PPIL2

Summary

PPIL2 (peptidylprolyl isomerase like 2, HGNC:9261) is a protein-coding gene on chromosome 22q11.21, encoding RING-type E3 ubiquitin-protein ligase PPIL2 (Q13356). Has a ubiquitin-protein ligase activity acting as an E3 ubiquitin protein ligase or as an ubiquitin-ubiquitin ligase promoting elongation of ubiquitin chains on substrates. It is a common-essential gene (DepMap: required in 97.8% of cancer cell lines).

This gene is a member of the cyclophilin family of peptidylprolyl isomerases. 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. This protein interacts with the proteinase inhibitor eglin c and is localized in the nucleus. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 23759 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 128 total
• Phenotypes (HPO): 1
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 97.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_014337

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9261
Approved symbol	PPIL2
Name	peptidylprolyl isomerase like 2
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Aliases	UBOX7, CYC4, Cyp-60
Ensembl gene	ENSG00000100023
Ensembl biotype	protein_coding
OMIM	607588
Entrez	23759

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 18 retained_intron, 17 protein_coding, 8 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000335025, ENST00000398831, ENST00000406385, ENST00000417788, ENST00000446951, ENST00000458567, ENST00000462188, ENST00000484439, ENST00000485930, ENST00000496819, ENST00000498109, ENST00000626352, ENST00000679477, ENST00000679479, ENST00000679534, ENST00000679540, ENST00000679564, ENST00000679580, ENST00000679586, ENST00000679692, ENST00000679795, ENST00000679827, ENST00000679857, ENST00000680022, ENST00000680061, ENST00000680094, ENST00000680109, ENST00000680113, ENST00000680183, ENST00000680393, ENST00000680426, ENST00000680434, ENST00000680463, ENST00000680573, ENST00000680860, ENST00000680962, ENST00000681027, ENST00000681137, ENST00000681286, ENST00000681338, ENST00000681353, ENST00000681394, ENST00000681612, ENST00000681735, ENST00000681791, ENST00000681956

RefSeq mRNA: 4 — MANE Select: NM_014337 NM_001317996, NM_014337, NM_148175, NM_148176

CCDS: CCDS13793, CCDS46670

Canonical transcript exons

ENST00000398831 — 20 exons

Exon	Start	End
ENSE00001651605	21695394	21697907
ENSE00003469627	21670566	21670611
ENSE00003530147	21684753	21684913
ENSE00003537909	21682437	21682526
ENSE00003601511	21672330	21672381
ENSE00003607932	21675064	21675115
ENSE00003625341	21683182	21683257
ENSE00003640331	21670997	21671059
ENSE00003677859	21669913	21669962
ENSE00003703317	21688073	21688106
ENSE00003703679	21693816	21693872
ENSE00003705363	21694755	21694817
ENSE00003706452	21688732	21688849
ENSE00003707868	21694937	21695070
ENSE00003709824	21686892	21686998
ENSE00003710225	21687643	21687732
ENSE00003710901	21694593	21694665
ENSE00003711192	21686483	21686558
ENSE00003784657	21681299	21681390
ENSE00003849845	21666012	21666131

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 94.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.0030 / max 418.1079, expressed in 1815 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191197	41.5711	1815
191198	0.9411	581
191199	0.4908	212

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of thyroid gland	UBERON:0001119	94.03	gold quality
left lobe of thyroid gland	UBERON:0001120	93.91	gold quality
granulocyte	CL:0000094	93.51	gold quality
body of pancreas	UBERON:0001150	92.96	gold quality
thyroid gland	UBERON:0002046	92.93	gold quality
lower esophagus mucosa	UBERON:0035834	92.85	gold quality
metanephros cortex	UBERON:0010533	92.52	gold quality
mucosa of stomach	UBERON:0001199	91.77	gold quality
minor salivary gland	UBERON:0001830	91.63	gold quality
apex of heart	UBERON:0002098	91.50	gold quality
esophagus mucosa	UBERON:0002469	91.22	gold quality
saliva-secreting gland	UBERON:0001044	91.20	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.86	gold quality
body of stomach	UBERON:0001161	90.85	gold quality
nipple	UBERON:0002030	90.75	gold quality
adenohypophysis	UBERON:0002196	90.62	gold quality
transverse colon	UBERON:0001157	90.50	gold quality
skin of leg	UBERON:0001511	90.41	gold quality
mucosa of transverse colon	UBERON:0004991	90.18	gold quality
right adrenal gland cortex	UBERON:0035827	90.18	gold quality
triceps brachii	UBERON:0001509	90.17	gold quality
gluteal muscle	UBERON:0002000	90.01	gold quality
skin of abdomen	UBERON:0001416	90.00	gold quality
stomach	UBERON:0000945	89.90	gold quality
mouth mucosa	UBERON:0003729	89.90	gold quality
esophagus	UBERON:0001043	89.89	gold quality
right adrenal gland	UBERON:0001233	89.88	gold quality
left adrenal gland	UBERON:0001234	89.83	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.82	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.77	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.59

