(CIS)-PRO-LYS-4-METHYLCOUMARIN-	—	0
SUCCINYL-ALA-ALA-(CIS)-PRO-PHE 4-METHYLCOUMARIN	—	0

Catalyzed reactions (Rhea), 1 shown:

• [protein]-peptidylproline (omega=180) = [protein]-peptidylproline (omega=0) (RHEA:16237)

UniProt features (24 total): strand 10, turn 4, helix 4, initiator methionine 1, chain 1, domain 1, modified residue 1, splice variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
1MZW	X-RAY DIFFRACTION	2
1QOI	X-RAY DIFFRACTION	2
8H6L	ELECTRON MICROSCOPY	2.6
8H6K	ELECTRON MICROSCOPY	2.7
6AHD	ELECTRON MICROSCOPY	3.8
8QZS	ELECTRON MICROSCOPY	4.1
8R09	ELECTRON MICROSCOPY	4.3
8R0B	ELECTRON MICROSCOPY	4.4
5O9Z	ELECTRON MICROSCOPY	4.5
8QO9	ELECTRON MICROSCOPY	5.29
8RM5	ELECTRON MICROSCOPY	6.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43447-F1	96.48	0.95

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 (1): 2

Mutagenesis-validated functional residues (1):

Position	Phenotype
133	abolishes inhibition by cyclosporin a.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-9692916	SARS-CoV-1 activates/modulates innate immune responses

MSigDB gene sets: 186 (showing top): TSENG_IRS1_TARGETS_UP, YAGI_AML_WITH_INV_16_TRANSLOCATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_VIRAL_GENOME_REPLICATION, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_PROTEIN_MATURATION, MARTINEZ_RB1_TARGETS_DN, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, chr1p34, GNF2_FBL, GOBP_RNA_SPLICING, GOBP_VIRAL_GENOME_REPLICATION, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_13, GOBP_VIRAL_LIFE_CYCLE

GO Biological Process (7): mRNA splicing, via spliceosome (GO:0000398), protein folding (GO:0006457), positive regulation of viral genome replication (GO:0045070), protein-containing complex assembly (GO:0065003), protein peptidyl-prolyl isomerization (GO:0000413), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (5): peptidyl-prolyl cis-trans isomerase activity (GO:0003755), cyclosporin A binding (GO:0016018), ribonucleoprotein complex binding (GO:0043021), protein binding (GO:0005515), isomerase activity (GO:0016853)

GO Cellular Component (8): nucleoplasm (GO:0005654), spliceosomal complex (GO:0005681), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear speck (GO:0016607), U4/U6 x U5 tri-snRNP complex (GO:0046540), U4/U6 snRNP (GO:0071001), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
mRNA Splicing	1
SARS-CoV-1-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
RNA processing	2
binding	2
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
cellular process	1
protein maturation	1
viral genome replication	1
regulation of viral genome replication	1
positive regulation of viral process	1
cellular component assembly	1
protein-containing complex organization	1
peptidyl-proline modification	1
mRNA metabolic process	1
cis-trans isomerase activity	1
catalytic activity, acting on a protein	1
protein-containing complex binding	1
catalytic activity	1
nuclear lumen	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1
intracellular anatomical structure	1
cytoplasm	1
nuclear ribonucleoprotein granule	1
U5 snRNP	1
U4/U6 snRNP	1
spliceosomal tri-snRNP complex	1
U4 snRNP	1
U6 snRNP	1
spliceosomal snRNP complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

3006 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPIH	PRPF3	O43395	988
PPIH	SH2D3A	Q9BRG2	933
PPIH	PRPF4	O43172	889
PPIH	PRPF18	Q99633	745
PPIH	PRPF31	Q8WWY3	686
PPIH	SNU13	P55769	658
PPIH	PRPF38A	Q8NAV1	518
PPIH	MFAP1	P55081	517
PPIH	ZMAT2	Q96NC0	502
PPIH	SMU1	Q2TAY7	501
PPIH	FKBP1B	P68106	490
PPIH	MINAR1	Q9UPX6	458
PPIH	SYF2	O95926	457
PPIH	CYP20A1	Q6UW02	453
PPIH	CYP51A1	Q16850	447

IntAct

132 interactions, top by confidence:

