PPIL1

Summary

PPIL1 (peptidylprolyl isomerase like 1, HGNC:9260) is a protein-coding gene on chromosome 6p21.2, encoding Peptidyl-prolyl cis-trans isomerase-like 1 (Q9Y3C6). Involved in pre-mRNA splicing as component of the spliceosome. It is a selective cancer dependency (DepMap: 76.9% of cell lines).

This gene is a member of the cyclophilin family of peptidylprolyl isomerases (PPIases). The cyclophilins are a highly conserved, ubiquitous family, members of which play an important role in protein folding, immunosuppression by cyclosporin A, and infection of HIV-1 virions. Based on similarity to other PPIases, this protein could accelerate the folding of proteins and might catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.

Source: NCBI Gene 51645 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pontocerebellar hypoplasia, type 14 (Strong, GenCC)
• GWAS associations: 13
• Clinical variants (ClinVar): 36 total — 7 likely-pathogenic
• Phenotypes (HPO): 24
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 76.9% of screened cell lines
• MANE Select transcript: NM_016059

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9260
Approved symbol	PPIL1
Name	peptidylprolyl isomerase like 1
Location	6p21.2
Locus type	gene with protein product
Status	Approved
Aliases	CYPL1
Ensembl gene	ENSG00000137168
Ensembl biotype	protein_coding
OMIM	601301
Entrez	51645

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000373699, ENST00000483552, ENST00000921230, ENST00000946228

RefSeq mRNA: 1 — MANE Select: NM_016059 NM_016059

CCDS: CCDS4826

Canonical transcript exons

ENST00000373699 — 4 exons

Exon	Start	End
ENSE00000929547	36871718	36871872
ENSE00001461336	36874717	36874803
ENSE00003619214	36856586	36856654
ENSE00003632779	36854829	36856033

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 97.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.6120 / max 497.7461, expressed in 1804 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73395	20.6711	1774
73399	3.2804	1308
73400	2.8916	1352
73396	2.3986	1239
73398	0.2394	102
73397	0.1310	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	97.57	gold quality
left ventricle myocardium	UBERON:0006566	97.30	gold quality
oocyte	CL:0000023	97.14	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	96.72	gold quality
myocardium	UBERON:0002349	96.37	gold quality
cardiac muscle of right atrium	UBERON:0003379	95.81	gold quality
secondary oocyte	CL:0000655	95.41	gold quality
cardiac atrium	UBERON:0002081	94.00	gold quality
right atrium auricular region	UBERON:0006631	93.96	gold quality
right adrenal gland cortex	UBERON:0035827	93.89	gold quality
cardiac ventricle	UBERON:0002082	93.87	gold quality
heart left ventricle	UBERON:0002084	93.87	gold quality
left adrenal gland	UBERON:0001234	93.63	gold quality
left adrenal gland cortex	UBERON:0035825	93.34	gold quality
right adrenal gland	UBERON:0001233	93.26	gold quality
adrenal cortex	UBERON:0001235	93.07	gold quality
heart	UBERON:0000948	92.99	gold quality
islet of Langerhans	UBERON:0000006	92.72	gold quality
adrenal gland	UBERON:0002369	92.67	gold quality
cortical plate	UBERON:0005343	91.93	gold quality
ventricular zone	UBERON:0003053	91.82	gold quality
ganglionic eminence	UBERON:0004023	91.23	gold quality
prefrontal cortex	UBERON:0000451	90.83	gold quality
sperm	CL:0000019	90.37	gold quality
nucleus accumbens	UBERON:0001882	90.33	gold quality
apex of heart	UBERON:0002098	90.18	gold quality
metanephros	UBERON:0000081	89.87	gold quality
hypothalamus	UBERON:0001898	89.78	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.68	gold quality
anterior cingulate cortex	UBERON:0009835	89.54	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.76
E-GEOD-124858	no	149.13

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

76 targeting PPIL1, 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-4795-3P	100.00	74.62	4024
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-7159-3P	99.51	70.17	1920

