DIS3L2

Summary

DIS3L2 (DIS3 like 3’-5’ exoribonuclease 2, HGNC:28648) is a protein-coding gene on chromosome 2q37.1, encoding DIS3-like exonuclease 2 (Q8IYB7). 3’-5’-exoribonuclease that specifically recognizes RNAs polyuridylated at their 3’ end and mediates their degradation.

The protein encoded by this gene is similar in sequence to 3’/5’ exonucleolytic subunits of the RNA exosome. The exosome is a large multimeric ribonucleotide complex responsible for degrading various RNA substrates. Several transcript variants, some protein-coding and some not, have been found for this gene.

Source: NCBI Gene 129563 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Perlman syndrome (Definitive, ClinGen)
• GWAS associations: 49
• Clinical variants (ClinVar): 2,372 total — 72 pathogenic, 45 likely-pathogenic
• Phenotypes (HPO): 87
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_152383

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28648
Approved symbol	DIS3L2
Name	DIS3 like 3’-5’ exoribonuclease 2
Location	2q37.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ36974, MGC42174
Ensembl gene	ENSG00000144535
Ensembl biotype	protein_coding
OMIM	614184
Entrez	129563

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 13 protein_coding, 3 nonsense_mediated_decay, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000273009, ENST00000325385, ENST00000390005, ENST00000409401, ENST00000417808, ENST00000418143, ENST00000429283, ENST00000433430, ENST00000434477, ENST00000441279, ENST00000445090, ENST00000464554, ENST00000470087, ENST00000498319, ENST00000869867, ENST00000869868, ENST00000869869, ENST00000922475, ENST00000922476, ENST00000941576

RefSeq mRNA: 3 — MANE Select: NM_152383 NM_001257281, NM_001257282, NM_152383

CCDS: CCDS42834, CCDS58752, CCDS58753

Canonical transcript exons

ENST00000325385 — 21 exons

Exon	Start	End
ENSE00001342665	231961713	231961765
ENSE00001667970	232336469	232337192
ENSE00001690037	232015514	232015671
ENSE00001795680	232014835	232014979
ENSE00003467451	232329813	232329996
ENSE00003482301	232136472	232136719
ENSE00003490869	232029979	232030080
ENSE00003503006	232335773	232335874
ENSE00003543192	232334369	232334499
ENSE00003560436	232263207	232263440
ENSE00003562115	232300040	232300119
ENSE00003562152	232163459	232163632
ENSE00003562327	232334631	232334735
ENSE00003600176	232249239	232249346
ENSE00003612789	232238533	232238645
ENSE00003618582	232024277	232024330
ENSE00003624902	232130619	232130719
ENSE00003625183	232087487	232087721
ENSE00003650144	232330690	232330776
ENSE00003665188	232333840	232333987
ENSE00003677882	232210326	232210405

Expression profiles

Bgee: expression breadth ubiquitous, 241 present calls, max score 93.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.3014 / max 244.0114, expressed in 1799 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25942	15.8908	1799
25941	0.4107	215

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	93.39	gold quality
sperm	CL:0000019	92.43	gold quality
buccal mucosa cell	CL:0002336	91.77	gold quality
lower esophagus mucosa	UBERON:0035834	90.72	gold quality
right uterine tube	UBERON:0001302	90.57	gold quality
right lobe of thyroid gland	UBERON:0001119	88.43	gold quality
adrenal tissue	UBERON:0018303	88.28	gold quality
right testis	UBERON:0004534	88.19	gold quality
left testis	UBERON:0004533	88.11	gold quality
cortical plate	UBERON:0005343	87.57	gold quality
calcaneal tendon	UBERON:0003701	87.52	gold quality
left lobe of thyroid gland	UBERON:0001120	87.51	gold quality
left ovary	UBERON:0002119	86.80	gold quality
right ovary	UBERON:0002118	86.77	gold quality
thyroid gland	UBERON:0002046	86.73	gold quality
bone marrow cell	CL:0002092	86.70	gold quality
skin of abdomen	UBERON:0001416	86.40	gold quality
testis	UBERON:0000473	86.21	gold quality
skin of leg	UBERON:0001511	86.11	gold quality
ectocervix	UBERON:0012249	86.07	gold quality
colonic epithelium	UBERON:0000397	86.02	gold quality
esophagus mucosa	UBERON:0002469	85.99	gold quality
ganglionic eminence	UBERON:0004023	85.85	gold quality
embryo	UBERON:0000922	85.84	gold quality
endocervix	UBERON:0000458	85.76	gold quality
right hemisphere of cerebellum	UBERON:0014890	85.39	gold quality
body of uterus	UBERON:0009853	85.15	gold quality
esophagus	UBERON:0001043	85.08	gold quality
granulocyte	CL:0000094	85.00	gold quality
adenohypophysis	UBERON:0002196	84.98	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.83
E-MTAB-7303	no	129.40