A	B	Type	Score
PRPF4	PPIH	psi-mi:“MI:2364”(proximity)	0.910
PPIH	PRPF4	psi-mi:“MI:0915”(physical association)	0.910
PRPF4	PPIH	psi-mi:“MI:0915”(physical association)	0.910
PRPF4	PPIH	psi-mi:“MI:0914”(association)	0.910
PPIH	PRPF4	psi-mi:“MI:0407”(direct interaction)	0.910
SART3	PRPF4	psi-mi:“MI:0914”(association)	0.730
PPIH	N4BP2L2	psi-mi:“MI:0915”(physical association)	0.720
N4BP2L2	PPIH	psi-mi:“MI:0915”(physical association)	0.720
SNRPD2	GEMIN2	psi-mi:“MI:0914”(association)	0.710
PPIH	XIAP	psi-mi:“MI:0915”(physical association)	0.700
PPIH	HTT	psi-mi:“MI:0915”(physical association)	0.670
PRPF8	PRPF4	psi-mi:“MI:0914”(association)	0.640
PPIH	PRPF18	psi-mi:“MI:0915”(physical association)	0.560
PPIH	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
PPIH	LNX1	psi-mi:“MI:0915”(physical association)	0.560
PPIH	BPIFA1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (177): PPIH (Affinity Capture-MS), PPIH (Two-hybrid), ITPA (Co-fractionation), PPIH (Co-fractionation), PPIH (Proximity Label-MS), PPIH (Affinity Capture-MS), PPIH (Affinity Capture-MS), PRPF3 (Affinity Capture-MS), PRPF4 (Affinity Capture-MS), LSM8 (Affinity Capture-MS), ALYREF (Affinity Capture-MS), SART3 (Affinity Capture-MS), LSM4 (Affinity Capture-MS), LSM6 (Affinity Capture-MS), RPL26L1 (Affinity Capture-MS)

ESM2 similar proteins: A0A075B759, A0A075B767, A0A0B4J2A2, F5H284, O00060, O43447, O74729, O94273, P0C1I0, P0C1I3, P0C1I5, P0C1I8, P0CP82, P0CP83, P0DN26, P0DN37, P17742, P23285, P24525, P25719, P52010, P52018, P62940, P84343, Q0P5D0, Q0ZQK7, Q0ZQK8, Q0ZQL0, Q0ZQL1, Q26516, Q26551, Q26565, Q27774, Q2TZ33, Q38867, Q38900, Q42406, Q4IPH4, Q4P6X6, Q4WCM6

Diamond homologs: A0A075B759, A0A075B767, A0A0B4J2A2, A0A0R0H9T5, A4FV72, F5H284, H2QII6, O00060, O00845, O43447, O49886, P0C1H7, P0C1H8, P0C1H9, P0C1I0, P0C1I1, P0C1I2, P0C1I7, P0C1I8, P0DN26, P0DN37, P10111, P14088, P14832, P14851, P17742, P18253, P21568, P21569, P22011, P24525, P25007, P25719, P29117, P30404, P30405, P34790, P34791, P34887, P48820

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 94 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
mRNA Splicing	15	22.9×	9e-15
mRNA Splicing - Major Pathway	29	22.0×	1e-29
mRNA Splicing - Minor Pathway	7	21.8×	1e-06
Processing of Capped Intron-Containing Pre-mRNA	18	20.5×	5e-17
mRNA Polyadenylation	14	17.1×	5e-12
SARS-CoV-2 modulates host translation machinery	5	15.6×	7e-04
CHD1 and CHD2 subfamily	9	13.6×	1e-06
Metabolism of RNA	17	9.8×	6e-11

GO biological processes:

GO term	Partners	Fold	FDR
spliceosomal tri-snRNP complex assembly	5	64.6×	7e-07
spliceosomal snRNP assembly	9	60.1×	3e-12
mRNA cis splicing, via spliceosome	5	57.0×	1e-06
RNA splicing, via transesterification reactions	7	50.2×	8e-09
U2-type prespliceosome assembly	6	43.0×	4e-07
mRNA splicing, via spliceosome	25	26.3×	2e-26
RNA splicing	17	17.2×	3e-14
mRNA processing	12	10.9×	1e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	7
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3062343	GRCh38/hg38 1p34.2(chr1:42278946-43598390)	Pathogenic

SpliceAI

1509 predictions. Top by Δscore:

Variant	Effect	Δscore
1:42658906:TAGG:T	donor_loss	1.0000
1:42658907:AGG:A	donor_loss	1.0000
1:42658909:GT:G	donor_loss	1.0000
1:42658910:T:G	donor_loss	1.0000
1:42659227:GGCA:G	acceptor_gain	1.0000
1:42660905:G:GG	donor_gain	1.0000
1:42664862:GGGA:G	acceptor_gain	1.0000
1:42666583:TTGAG:T	donor_gain	1.0000
1:42666585:GAG:G	donor_gain	1.0000
1:42666588:G:GG	donor_gain	1.0000
1:42666588:GTAA:G	donor_loss	1.0000
1:42667350:GAAT:G	acceptor_gain	1.0000
1:42658602:G:T	donor_gain	0.9900
1:42658614:A:T	donor_gain	0.9900
1:42658838:TTGCA:T	acceptor_loss	0.9900
1:42658839:TGCA:T	acceptor_loss	0.9900
1:42658840:GCA:G	acceptor_loss	0.9900
1:42658841:CA:C	acceptor_loss	0.9900
1:42658843:GGAA:G	acceptor_gain	0.9900
1:42658909:G:GG	donor_gain	0.9900
1:42659226:A:AG	acceptor_gain	0.9900
1:42659227:G:GG	acceptor_gain	0.9900
1:42659227:GGC:G	acceptor_gain	0.9900
1:42660860:A:AG	acceptor_gain	0.9900
1:42660860:AG:A	acceptor_gain	0.9900
1:42660861:G:GG	acceptor_gain	0.9900
1:42660861:GG:G	acceptor_gain	0.9900
1:42660900:TTAAT:T	donor_gain	0.9900
1:42660903:AT:A	donor_gain	0.9900
1:42660905:GTAA:G	donor_loss	0.9900