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 76.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 4)

• NMR protein structure of PPIL1 (PMID:15772761)
• here the solution structure of PPIL1 determined by NMR spectroscopy (PMID:16595688)
• The large disordered region in SKIP provides an interaction platform. Its disorder-order transition, induced by PPIL1 binding, may adapt the requirement for a large structural rearrangement occurred in the activation of spliceosome (PMID:20007319)
• molecular model for the binding mode of SKIP to PPIL1 which emphasizes the versatility of cyclophilin-type PPIases to engage in additional interactions with other proteins apart from active site contacts despite their limited surface area. (PMID:20368803)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppil1	ENSDARG00000015422
mus_musculus	Ppil1	ENSMUSG00000024007
rattus_norvegicus	Ppil1	ENSRNOG00000000523
drosophila_melanogaster	Cypl	FBGN0035141
caenorhabditis_elegans		WBGENE00000888

Paralogs (22): PPIE (ENSG00000084072), PPIL2 (ENSG00000100023), PPIF (ENSG00000108179), PPWD1 (ENSG00000113593), NKTR (ENSG00000114857), PPIL4 (ENSG00000131013), PPIG (ENSG00000138398), CWC27 (ENSG00000153015), PPIB (ENSG00000166794), PPIC (ENSG00000168938), PPID (ENSG00000171497), PPIH (ENSG00000171960), 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-like 1 — Q9Y3C6 (reviewed: Q9Y3C6)

Alternative names: Rotamase PPIL1

All UniProt accessions (1): Q9Y3C6

UniProt curated annotations — full annotation on UniProt →

Function. Involved in pre-mRNA splicing as component of the spliceosome. PPIases accelerate the folding of proteins. Catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Catalyzes prolyl peptide bond isomerization in CDC40/PRP17. Plays an important role in embryonic brain development; this function is independent of its isomerase activity.

Subunit / interactions. Identified in the spliceosome C complex. Interacts with SNW1/SKIP. Interacts with CDC40/PRP17; this interaction leads to CDC40 isomerization. Interacts with RBM22.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitous, with the most abundant expression in heart and skeletal muscle.

Disease relevance. Pontocerebellar hypoplasia 14 (PCH14) [MIM:619301] A form of pontocerebellar hypoplasia, a disorder characterized by structural defects of the pons and cerebellum, evident upon brain imaging. PCH14 is a severe autosomal recessive form characterized by progressive microcephaly, and poor or absent psychomotor development with severely impaired intellectual development apparent from birth. Other features may include hypotonia, spastic quadriplegia, and early-onset seizures. Early death may occur in some patients. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by Cyclosporin A.

Similarity. Belongs to the cyclophilin-type PPIase family. PPIL1 subfamily.

RefSeq proteins (1): NP_057143* (*=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
IPR044666	Cyclophilin_A-like	Family

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 (41 total): strand 14, sequence variant 10, binding site 6, turn 4, helix 3, chain 1, domain 1, mutagenesis site 1, modified residue 1

Structure

Experimental structures (PDB)

28 structures.

PDB	Method	Resolution (Å)
2X7K	X-RAY DIFFRACTION	1.15
8C6J	ELECTRON MICROSCOPY	2.8
6ID1	ELECTRON MICROSCOPY	2.86
6ID0	ELECTRON MICROSCOPY	2.9
6ICZ	ELECTRON MICROSCOPY	3
8I0T	ELECTRON MICROSCOPY	3
8I0V	ELECTRON MICROSCOPY	3
7QTT	ELECTRON MICROSCOPY	3.1
6QDV	ELECTRON MICROSCOPY	3.3
8I0U	ELECTRON MICROSCOPY	3.3
9FMD	ELECTRON MICROSCOPY	3.3
6FF4	ELECTRON MICROSCOPY	3.4
6ZYM	ELECTRON MICROSCOPY	3.4
8I0W	ELECTRON MICROSCOPY	3.4
8RO2	ELECTRON MICROSCOPY	3.5
5XJC	ELECTRON MICROSCOPY	3.6
7W59	ELECTRON MICROSCOPY	3.6
7W5A	ELECTRON MICROSCOPY	3.6
5YZG	ELECTRON MICROSCOPY	4.1
8I0S	ELECTRON MICROSCOPY	4.2
7W5B	ELECTRON MICROSCOPY	4.3
6FF7	ELECTRON MICROSCOPY	4.5
5Z56	ELECTRON MICROSCOPY	5.1
5MQF	ELECTRON MICROSCOPY	5.9
8CH6	ELECTRON MICROSCOPY	5.9
5Z57	ELECTRON MICROSCOPY	6.5
1XWN	SOLUTION NMR
2K7N	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y3C6-F1	95.06	0.94