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

46 targeting DIS3L2, 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-3925-3P	100.00	69.95	1237
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-6852-5P	99.17	66.69	2073

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 15)

• Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility. (PMID:22306653)
• in cellular models DIS3L2 knockdown is associated with abnormalities of cell growth and division (PMID:23613427)
• DIS3L2 is the missing component of the LIN28-TUT4/7-DIS3L2 pathway required for the repression of let-7 in pluripotent cells. (PMID:24141620)
• DIS3L2 interacts with Ago2 and governs target RNA-directed miRNA degradation. (PMID:26809675)
• these results indicate that catalytically inactive DIS3L2, characteristic of Perlman syndrome, can lead to deregulation of its target RNAs to disturb transcriptome homeostasis. (PMID:27431325)
• Our findings establish the role of DIS3L2 and oligouridylation as the cytoplasmic quality control for highly structured ncRNAs (PMID:27647875)
• The evidence has been presented that Dis3l2 controls miRNA-9 production. (PMID:27881476)
• Studies indicate important roles of the exoribonucleases DIS3L2 and XRN1 in cellular function, viability and disease. (PMID:27911720)
• These findings suggest that sequestration of the exoribonucleases DIS3L2 and XRN1 to nuclear inclusions may be related to the pathogenesis of intranuclear inclusion body disease (PMID:29100804)
• our findings uncover an oncogenic role of DIS3L2, in which it promotes liver cancer progression through a previously unappreciated mechanism of regulating hnRNP U-mediated alterative splicing (PMID:31331910)
• Findings indicate a role for DIS3 like 3’-5’ exoribonuclease 2 (DIS3L2) and uridylation in nonsense-mediated mRNA decay (NMD). (PMID:31466720)
• DIS3L2 and LSm proteins are involved in the surveillance of Sm ring-deficient snRNAs. (PMID:32374871)
• The Perlman syndrome DIS3L2 exoribonuclease safeguards endoplasmic reticulum-targeted mRNA translation and calcium ion homeostasis. (PMID:32457326)
• AGO-bound mature miRNAs are oligouridylated by TUTs and subsequently degraded by DIS3L2. (PMID:32488030)
• DIS3L2 knockdown impairs key oncogenic properties of colorectal cancer cells via the mTOR signaling pathway. (PMID:37340282)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dis3l2	ENSDARG00000033259
mus_musculus	Dis3l2	ENSMUSG00000053333
rattus_norvegicus	Dis3l2	ENSRNOG00000018931
drosophila_melanogaster	Dis3l2	FBGN0035111
caenorhabditis_elegans		WBGENE00018612

Paralogs (2): DIS3 (ENSG00000083520), DIS3L (ENSG00000166938)

Protein

Protein identifiers

DIS3-like exonuclease 2 — Q8IYB7 (reviewed: Q8IYB7)

All UniProt accessions (5): Q8IYB7, C9JGP4, H7C036, H7C1Q8, H7C302

UniProt curated annotations — full annotation on UniProt →

Function. 3’-5’-exoribonuclease that specifically recognizes RNAs polyuridylated at their 3’ end and mediates their degradation. Component of an exosome-independent RNA degradation pathway that mediates degradation of both mRNAs and miRNAs that have been polyuridylated by a terminal uridylyltransferase, such as ZCCHC11/TUT4. Mediates degradation of cytoplasmic mRNAs that have been deadenylated and subsequently uridylated at their 3’. Mediates degradation of uridylated pre-let-7 miRNAs, contributing to the maintenance of embryonic stem (ES) cells. Essential for correct mitosis, and negatively regulates cell proliferation.

Subunit / interactions. Interacts with XRN1.

Subcellular location. Cytoplasm. P-body.