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA3

miRNA regulators (miRDB)

63 targeting PPIL2, 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-4692	100.00	67.32	2066
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-520E-5P	99.27	68.90	1513
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-1253	99.12	67.08	1688
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-4478	99.07	65.16	2320

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 2)

• cyclophilin 60 regulates cell surface expression of CD147/EMMPRIN (PMID:15946952)
• common genetic variation in the BACE1-interacting proteins, RTN3 an PPIL2, does not influence platelet b-secretase activity or susceptibility to Alzheimer’s disease in this population. (PMID:19669607)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppil2	ENSDARG00000002016
mus_musculus	Ppil2	ENSMUSG00000022771
rattus_norvegicus	Ppil2	ENSRNOG00000026900
rattus_norvegicus		ENSRNOG00000071960
rattus_norvegicus		ENSRNOG00000080472
drosophila_melanogaster	CG7747	FBGN0034109
caenorhabditis_elegans		WBGENE00000880

Paralogs (22): PPIE (ENSG00000084072), PPIF (ENSG00000108179), PPWD1 (ENSG00000113593), NKTR (ENSG00000114857), PPIL4 (ENSG00000131013), PPIL1 (ENSG00000137168), 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

RING-type E3 ubiquitin-protein ligase PPIL2 — Q13356 (reviewed: Q13356)

Alternative names: CYC4, Cyclophilin-60, Probable inactive peptidyl-prolyl cis-trans isomerase-like 2, Rotamase PPIL2

All UniProt accessions (14): Q13356, A0A7P0T839, A0A7P0T843, A0A7P0T896, A0A7P0T8E8, A0A7P0T8P6, A0A7P0T9A5, A0A7P0TA15, A0A7P0TAH4, A0A7P0TB19, A0A7P0TBL3, A0A7P0Z4K4, C9JDF0, F8WC56

UniProt curated annotations — full annotation on UniProt →

Function. Has a ubiquitin-protein ligase activity acting as an E3 ubiquitin protein ligase or as an ubiquitin-ubiquitin ligase promoting elongation of ubiquitin chains on substrates. By mediating ‘Lys-48’-linked polyubiquitination of proteins could target them for proteasomal degradation. May also function as a chaperone, playing a role in transport to the cell membrane of BSG/Basigin for instance. Probable inactive PPIase with no peptidyl-prolyl cis-trans isomerase activity. As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs.

Subunit / interactions. Component of the minor spliceosome, which splices U12-type introns. Within this complex, interacts with PRPF8/PRP8, EFTUD2/SNU114 and PLRG1. Interacts with isoform 2 of BSG. Interacts (via the PPIase cyclophilin-type domain) with CRNKL1; they may form a trimeric complex with HSP90.

Subcellular location. Nucleus.

Tissue specificity. Highest expression in thymus, pancreas and testis. Also detected in heart, placenta, lung, liver, skeletal muscle, kidney, spleen, prostate, ovary, small intestine and colon. Poorly detected in brain and leukocytes. Strong protein expression in lymph node (cortical, paracortical and medullar regions), thyroid (follicular epithelial cells), testis (developing spermatozoa), stomach (cells lining the gastric pit), pancreas, kidney (proximal and distal-tubule cells and collecting duct cells but not in glomeruli), endometrium and colon (goblet cells). Moderate protein expression in spleen, prostate (epithelium and squamous cell carcinomas), placenta and adrenal gland. Weak protein expression in liver, heart, breast, ovary, and lung. No protein expression in brain and bladder. High protein expression in most lymphomas and melanomas.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the cyclophilin-type PPIase family. PPIL2 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13356-1	1	yes
Q13356-2	2

RefSeq proteins (4): NP_001304925, NP_055152, NP_680480, NP_680481 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002130	Cyclophilin-type_PPIase_dom	Domain
IPR003613	Ubox_domain	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR020892	Cyclophilin-type_PPIase_CS	Conserved_site
IPR026951	PPIL2_U-box_dom	Domain
IPR029000	Cyclophilin-like_dom_sf	Homologous_superfamily
IPR044666	Cyclophilin_A-like	Family