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 (6): 54–65; 70–71; 99–104; 109–113; 119; 125

Post-translational modifications (1): 149

Mutagenesis-validated functional residues (1):

Position	Phenotype
55	loss of isomerase activity. can rescue splicing defects when transfected in knockout cells.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-9918481	Dengue Virus-Host Interactions

MSigDB gene sets: 186 (showing top): CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_PROTEIN_MATURATION, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, GOBP_RNA_SPLICING, GARCIA_TARGETS_OF_FLI1_AND_DAX1_DN, GOBP_PROTEIN_FOLDING, GARY_CD5_TARGETS_DN, REACTOME_MRNA_SPLICING, GOBP_PEPTIDYL_PROLINE_MODIFICATION, GOBP_EMBRYO_DEVELOPMENT, GOBP_EMBRYONIC_ORGAN_DEVELOPMENT, CETS1P54_01, REACTOME_METABOLISM_OF_RNA

GO Biological Process (6): mRNA splicing, via spliceosome (GO:0000398), protein peptidyl-prolyl isomerization (GO:0000413), protein folding (GO:0006457), embryonic brain development (GO:1990403), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (4): peptidyl-prolyl cis-trans isomerase activity (GO:0003755), disordered domain specific binding (GO:0097718), protein binding (GO:0005515), isomerase activity (GO:0016853)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), U2-type catalytic step 2 spliceosome (GO:0071007), catalytic step 2 spliceosome (GO:0071013), spliceosomal complex (GO:0005681)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
mRNA Splicing	1
Dengue Virus Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	2
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
peptidyl-proline modification	1
cellular process	1
protein maturation	1
embryonic organ development	1
mRNA metabolic process	1
cis-trans isomerase activity	1
catalytic activity, acting on a protein	1
protein domain specific binding	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
U2-type spliceosomal complex	1
U2 snRNP	1
U6 snRNP	1
catalytic step 2 spliceosome	1
Prp19 complex	1
spliceosomal complex	1
U5 snRNP	1
catalytic complex	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1

Protein interactions and networks

STRING

2915 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPIL1	SNW1	Q13573	936
PPIL1	SYF2	O95926	729
PPIL1	CDC40	O60508	643
PPIL1	CDC5L	Q99459	578
PPIL1	GLO1	P78375	512
PPIL1	SF3A1	Q15459	501
PPIL1	PRPF19	Q9UMS4	494
PPIL1	BCAS2	O75934	475
PPIL1	LSM2	Q9Y333	469
PPIL1	VPS52	Q8N1B4	461
PPIL1	SF3A3	Q12874	439
PPIL1	NCKAP1L	P55160	431
PPIL1	GFER	P55789	424
PPIL1	DHX16	O60231	417
PPIL1	HSD17B8	Q92506	417
PPIL1	KLHL42	Q9P2K6	417

IntAct

135 interactions, top by confidence:

A	B	Type	Score
PPIL1	SNW1	psi-mi:“MI:0915”(physical association)	0.930
SNW1	PPIL1	psi-mi:“MI:0915”(physical association)	0.930
PPIL1	SNW1	psi-mi:“MI:0914”(association)	0.930
SNW1	PPIL1	psi-mi:“MI:0407”(direct interaction)	0.930
PPIL1	SNW1	psi-mi:“MI:0407”(direct interaction)	0.930
PPIL1	CPSF6	psi-mi:“MI:0915”(physical association)	0.670
CPSF6	PPIL1	psi-mi:“MI:0915”(physical association)	0.670
SNW1	AQR	psi-mi:“MI:0914”(association)	0.650
SF3B1	SAP18	psi-mi:“MI:0914”(association)	0.640
PPIL1	WDR83	psi-mi:“MI:0915”(physical association)	0.630
TCF4	PPIL1	psi-mi:“MI:0915”(physical association)	0.560
	PPIL1	psi-mi:“MI:0915”(physical association)	0.560
RIMBP3	PPIL1	psi-mi:“MI:0915”(physical association)	0.560
PPIL1	RIMBP3	psi-mi:“MI:0915”(physical association)	0.560
PPIL1		psi-mi:“MI:0915”(physical association)	0.560
LHX2	PPIL1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (169): PPIL1 (Two-hybrid), PPIL1 (Two-hybrid), PPIL1 (Two-hybrid), RIMBP3 (Two-hybrid), PRR22 (Two-hybrid), PPIL1 (Affinity Capture-MS), SNW1 (Co-fractionation), PPIL1 (Affinity Capture-MS), PPIL1 (Affinity Capture-MS), PPIL1 (Affinity Capture-MS), GPALPP1 (Affinity Capture-MS), SNW1 (Affinity Capture-MS), DERA (Affinity Capture-MS), PPIL1 (Affinity Capture-MS), PPIL1 (Affinity Capture-MS)

ESM2 similar proteins: O25982, P0C1I4, P0C1I5, P0CP84, P0CP85, P0CP86, P0CP87, P23285, P29820, P35137, P35176, P52017, P65763, P77949, P84343, P87051, P9WHW2, P9WHW3, Q2FIC1, Q2FZU9, Q2YWT2, Q49W93, Q4L4W9, Q4PCH8, Q4WCR3, Q54E95, Q5ASQ0, Q5E992, Q5HHD1, Q5ZLV2, Q6GAX2, Q6GID4, Q6MWS8, Q7A1C0, Q7A6I1, Q812D3, Q8G0J9, Q8SRE1, Q8X191, Q8YHB5

Diamond homologs: D4AY02, G5EEW6, O42941, O74942, O93826, P0C196, P0C1I4, P0C1I5, P0C1I6, P0C1J0, P0C1J1, P0C1J2, P0CP84, P0CP85, P0CP86, P0CP87, P0CP88, P0CP89, P0CP90, P0CP91, P0CP92, P0CP93, P23284, P23285, P24367, P24369, P34790, P52012, P52013, P52014, P52017, P73789, P80311, P87051, Q08E11, Q09637, Q09928, Q13356, Q17QX9, Q27774

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 98 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	14	20.5×	5e-13
mRNA Polyadenylation	17	19.9×	1e-15
Processing of Capped Intron-Containing Pre-mRNA	17	18.6×	3e-15
mRNA 3’-end processing	7	18.4×	5e-06
mRNA Splicing - Major Pathway	25	18.2×	9e-23
RNA Polymerase II Transcription Termination	6	17.6×	5e-05
mRNA Splicing - Minor Pathway	5	14.9×	8e-04
CHD1 and CHD2 subfamily	9	13.1×	2e-06