Disease relevance. Perlman syndrome (PRLMNS) [MIM:267000] An autosomal recessive congenital overgrowth syndrome. Affected children are large at birth, are hypotonic, and show organomegaly, characteristic facial dysmorphisms (inverted V-shaped upper lip, prominent forehead, deep-set eyes, broad and flat nasal bridge, and low-set ears), renal anomalies (nephromegaly and hydronephrosis), frequent neurodevelopmental delay, and high neonatal mortality. Perlman syndrome is associated with a high risk of Wilms tumor. Histologic examination of the kidneys in affected children shows frequent nephroblastomatosis, which is a precursor lesion for Wilms tumor. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Specifically recognizes and binds polyuridylated RNAs via 3 RNA-binding regions (named U-zone 1, U-zone 2 and U-zone 3) that form an open funnel on one face of the catalytic domain, allowing RNA to navigate a path to the active site.

Polymorphism. Disrupted by a t(2;7)(q37.1;q21.3) chromosomal translocation found in a patient suffering from Marfanoid habitus and skeletal anomalies. However, its absence does not seem to be the cause of the disease.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the RNR ribonuclease family. DIS3L2 subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8IYB7-1	1	yes
Q8IYB7-2	2
Q8IYB7-3	3
Q8IYB7-4	4
Q8IYB7-5	5

RefSeq proteins (3): NP_001244210, NP_001244211, NP_689596* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001900	RNase_II/R	Domain
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR022966	RNase_II/R_CS	Conserved_site
IPR028591	DIS3L2	Family
IPR033771	Rrp44_CSD1	Domain
IPR041093	Dis3l2-like_C	Domain
IPR041505	Dis3_CSD2	Domain
IPR050180	RNR_Ribonuclease	Family

Pfam: PF00773, PF17216, PF17849, PF17877

UniProt features (91 total): strand 36, helix 18, turn 10, splice variant 8, sequence variant 5, modified residue 4, region of interest 2, sequence conflict 2, binding site 2, chain 1, mutagenesis site 1, compositionally biased region 1, site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8E2A	ELECTRON MICROSCOPY	2.8
8E28	ELECTRON MICROSCOPY	3.1
8E29	ELECTRON MICROSCOPY	3.1
8E27	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IYB7-F1	83.26	0.72

Functional residue map

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

Catalytic / active sites (1): 391 (important for catalytic activity)

Ligand- & substrate-binding residues (2): 383; 392

Post-translational modifications (4): 875, 31, 173, 252

Mutagenesis-validated functional residues (1):

Position	Phenotype
391	loss of exoribonuclease activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9820865	Z-decay: degradation of maternal mRNAs by zygotically expressed factors

MSigDB gene sets: 331 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOMF_NUCLEASE_ACTIVITY, AAGCCAT_MIR135A_MIR135B, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CHROMOSOME_SEPARATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, CEBP_Q2, GOBP_ORGANELLE_FISSION, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, GOBP_MITOTIC_NUCLEAR_DIVISION, GOBP_MAINTENANCE_OF_CELL_NUMBER, GOBP_MITOTIC_CELL_CYCLE

GO Biological Process (9): mitotic cell cycle (GO:0000278), nuclear-transcribed mRNA catabolic process (GO:0000956), mRNA catabolic process (GO:0006402), negative regulation of cell population proliferation (GO:0008285), miRNA catabolic process (GO:0010587), stem cell population maintenance (GO:0019827), cell division (GO:0051301), mitotic sister chromatid separation (GO:0051306), polyuridylation-dependent mRNA catabolic process (GO:1990074)

GO Molecular Function (10): 3’-5’-RNA exonuclease activity (GO:0000175), magnesium ion binding (GO:0000287), RNA nuclease activity (GO:0004540), poly(U) RNA binding (GO:0008266), RNA binding (GO:0003723), nuclease activity (GO:0004518), exonuclease activity (GO:0004527), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (2): P-body (GO:0000932), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Maternal to zygotic transition (MZT)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mRNA catabolic process	2
RNA catabolic process	2
nuclease activity	2
cell cycle	1
mitotic nuclear division	1
negative regulation of gene expression	1
mRNA metabolic process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
miRNA metabolic process	1
multicellular organismal process	1
maintenance of cell number	1
cellular process	1
mitotic sister chromatid segregation	1
chromosome separation	1
mitotic cell cycle process	1
modification-dependent macromolecule catabolic process	1
mRNA destabilization	1
3’-5’ exonuclease activity	1
RNA exonuclease activity, producing 5’-phosphomonoesters	1
metal ion binding	1
catalytic activity, acting on RNA	1
poly-pyrimidine tract binding	1
nucleic acid binding	1
catalytic activity, acting on a nucleic acid	1
hydrolase activity, acting on ester bonds	1
binding	1
catalytic activity	1
cation binding	1
cytoplasmic ribonucleoprotein granule	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3104 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DIS3L2	TUT4	Q5TAX3	885
DIS3L2	TUT7	Q5VYS8	814
DIS3L2	EXOSC10	Q01780	805
DIS3L2	TUT1	Q9H6E5	763
DIS3L2	LIN28A	Q9H9Z2	762
DIS3L2	XRN1	Q8IZH2	726
DIS3L2	TENT2	Q6PIY7	632
DIS3L2	MTREX	P42285	621
DIS3L2	EXOSC3	Q9NQT5	613
DIS3L2	DICER1	Q9UPY3	592
DIS3L2	PARN	O95453	591
DIS3L2	EXOSC4	Q9NPD3	587
DIS3L2	TENT4B	Q8NDF8	587
DIS3L2	XRN2	Q9H0D6	585
DIS3L2	ERI1	Q8IV48	580

IntAct

22 interactions, top by confidence:

A	B	Type	Score
LIN28A	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
DIS3L2	PDIA3	psi-mi:“MI:0915”(physical association)	0.400
Mad2l1	MAD1L1	psi-mi:“MI:0914”(association)	0.350
Wipi2	MACF1	psi-mi:“MI:0914”(association)	0.350
CBX2	TRANK1	psi-mi:“MI:0914”(association)	0.350
	POLR3A	psi-mi:“MI:0914”(association)	0.350
	POLRMT	psi-mi:“MI:0914”(association)	0.350
RTP3	CASC3	psi-mi:“MI:0914”(association)	0.350
CACNG8	CLTCL1	psi-mi:“MI:0914”(association)	0.350
RPLP0	ZNF320	psi-mi:“MI:0914”(association)	0.350
H2AC11		psi-mi:“MI:0914”(association)	0.350
SRSF6	MPHOSPH10	psi-mi:“MI:0914”(association)	0.350
TICAM1	INPPL1	psi-mi:“MI:0914”(association)	0.350
IFIT5	CAND2	psi-mi:“MI:0914”(association)	0.350
NAT10	DIS3L2	psi-mi:“MI:0914”(association)	0.350
PEX7	UBA6	psi-mi:“MI:0914”(association)	0.350
SPIN4	DIS3L2	psi-mi:“MI:0914”(association)	0.350
DIS3L2	COPS6	psi-mi:“MI:0915”(physical association)	0.000
DIS3L2	FEZ1	psi-mi:“MI:0915”(physical association)	0.000
DIS3L2	VIM	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (41): DIS3L2 (Affinity Capture-MS), DIS3L2 (Affinity Capture-MS), DIS3L2 (Co-fractionation), DIS3L2 (Affinity Capture-MS), DIS3L2 (Affinity Capture-MS), DIS3L2 (Affinity Capture-MS), DIS3L2 (Affinity Capture-MS), DIS3L2 (Affinity Capture-RNA), COPS6 (Two-hybrid), FEZ1 (Two-hybrid), VIM (Two-hybrid), DIS3L2 (Proximity Label-MS), DIS3L2 (Proximity Label-MS), DIS3L2 (Negative Genetic), DIS3L2 (Affinity Capture-MS)

ESM2 similar proteins: A2VD33, A4QP75, A5D7V9, A6QPU5, A7YW45, B5DEQ3, B8JMH0, O14744, O95363, P07178, P31754, P49590, P70076, Q01415, Q0V9R3, Q16798, Q2KI84, Q32PX9, Q3KRD0, Q3T056, Q3V384, Q4R5M3, Q4V7N2, Q503J2, Q5EBA1, Q5M7W7, Q5R5E5, Q5R698, Q5R6J8, Q5XIG6, Q641Y5, Q68FH4, Q6AYQ3, Q6PI48, Q7L3T8, Q80YD1, Q8BGV0, Q8BIP0, Q8BMF3, Q8CFI5

Diamond homologs: A0JN80, A2RV18, O14040, O32231, O67834, O84402, P0DM58, P21499, P30851, P37202, P40611, P44907, P47950, P54084, P56123, P57628, Q02146, Q08162, Q09568, Q0V9R3, Q0WPN0, Q17632, Q5R5N8, Q5U2P0, Q8C0S1, Q8CI75, Q8IYB7, Q8K917, Q8TF46, Q9CSH3, Q9KNY1, Q9PK00, Q9SHL7, Q9Y2L1, Q9Z848, Q9ZJX9, A0QYY6, A0RHH8, A3DCH7, A5I4I7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

2372 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	72
Likely pathogenic	45
Uncertain significance	1283
Likely benign	833
Benign	47

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069819	NM_152383.5(DIS3L2):c.1879_1882del (p.Gln627fs)	Pathogenic
1069914	NM_152383.5(DIS3L2):c.973C>T (p.Gln325Ter)	Pathogenic
1070340	NM_152383.5(DIS3L2):c.695C>G (p.Ser232Ter)	Pathogenic
1071530	NC_000002.11:g.(?233028159)(233028352_?)del	Pathogenic
1071531	NC_000002.11:g.(?232879638)(232952441_?)del	Pathogenic
1071532	NC_000002.11:g.(?233001172)(233075125_?)del	Pathogenic
1076242	NM_152383.5(DIS3L2):c.264+1del	Pathogenic
1076634	NM_152383.5(DIS3L2):c.1545dup (p.Ile516fs)	Pathogenic
1376575	NM_152383.5(DIS3L2):c.1570G>T (p.Glu524Ter)	Pathogenic
1380518	NM_152383.5(DIS3L2):c.86del (p.Gly29fs)	Pathogenic
1398363	NM_152383.5(DIS3L2):c.285dup (p.Ile96fs)	Pathogenic
1417497	NM_152383.5(DIS3L2):c.2088C>G (p.Tyr696Ter)	Pathogenic
1425758	NM_152383.5(DIS3L2):c.1859_1866del (p.Asp620fs)	Pathogenic
1448959	NM_152383.5(DIS3L2):c.1403G>A (p.Trp468Ter)	Pathogenic
1453485	NM_152383.5(DIS3L2):c.375del (p.Lys125fs)	Pathogenic
1453905	NM_152383.5(DIS3L2):c.581C>G (p.Ser194Ter)	Pathogenic
1454907	NM_152383.5(DIS3L2):c.820C>T (p.Arg274Ter)	Pathogenic
1457090	NC_000002.11:g.(?232952187)(232952441_?)del	Pathogenic
1457219	NM_152383.5(DIS3L2):c.2219del (p.Asn740fs)	Pathogenic
1459337	NM_152383.5(DIS3L2):c.363G>A (p.Trp121Ter)	Pathogenic
1459583	NC_000002.11:g.(?232952187)(233028352_?)del	Pathogenic
1878671	GRCh38/hg38 2q37.1(chr2:232154529-232177529)x0	Pathogenic
2017168	NM_152383.5(DIS3L2):c.1170del (p.Asp391fs)	Pathogenic
2022087	NM_152383.5(DIS3L2):c.1545del (p.Ile516fs)	Pathogenic
2022239	NM_152383.5(DIS3L2):c.906dup (p.Cys303fs)	Pathogenic
2028153	NM_152383.5(DIS3L2):c.778_797del (p.Glu260fs)	Pathogenic
2086659	NM_152383.5(DIS3L2):c.1835dup (p.Pro613fs)	Pathogenic
2087451	NM_152383.5(DIS3L2):c.869del (p.Val290fs)	Pathogenic
2153204	NM_152383.5(DIS3L2):c.1133_1134del (p.Cys378fs)	Pathogenic
241972	NM_152383.5(DIS3L2):c.2270del (p.Phe757fs)	Pathogenic

SpliceAI

6109 predictions. Top by Δscore:

Variant	Effect	Δscore
2:231961762:AACGG:A	donor_loss	1.0000
2:231961763:ACGG:A	donor_loss	1.0000
2:231961764:CGGT:C	donor_loss	1.0000
2:231961765:GGTG:G	donor_loss	1.0000
2:231961767:T:G	donor_loss	1.0000
2:231973144:TCTC:T	donor_gain	1.0000
2:232024273:AAAG:A	acceptor_gain	1.0000
2:232029972:A:AG	acceptor_gain	1.0000
2:232029973:A:G	acceptor_gain	1.0000
2:232029974:CCTA:C	acceptor_loss	1.0000
2:232029976:TAG:T	acceptor_loss	1.0000
2:232029977:A:AG	acceptor_gain	1.0000
2:232029977:AG:A	acceptor_gain	1.0000
2:232029977:AGGAT:A	acceptor_gain	1.0000
2:232029978:G:GT	acceptor_gain	1.0000
2:232029978:GG:G	acceptor_gain	1.0000
2:232029978:GGAT:G	acceptor_gain	1.0000
2:232029978:GGATG:G	acceptor_gain	1.0000
2:232030076:GGAAG:G	donor_gain	1.0000
2:232030077:GAAG:G	donor_gain	1.0000
2:232030077:GAAGG:G	donor_gain	1.0000
2:232030078:AAGGT:A	donor_loss	1.0000
2:232030081:G:GG	donor_gain	1.0000
2:232030082:T:A	donor_loss	1.0000
2:232030086:T:G	donor_gain	1.0000
2:232087486:GGT:G	acceptor_gain	1.0000
2:232087486:GGTA:G	acceptor_gain	1.0000
2:232087717:GAAAG:G	donor_gain	1.0000
2:232087718:AAAG:A	donor_gain	1.0000
2:232087719:AAG:A	donor_gain	1.0000

AlphaMissense

5813 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:232030025:G:C	R104T	1.000
2:232238625:A:C	S433R	1.000
2:232238627:C:A	S433R	1.000
2:232238627:C:G	S433R	1.000
2:232334467:A:C	S753R	1.000
2:232334469:T:A	S753R	1.000
2:232334469:T:G	S753R	1.000
2:232024313:G:C	A83P	0.999
2:232030025:G:T	R104I	0.999
2:232030026:A:C	R104S	0.999
2:232030026:A:T	R104S	0.999
2:232030028:C:A	A105D	0.999
2:232136515:G:A	G249D	0.999
2:232136590:G:C	R274P	0.999
2:232136691:T:A	W308R	0.999
2:232136691:T:C	W308R	0.999
2:232136713:C:A	A315D	0.999
2:232163518:T:C	L337P	0.999
2:232333943:G:C	R705P	0.999
2:232030019:G:C	R102P	0.998
2:232030039:G:C	D109H	0.998
2:232030040:A:C	D109A	0.998
2:232136514:G:C	G249R	0.998
2:232136572:T:C	F268S	0.998
2:232136608:T:A	V280E	0.998
2:232136676:T:C	C303R	0.998
2:232136693:G:C	W308C	0.998
2:232136693:G:T	W308C	0.998
2:232136718:G:A	G317R	0.998
2:232136718:G:C	G317R	0.998

dbSNP variants (sampled 300 via entrez): RS1000017735 (2:232046703 A>C,G), RS1000018171 (2:232276045 T>C), RS1000025501 (2:232137918 G>A,T), RS1000040379 (2:232318552 G>A,C,T), RS1000042505 (2:232267746 T>A), RS1000056287 (2:232086707 G>A,T), RS1000059750 (2:232039885 C>G,T), RS1000060297 (2:232096331 C>T), RS1000085749 (2:232181756 A>G,T), RS1000088505 (2:232086351 A>G), RS1000121114 (2:232257862 A>G), RS1000122202 (2:232181853 T>C), RS1000140391 (2:232277551 C>A,T), RS1000153380 (2:232007162 G>A), RS1000176475 (2:232212888 G>A)

Disease associations

OMIM: gene MIM:614184 | disease phenotypes: MIM:267000

GenCC curated gene-disease

Disease	Classification	Inheritance
Perlman syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Perlman syndrome	Definitive	AR

Mondo (4): Perlman syndrome (MONDO:0009965), hepatoblastoma (MONDO:0018666), neurodevelopmental disorder (MONDO:0700092), Wilms tumor (MONDO:0006058)

Orphanet (3): Perlman syndrome (Orphanet:2849), Hepatoblastoma (Orphanet:449), Nephroblastoma (Orphanet:654)