Pfam: PF00160

UniProt features (62 total): strand 27, helix 13, turn 9, domain 2, mutagenesis site 2, modified residue 2, chain 1, sequence conflict 1, region of interest 1, coiled-coil region 1, compositionally biased region 1, cross-link 1, splice variant 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
1ZKC	X-RAY DIFFRACTION	1.65
7DVQ	ELECTRON MICROSCOPY	2.89
8I0R	ELECTRON MICROSCOPY	3
8I0T	ELECTRON MICROSCOPY	3
7QTT	ELECTRON MICROSCOPY	3.1
9R3D	ELECTRON MICROSCOPY	3.12
8I0P	ELECTRON MICROSCOPY	3.4
8I0S	ELECTRON MICROSCOPY	4.2
8CH6	ELECTRON MICROSCOPY	5.9
7ABI	ELECTRON MICROSCOPY	8
9R8V	ELECTRON MICROSCOPY	8.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13356-F1	81.45	0.41

Functional residue map

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

Post-translational modifications (3): 470, 482, 216

Mutagenesis-validated functional residues (2):

Position	Phenotype
389	no peptidyl-prolyl cis-trans isomerase activity; enables interaction with cyclosporin a.
389	gain of a peptidyl-prolyl cis-trans isomerase activity; enables interaction with cyclosporin a.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-210991	Basigin interactions
R-HSA-72163	mRNA Splicing - Major Pathway

MSigDB gene sets: 151 (showing top): WANG_CLIM2_TARGETS_UP, YAGI_AML_WITH_INV_16_TRANSLOCATION, MORF_ATRX, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, CAGCAGG_MIR370, GOBP_PROTEIN_MATURATION, MORF_FANCG, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, GOBP_RNA_SPLICING, LIAO_METASTASIS, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEIN_FOLDING, GOBP_PROTEIN_POLYUBIQUITINATION, REACTOME_MRNA_SPLICING, KEGG_UBIQUITIN_MEDIATED_PROTEOLYSIS

GO Biological Process (7): protein polyubiquitination (GO:0000209), mRNA processing (GO:0006397), protein folding (GO:0006457), RNA splicing (GO:0008380), protein localization to plasma membrane (GO:0072659), protein peptidyl-prolyl isomerization (GO:0000413), protein ubiquitination (GO:0016567)

GO Molecular Function (7): ubiquitin-ubiquitin ligase activity (GO:0034450), ubiquitin protein ligase activity (GO:0061630), peptidyl-prolyl cis-trans isomerase activity (GO:0003755), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740), isomerase activity (GO:0016853)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), Golgi lumen (GO:0005796), plasma membrane (GO:0005886), catalytic step 2 spliceosome (GO:0071013), spliceosomal complex (GO:0005681)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Cell surface interactions at the vascular wall	1
mRNA Splicing	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	2
catalytic activity	2
cellular anatomical structure	2
protein ubiquitination	1
mRNA metabolic process	1
cellular process	1
protein maturation	1
protein localization to membrane	1
protein localization to cell periphery	1
peptidyl-proline modification	1
protein modification by small protein conjugation	1
ubiquitin protein ligase activity	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
cis-trans isomerase activity	1
catalytic activity, acting on a protein	1
ubiquitin-like protein transferase activity	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
Golgi apparatus	1
intracellular organelle lumen	1
membrane	1
cell periphery	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

2684 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPIL2	BSG	P35613	643
PPIL2	PRPF19	Q9UMS4	498
PPIL2	PRCC	Q92733	497
PPIL2	DHX38	Q92620	457
PPIL2	SNAPC3	Q92966	444
PPIL2	ASCC2	Q9H1I8	436
PPIL2	KANSL2	Q9H9L4	431
PPIL2	TCF15	Q12870	421
PPIL2	ZNF830	Q96NB3	420
PPIL2	SDC1	P18827	418
PPIL2	UBOX5	O94941	417
PPIL2	KANK2	Q63ZY3	411
PPIL2	PPIA	P05092	408
PPIL2	CRNKL1	Q9BZJ0	394
PPIL2	MED15	Q96RN5	391

IntAct

72 interactions, top by confidence:

A	B	Type	Score
CDK8	MED19	psi-mi:“MI:2364”(proximity)	0.850
CDA	LIN7A	psi-mi:“MI:0914”(association)	0.640
FGL1	LCMT2	psi-mi:“MI:0914”(association)	0.640
ZNF830	PPIL2	psi-mi:“MI:0915”(physical association)	0.630
PPIL2	ZNF830	psi-mi:“MI:0915”(physical association)	0.630
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
PPIL2	TRIM23	psi-mi:“MI:0915”(physical association)	0.560
TRIM23	PPIL2	psi-mi:“MI:0915”(physical association)	0.560
BAIAP2	WASL	psi-mi:“MI:0914”(association)	0.550
KLC2	KIF5B	psi-mi:“MI:0914”(association)	0.530
FKBP6	EEF2K	psi-mi:“MI:0914”(association)	0.530
NAGK	ZBTB43	psi-mi:“MI:0914”(association)	0.530
PPIL2	YWHAH	psi-mi:“MI:0914”(association)	0.530
PPIL2	DCAF10	psi-mi:“MI:0915”(physical association)	0.500
PPIL2	DCAF10	psi-mi:“MI:0914”(association)	0.500
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
PPIL2	KANSL2	psi-mi:“MI:0915”(physical association)	0.400
PPIL2	PRCC	psi-mi:“MI:0915”(physical association)	0.370
Racgap1	DDX3X	psi-mi:“MI:0914”(association)	0.350
Smad3		psi-mi:“MI:0914”(association)	0.350
Naa15	TBX3	psi-mi:“MI:0914”(association)	0.350
Ccdc12	PLRG1	psi-mi:“MI:0914”(association)	0.350
PDGFRA	RNPS1	psi-mi:“MI:0914”(association)	0.350
PIM2	NUP98	psi-mi:“MI:0914”(association)	0.350
KLC3	KLC1	psi-mi:“MI:0914”(association)	0.350
VPS26B	KIF1B	psi-mi:“MI:0914”(association)	0.350

BioGRID (131): PPIL2 (Two-hybrid), PPIL2 (Affinity Capture-MS), PPIL2 (Affinity Capture-MS), PPIL2 (Affinity Capture-MS), PPIL2 (Affinity Capture-MS), PPIL2 (Proximity Label-MS), PPIL2 (Affinity Capture-MS), PPIL2 (Affinity Capture-MS), PPIL2 (Affinity Capture-MS), PPIL2 (Affinity Capture-MS), PPIL2 (Affinity Capture-MS), PPIL2 (Affinity Capture-MS), KANSL2 (Affinity Capture-MS), PPIL2 (Affinity Capture-MS), PPIL2 (Affinity Capture-MS)

ESM2 similar proteins: A4FV72, D4AY02, O49605, O93826, P0C1I0, P0C1I1, P0C1I2, P0C1J0, P0CP79, P10255, P23285, P25007, P26882, P34791, P35176, P47103, P53691, Q08752, Q11004, Q13356, Q1RMP7, Q26548, Q27774, Q2TZ33, Q2U0E0, Q2UGK2, Q4G338, Q4HXF6, Q4WIF3, Q5ACI8, Q5B4E7, Q5B4R3, Q5R723, Q5U8Z7, Q6BXZ7, Q6CBP4, Q6CL78, Q6DGG0, Q6FNU6, Q8IXY8

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 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
SARS-CoV-1-host interactions	7	19.2×	4e-06
Kinesins	6	16.7×	5e-05
mRNA Splicing	9	15.4×	4e-07
mRNA 3’-end processing	5	15.4×	3e-04
Transport of Mature mRNA derived from an Intron-Containing Transcript	6	14.3×	1e-04
Processing of Capped Intron-Containing Pre-mRNA	11	14.1×	4e-08
mRNA Splicing - Major Pathway	16	13.7×	9e-12
SARS-CoV-1 Infection	6	13.4×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
chondrocyte differentiation	5	18.1×	7e-04
microtubule-based movement	5	17.8×	7e-04
mRNA splicing, via spliceosome	14	15.4×	2e-10
RNA splicing	11	11.7×	7e-07
mRNA processing	9	8.5×	2e-04
intracellular protein localization	6	7.6×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	95
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3467 predictions. Top by Δscore:

Variant	Effect	Δscore
22:21666130:AT:A	donor_gain	1.0000
22:21666130:ATG:A	donor_loss	1.0000
22:21666131:TGTA:T	donor_loss	1.0000
22:21666132:G:GG	donor_gain	1.0000
22:21666132:GTAA:G	donor_loss	1.0000
22:21670609:CAGGT:C	donor_loss	1.0000
22:21670612:G:A	donor_loss	1.0000
22:21670613:T:A	donor_loss	1.0000
22:21672382:G:GC	donor_loss	1.0000
22:21672383:T:A	donor_loss	1.0000
22:21681295:CTA:C	acceptor_loss	1.0000
22:21681297:A:AG	acceptor_gain	1.0000
22:21681297:AG:A	acceptor_gain	1.0000
22:21681298:G:GA	acceptor_loss	1.0000
22:21681298:G:GG	acceptor_gain	1.0000
22:21681298:GG:G	acceptor_gain	1.0000
22:21681298:GGGA:G	acceptor_gain	1.0000
22:21681298:GGGAA:G	acceptor_gain	1.0000
22:21681390:GGTG:G	donor_loss	1.0000
22:21681391:G:GG	donor_gain	1.0000
22:21681391:GTGT:G	donor_loss	1.0000
22:21682428:T:TA	acceptor_gain	1.0000
22:21682429:G:A	acceptor_gain	1.0000
22:21682432:TATA:T	acceptor_loss	1.0000
22:21682435:A:AG	acceptor_gain	1.0000
22:21682436:G:GG	acceptor_gain	1.0000
22:21682436:GGCA:G	acceptor_gain	1.0000
22:21682522:TCCAG:T	donor_gain	1.0000
22:21682523:CCAG:C	donor_gain	1.0000
22:21682523:CCAGG:C	donor_loss	1.0000

AlphaMissense

3463 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:21681310:T:C	C103R	0.999
22:21666115:C:G	H6D	0.998
22:21666124:G:C	D9H	0.998
22:21670609:C:G	C42W	0.998
22:21686507:A:C	S247R	0.998
22:21686509:C:A	S247R	0.998
22:21686509:C:G	S247R	0.998
22:21688809:A:C	S367R	0.998
22:21688811:C:A	S367R	0.998
22:21688811:C:G	S367R	0.998
22:21693869:G:A	G398E	0.998
22:21666129:A:C	K10N	0.997
22:21666129:A:T	K10N	0.997
22:21669914:T:G	Y12D	0.997
22:21670607:T:C	C42R	0.997
22:21681312:C:G	C103W	0.997
22:21681377:T:A	V125D	0.997
22:21682450:T:C	L134P	0.997
22:21686522:T:C	S252P	0.997
22:21687663:C:A	N306K	0.997
22:21687663:C:G	N306K	0.997
22:21687727:T:C	F328L	0.997
22:21687729:T:A	F328L	0.997
22:21687729:T:G	F328L	0.997
22:21666104:G:A	G2E	0.996
22:21666125:A:T	D9V	0.996
22:21669918:T:A	I13N	0.996
22:21688788:C:G	H360D	0.996
22:21669930:A:T	E17V	0.995
22:21670608:G:A	C42Y	0.995

dbSNP variants (sampled 300 via entrez): RS1000049776 (22:21673857 T>C), RS1000081292 (22:21683077 C>T), RS1000116470 (22:21666557 A>C), RS1000131533 (22:21677449 C>T), RS1000171044 (22:21667068 G>C), RS1000275386 (22:21672883 TGGAGCCGCTGGGAG>T), RS1000284225 (22:21693080 C>T), RS1000339705 (22:21696006 A>AC), RS1000431713 (22:21682924 C>T), RS1000453471 (22:21665373 A>G), RS1000456484 (22:21679042 A>C,G), RS1000623611 (22:21668879 T>C), RS1000806198 (22:21697310 A>T), RS1000854385 (22:21677635 G>A,C), RS1000873665 (22:21696266 G>A,C)

Disease associations

OMIM: gene MIM:607588 | disease phenotypes: MIM:209850

GenCC curated gene-disease

Mondo (1): autism (MONDO:0005260)

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
GCST006196_5	Type 1 diabetes in high risk HLA genotype individuals (time to event)	2.000000e-06
GCST006197_3	Type 1 diabetes autoantibodies in high risk HLA genotype individuals (time to event)	1.000000e-06
GCST008103_64	Bipolar disorder	6.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0000409	disease free survival
EFO:0000482	event free survival time
EFO:0004866	autoantibody measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725170 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation, decreases expression, increases abundance, increases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
p-Chloromercuribenzoic Acid	decreases expression, affects cotreatment	2
GSK-J4	decreases expression	1
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
bisphenol A	increases expression	1
methylselenic acid	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
Acrolein	affects cotreatment, increases expression, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Methotrexate	decreases expression	1
Ozone	affects cotreatment, increases expression, increases abundance	1
Selenium	increases expression	1
Smoke	decreases expression	1
Thimerosal	decreases expression	1
Thiram	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697403	Binding	Inhibition of PPIL2 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
NCT00541346	PHASE3	COMPLETED	A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD) Symptoms