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of mRNA splicing, via spliceosome	5	42.1×	2e-05
U2-type prespliceosome assembly	5	34.3×	4e-05
spliceosomal complex assembly	5	33.1×	4e-05
mRNA splicing, via spliceosome	22	22.1×	5e-21
RNA splicing	17	16.5×	8e-14
mRNA processing	12	10.4×	4e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	7
Uncertain significance	22
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1065403	NM_016059.5(PPIL1):c.280+1G>A	Likely pathogenic
1344820	NM_016059.5(PPIL1):c.233A>G (p.Tyr78Cys)	Likely pathogenic
1344821	NM_016059.5(PPIL1):c.392G>A (p.Arg131Gln)	Likely pathogenic
1344822	NM_016059.5(PPIL1):c.301_318dup (p.Ala101_Asp106dup)	Likely pathogenic
1344823	NM_016059.5(PPIL1):c.325G>T (p.Gly109Cys)	Likely pathogenic
1344824	NM_016059.5(PPIL1):c.245T>C (p.Phe82Ser)	Likely pathogenic
929944	NM_016059.5(PPIL1):c.133C>T (p.Arg45Ter)	Likely pathogenic

SpliceAI

698 predictions. Top by Δscore:

Variant	Effect	Δscore
6:36856581:CTTA:C	donor_loss	1.0000
6:36856582:TTACC:T	donor_loss	1.0000
6:36856583:TACCC:T	donor_loss	1.0000
6:36856584:A:AC	donor_gain	1.0000
6:36856584:AC:A	donor_gain	1.0000
6:36856584:ACC:A	donor_gain	1.0000
6:36856585:C:CC	donor_gain	1.0000
6:36856585:CC:C	donor_gain	1.0000
6:36856585:CCC:C	donor_gain	1.0000
6:36856659:CCGAT:C	acceptor_gain	1.0000
6:36856661:G:T	acceptor_gain	1.0000
6:36856663:T:TC	acceptor_gain	1.0000
6:36871711:A:C	donor_gain	1.0000
6:36871715:TA:T	donor_loss	1.0000
6:36871717:C:CG	donor_loss	1.0000
6:36871737:T:TA	donor_gain	1.0000
6:36871868:CCATG:C	acceptor_gain	1.0000
6:36871869:CATG:C	acceptor_gain	1.0000
6:36871869:CATGC:C	acceptor_gain	1.0000
6:36871870:ATG:A	acceptor_gain	1.0000
6:36871871:TG:T	acceptor_gain	1.0000
6:36871873:C:CC	acceptor_gain	1.0000
6:36874711:CCTCA:C	donor_loss	1.0000
6:36874712:CTCAC:C	donor_loss	1.0000
6:36874713:TCA:T	donor_loss	1.0000
6:36874714:CA:C	donor_loss	1.0000
6:36874715:ACC:A	donor_loss	1.0000
6:36874716:C:CT	donor_loss	1.0000
6:36874814:T:TA	donor_gain	1.0000
6:36856030:GCCC:G	acceptor_gain	0.9900

AlphaMissense

1094 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:36855925:C:T	G130D	0.999
6:36856027:C:T	G96E	0.999
6:36856590:G:C	F92L	0.999
6:36856590:G:T	F92L	0.999
6:36856592:A:G	F92L	0.999
6:36871749:G:C	F60L	0.999
6:36871749:G:T	F60L	0.999
6:36871751:A:G	F60L	0.999
6:36871764:T:A	R55S	0.999
6:36871764:T:G	R55S	0.999
6:36871765:C:G	R55T	0.999
6:36871769:G:C	H54D	0.999
6:36871821:A:C	C36W	0.999
6:36871822:C:T	C36Y	0.999
6:36855925:C:A	G130V	0.998
6:36855926:C:G	G130R	0.998
6:36855949:A:G	L122P	0.998
6:36855949:A:T	L122H	0.998
6:36855975:A:C	F113L	0.998
6:36855975:A:T	F113L	0.998
6:36855977:A:G	F113L	0.998
6:36855978:G:C	F112L	0.998
6:36855978:G:T	F112L	0.998
6:36855979:A:G	F112S	0.998
6:36855980:A:G	F112L	0.998
6:36855981:C:A	Q111H	0.998
6:36855981:C:G	Q111H	0.998
6:36855984:G:C	S110R	0.998
6:36855984:G:T	S110R	0.998
6:36855986:T:G	S110R	0.998