AlphaMissense

1183 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:42659566:G:T	R67M	1.000
1:42660875:T:C	F72L	1.000
1:42660877:C:A	F72L	1.000
1:42660877:C:G	F72L	1.000
1:42658903:C:A	N42K	0.999
1:42658903:C:G	N42K	0.999
1:42659236:G:A	C47Y	0.999
1:42659237:C:G	C47W	0.999
1:42659562:C:G	H66D	0.999
1:42659566:G:C	R67T	0.999
1:42660862:G:C	R67S	0.999
1:42660862:G:T	R67S	0.999
1:42660864:T:A	V68D	0.999
1:42660887:G:C	G76R	0.999
1:42660891:G:A	G77E	0.999
1:42660891:G:T	G77V	0.999
1:42660893:G:C	D78H	0.999
1:42660894:A:T	D78V	0.999
1:42664870:G:A	G84D	0.999
1:42664870:G:T	G84V	0.999
1:42664876:G:A	G86E	0.999
1:42664942:G:A	G108D	0.999
1:42664948:T:A	L110H	0.999
1:42666007:T:C	C122R	0.999
1:42666013:T:C	F124L	0.999
1:42666015:C:A	F124L	0.999
1:42666015:C:G	F124L	0.999
1:42666016:T:C	F125L	0.999
1:42666018:T:A	F125L	0.999
1:42666018:T:G	F125L	0.999

dbSNP variants (sampled 300 via entrez): RS1000074381 (1:42659687 T>C), RS1000178335 (1:42665666 G>A,C), RS1000452702 (1:42672491 C>T), RS1000688579 (1:42658385 C>G), RS1000822416 (1:42677574 T>G), RS1001051756 (1:42671078 G>A), RS1001139483 (1:42682085 T>C), RS1001316607 (1:42678233 C>T), RS1001369228 (1:42678522 C>T), RS1001481881 (1:42671861 C>T), RS1001484375 (1:42671317 A>G), RS1001604221 (1:42681504 T>C,G), RS1001762357 (1:42660851 C>G,T), RS1002159744 (1:42668120 G>A), RS1002196157 (1:42658121 G>T)

Disease associations

OMIM: gene MIM:606095 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): epilepsy syndrome (MONDO:0015650)

Orphanet (1): Epilepsy syndrome (Orphanet:166463)

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067038 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.49	Kd	32.55	nM	CHEMBL5653589
7.49	ED50	32.55	nM	CHEMBL5653589
5.69	Kd	2053	nM	CHEMBL3752910
5.69	ED50	2053	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 6 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149044: Binding affinity to human PPIH incubated for 45 mins by Kinobead based pull down assay	kd	0.0326	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149044: Binding affinity to human PPIH incubated for 45 mins by Kinobead based pull down assay	kd	2.0529	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression	3
sodium arsenite	increases expression, decreases expression	3
decabromobiphenyl ether	increases expression	1
beta-lapachone	increases expression	1
cobaltous chloride	decreases expression	1
2,3-dimethoxy-1,4-naphthoquinone	increases expression	1
yessotoxin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	increases expression	1
jinfukang	increases expression	1
(+)-JQ1 compound	decreases expression	1
PP242	increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Troglitazone	decreases expression	1
Antimony	increases expression	1
Antimony Potassium Tartrate	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Calcitriol	decreases expression, affects cotreatment	1
Chromium	increases expression	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Mercury	increases expression	1
Methotrexate	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Mustard Gas	decreases expression	1
Potassium Dichromate	increases expression	1
Testosterone	affects cotreatment, decreases 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
CHEMBL5652086	Binding	Binding affinity to human PPIH 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

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3EE	Abcam HEK293T PPIH KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04639310	PHASE3	TERMINATED	XEN496 (Ezogabine) in Children With KCNQ2 Developmental and Epileptic Encephalopathy
NCT04912856	PHASE3	TERMINATED	An Open-Label Extension of the Study XEN496 (Ezogabine) in Children With KCNQ2-DEE
NCT04048213	Not specified	UNKNOWN	The Becoming of Children With Doose Syndrome
NCT05097742	Not specified	COMPLETED	Cognitive Impairments in Children With Epilepsy
NCT06222840	Not specified	COMPLETED	Electro-clinical Features and Functional Connectivity Analysis in SYN1 Gene Mutation-related Epilepsy
NCT06223334	Not specified	UNKNOWN	Epileptic Syndromes in Infants and Early Childhood