HPO phenotypes

87 total (30 of 87 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000085	Horseshoe kidney
HP:0000086	Ectopic kidney
HP:0000098	Tall stature
HP:0000177	Abnormal upper lip morphology
HP:0000187	Broad alveolar ridges
HP:0000194	Open mouth
HP:0000256	Macrocephaly
HP:0000268	Dolichocephaly
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000311	Round face
HP:0000319	Smooth philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000391	Thickened helices
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000490	Deeply set eye
HP:0000508	Ptosis
HP:0000526	Aniridia
HP:0000776	Congenital diaphragmatic hernia
HP:0000822	Hypertension
HP:0000842	Hyperinsulinemia
HP:0000969	Edema

GWAS associations

49 associations (top):

Study	Trait	p-value
GCST000175_5	Height	1.000000e-06
GCST000431_1	Height	3.000000e-09
GCST000611_20	Height	9.000000e-09
GCST001956_86	Height	3.000000e-08
GCST002647_8	Height	3.000000e-23
GCST002702_37	Height	8.000000e-44
GCST004063_2	Waist circumference adjusted for body mass index	2.000000e-08
GCST004063_59	Waist circumference adjusted for body mass index	2.000000e-06
GCST004067_133	Hip circumference adjusted for BMI	2.000000e-07
GCST004067_89	Hip circumference adjusted for BMI	2.000000e-10
GCST004500_30	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	1.000000e-06
GCST004501_17	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	3.000000e-06
GCST004504_36	Waist circumference adjusted for BMI in non-smokers	4.000000e-06
GCST004562_174	Waist circumference adjusted for body mass index	9.000000e-06
GCST004562_216	Waist circumference adjusted for body mass index	1.000000e-06
GCST004562_217	Waist circumference adjusted for body mass index	2.000000e-09
GCST004562_77	Waist circumference adjusted for body mass index	1.000000e-08
GCST004563_179	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	1.000000e-06
GCST004563_180	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	1.000000e-09
GCST004563_224	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	7.000000e-09
GCST004564_75	Waist circumference adjusted for BMI in active individuals	2.000000e-07
GCST004564_76	Waist circumference adjusted for BMI in active individuals	9.000000e-07
GCST007152_2	Chronic back pain	4.000000e-07
GCST008163_154	Height	5.000000e-08
GCST008163_302	Height	2.000000e-12
GCST008163_422	Height	3.000000e-06
GCST008839_347	Height	1.000000e-82
GCST010002_411	Refractive error	1.000000e-123
GCST012226_202	Waist circumference adjusted for body mass index	9.000000e-11
GCST012226_26	Waist circumference adjusted for body mass index	9.000000e-14

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007789	BMI-adjusted waist circumference
EFO:0008039	BMI-adjusted hip circumference
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0004980	appendicular lean mass

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D018197	Hepatoblastoma	C04.557.435.380
D065886	Neurodevelopmental Disorders	F03.625
D009396	Wilms Tumor	C04.557.435.595; C04.588.945.947.535.585; C04.700.900; C12.050.351.937.820.535.585; C12.050.351.968.419.473.585; C12.200.758.820.750.585; C12.200.777.419.473.585; C12.900.820.535.585; C12.950.419.473.585; C12.950.983.535.585; C16.320.700.900
C536399	Nephroblastomatosis, fetal ascites, macrosomia and Wilms tumor (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6196111 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.33	Kd	4670	nM	CHEMBL6163426

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	5
sodium arsenite	decreases expression, affects expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
ochratoxin A	increases expression	1
aflatoxin B2	decreases methylation	1
coumarin	increases phosphorylation	1
methacrylaldehyde	increases expression, increases abundance, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
abrine	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Acrolein	affects cotreatment, increases expression, increases abundance	1
Air Pollutants	increases abundance, increases expression, affects cotreatment	1
Caffeine	affects phosphorylation	1
Calcitriol	increases expression, affects cotreatment	1
Catechin	affects cotreatment, decreases expression	1
Cisplatin	decreases expression	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Ozone	affects cotreatment, increases expression, increases abundance	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
CHEMBL6106010	Binding	Binding affinity to DIS3L2 in human NCI-H460 cells assessed as increase in thermal stability at 10 uM incubated for 6 hrs followed by heat exposure at 55 to 75 degreeC for 3 mins by CETSA	Synthesis and evolution of 16-membered macrolide carrimycin derivatives as a novel class of anti-HCoV-OC43 agents targeting viral FSE RNA. — Eur J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_XY60	C3948	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02933333	PHASE4	UNKNOWN	G-CSF Alone or Combination With GM-CSF on Prevention and Treatment of Infection in Children With Malignant Tumor
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,
NCT00336531	PHASE4	COMPLETED	Efficacy of Prophylactic Itraconazole in High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation
NCT03017326	PHASE3	ACTIVE_NOT_RECRUITING	Paediatric Hepatic International Tumour Trial
NCT03533582	PHASE3	ACTIVE_NOT_RECRUITING	Cisplatin and Combination Chemotherapy in Treating Children and Young Adults With Hepatoblastoma or Liver Cancer After Surgery
NCT04478292	PHASE3	RECRUITING	A Multi-institutional Study for Treatment of Children With Newly Diagnosed Hepatoblastoma Using a Modified PHITT Strategy
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
NCT01154816	PHASE2	COMPLETED	Alisertib in Treating Young Patients With Recurrent or Refractory Solid Tumors or Leukemia
NCT02011126	PHASE2	WITHDRAWN	Imetelstat Sodium in Treating Younger Patients With Relapsed or Refractory Solid Tumors
NCT02867592	PHASE2	ACTIVE_NOT_RECRUITING	Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumors
NCT03155620	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03210714	PHASE2	ACTIVE_NOT_RECRUITING	Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213652	PHASE2	ACTIVE_NOT_RECRUITING	Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
NCT03213665	PHASE2	COMPLETED	Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)
NCT03213678	PHASE2	COMPLETED	Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213704	PHASE2	ACTIVE_NOT_RECRUITING	Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)
NCT03220035	PHASE2	COMPLETED	Vemurafenib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With BRAF V600 Mutations (A Pediatric MATCH Treatment Trial)
NCT03233204	PHASE2	COMPLETED	Olaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)
NCT03526250	PHASE2	COMPLETED	Palbociclib in Treating Patients With Relapsed or Refractory Rb Positive Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Activating Alterations in Cell Cycle Genes (A Pediatric MATCH Treatment Trial)
NCT03698994	PHASE2	ACTIVE_NOT_RECRUITING	Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)
NCT04195555	PHASE2	ACTIVE_NOT_RECRUITING	Ivosidenib in Treating Patients With Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With IDH1 Mutations (A Pediatric MATCH Treatment Trial)
NCT04284774	PHASE2	ACTIVE_NOT_RECRUITING	Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial
NCT04320888	PHASE2	ACTIVE_NOT_RECRUITING	Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediatric MATCH Treatment Trial
NCT05302921	PHASE2	COMPLETED	Neoadjuvant Dual Checkpoint Inhibition and Cryoablation in Relapsed/Refractory Pediatric Solid Tumors
NCT06638931	PHASE2	RECRUITING	Agnostic Therapy in Rare Solid Tumors
NCT07300449	PHASE2	RECRUITING	A Prospective Multicenter Clinical Study of SCCG Protocol and ctDNA 5hmc in Predicting the Chemotherapy Sensitivity and Monitoring the Recurrence and Metastasis of Hepatoblastoma in Children and Adolescents
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
NCT00038207	PHASE2	COMPLETED	Liposomal Vincristine for Pediatric and Adolescent Patients With Relapsed Malignancies
NCT00141765	PHASE2	COMPLETED	Study of High-Dose Chemotherapy With Bone Marrow or Stem Cell Transplant for Rare Poor-Prognosis Cancers
NCT00187031	PHASE2	COMPLETED	A Phase II Study of Topotecan in Children With Recurrent Wilms Tumor
NCT01095926	PHASE2	COMPLETED	Pharmacokinetic Study of Doxorubicin in Children With Cancer
NCT02452554	PHASE2	COMPLETED	Lorvotuzumab Mertansine in Treating Younger Patients With Relapsed or Refractory Wilms Tumor, Rhabdomyosarcoma, Neuroblastoma, Pleuropulmonary Blastoma, Malignant Peripheral Nerve Sheath Tumor, or Synovial Sarcoma
NCT02624388	PHASE2	TERMINATED	Study of Genistein in Pediatric Oncology Patients (UVA-Gen001)
NCT02689336	PHASE2	WITHDRAWN	Erlotinib in Combination With Temozolomide in Treating Relapsed/Recurrent/Refractory Pediatric Solid Tumors