dbSNP variants (sampled 300 via entrez): RS1000115008 (6:36860852 G>A,C), RS1000152373 (6:36862870 G>T), RS1000161101 (6:36866663 A>C), RS1000300670 (6:36854558 T>C), RS1000719316 (6:36866969 C>T), RS1000760226 (6:36871785 G>A,T), RS1000899979 (6:36865220 C>T), RS1000951496 (6:36872179 T>C), RS1001053334 (6:36858131 G>A,C), RS1001486577 (6:36866574 A>C), RS1001580894 (6:36860294 G>A,C), RS1001675034 (6:36870343 A>C), RS1001690636 (6:36870033 G>T), RS1001997113 (6:36859209 G>T), RS1001997341 (6:36871365 T>C)

Disease associations

OMIM: gene MIM:601301 | disease phenotypes: MIM:619301

GenCC curated gene-disease

Disease	Classification	Inheritance
pontocerebellar hypoplasia, type 14	Strong	Autosomal recessive

Mondo (2): pontocerebellar hypoplasia, type 14 (MONDO:0030258), neurodevelopmental disorder (MONDO:0700092)

Orphanet (1): Pontocerebellar hypoplasia type 14 (Orphanet:613274)

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000238	Hydrocephalus
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001274	Agenesis of corpus callosum
HP:0001276	Hypertonia
HP:0001321	Cerebellar hypoplasia
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001348	Brisk reflexes
HP:0001522	Death in infancy
HP:0001873	Thrombocytopenia
HP:0002069	Bilateral tonic-clonic seizure
HP:0002188	Delayed CNS myelination
HP:0002365	Hypoplasia of the brainstem
HP:0002510	Spastic tetraplegia
HP:0007359	Focal-onset seizure
HP:0009879	Simplified gyral pattern
HP:0010864	Severe intellectual disability
HP:0012110	Hypoplasia of the pons
HP:0012434	Delayed early-childhood social milestone development
HP:0012469	Infantile spasms
HP:0032794	Myoclonic seizure
HP:0410252	Persistently decreased total neutrophil count

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST002481_11	Acne (severe)	2.000000e-06
GCST003818_45	Resting heart rate	1.000000e-15
GCST004715_1	Heart rate	9.000000e-07
GCST004732_8	Heart rate variability traits (pvRSA/HF)	5.000000e-15
GCST004732_9	Heart rate variability traits (pvRSA/HF)	3.000000e-15
GCST004733_5	Heart rate variability traits (RMSSD)	9.000000e-17
GCST004733_6	Heart rate variability traits (RMSSD)	6.000000e-20
GCST004734_14	Heart rate variability traits (SDNN)	2.000000e-28
GCST004734_6	Heart rate variability traits (SDNN)	4.000000e-25
GCST005787_8	Heart rate response to exercise	6.000000e-10
GCST005788_6	Heart rate response to recovery post exercise	5.000000e-06
GCST006585_592	Blood protein levels	1.000000e-21
GCST008152_167	Weight	7.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0008003	heart rate variability measurement
EFO:0009184	heart rate response to exercise
EFO:0009185	heart rate response to recovery post exercise
EFO:0004338	body weight

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291529 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
GSK-J4	decreases expression	1
bisphenol F	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	decreases expression	1
lead acetate	affects cotreatment, decreases expression	1
trichostatin A	affects expression	1
zinc protoporphyrin	affects cotreatment, decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
HC toxin	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
yessotoxin	decreases expression	1
4-phenylbutyric acid	decreases expression	1
azoxystrobin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
apicidin	decreases expression	1
deguelin	decreases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
pyrachlostrobin	decreases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
picoxystrobin	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	increases methylation	1
Acetaminophen	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5253377	Binding	Inhibition of PPIL1 (unknown origin)	Peptidyl-Proline Isomerases (PPIases): Targets for Natural Products and Natural Product-Inspired Compounds. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TF32	HAP1 PPIL1 (-) 1	Cancer cell line	Male
CVCL_XR79	HAP1 PPIL1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

202 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
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
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice