USP44

Summary

USP44 (ubiquitin specific peptidase 44, HGNC:20064) is a protein-coding gene on chromosome 12q22, encoding Ubiquitin carboxyl-terminal hydrolase 44 (Q9H0E7). Deubiquitinase that plays a key regulatory role in the spindle assembly checkpoint or mitotic checkpoint by preventing premature anaphase onset.

The protein encoded by this gene is a protease that functions as a deubiquitinating enzyme. The encoded protein is thought to help regulate the spindle assembly checkpoint by preventing early anaphase onset. This protein specifically deubiquitinates CDC20, which stabilizes the anaphase promoting complex/cyclosome.

Source: NCBI Gene 84101 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (Limited, ClinGen)
• GWAS associations: 6
• Clinical variants (ClinVar): 101 total
• MANE Select transcript: NM_032147

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20064
Approved symbol	USP44
Name	ubiquitin specific peptidase 44
Location	12q22
Locus type	gene with protein product
Status	Approved
Aliases	FLJ14528
Ensembl gene	ENSG00000136014
Ensembl biotype	protein_coding
OMIM	610993
Entrez	84101

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 41 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000258499, ENST00000393091, ENST00000537435, ENST00000547951, ENST00000549639, ENST00000551837, ENST00000552237, ENST00000552440, ENST00000876803, ENST00000916587, ENST00000916588, ENST00000916589, ENST00000916590, ENST00000916591, ENST00000916592, ENST00000916593, ENST00000916594, ENST00000916595, ENST00000916596, ENST00000916597, ENST00000916598, ENST00000916599, ENST00000916600, ENST00000916601, ENST00000916602, ENST00000916603, ENST00000916604, ENST00000916605, ENST00000916606, ENST00000916607, ENST00000916608, ENST00000916609, ENST00000916610, ENST00000916611, ENST00000916612, ENST00000916613, ENST00000916614, ENST00000916615, ENST00000916616, ENST00000916617, ENST00000916618, ENST00000916619, ENST00000916620

RefSeq mRNA: 5 — MANE Select: NM_032147 NM_001042403, NM_001278393, NM_001347936, NM_001347937, NM_032147

CCDS: CCDS9053

Canonical transcript exons

ENST00000258499 — 6 exons

Exon	Start	End
ENSE00000922703	95528807	95529002
ENSE00001127544	95520997	95521202
ENSE00001155152	95532829	95534326
ENSE00001283307	95551272	95551476
ENSE00002354184	95516560	95518353
ENSE00003513361	95524680	95524788

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 93.46.

FANTOM5 (CAGE): breadth broad, TPM avg 2.8442 / max 244.2467, expressed in 474 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
132735	1.2063	446
132737	0.6888	77
132739	0.4264	71
132740	0.2328	60
132738	0.1498	50
132734	0.0572	33
132736	0.0550	23
132733	0.0279	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	93.46	gold quality
sperm	CL:0000019	92.19	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.25	gold quality
oocyte	CL:0000023	87.12	gold quality
left testis	UBERON:0004533	79.73	gold quality
right testis	UBERON:0004534	79.36	gold quality
testis	UBERON:0000473	79.22	gold quality
buccal mucosa cell	CL:0002336	78.00	silver quality
lower lobe of lung	UBERON:0008949	76.70	gold quality
cerebellar hemisphere	UBERON:0002245	76.56	gold quality
cerebellar cortex	UBERON:0002129	76.43	gold quality
tibial nerve	UBERON:0001323	76.12	gold quality
right hemisphere of cerebellum	UBERON:0014890	75.97	gold quality
cerebellum	UBERON:0002037	75.75	gold quality
body of pancreas	UBERON:0001150	73.02	gold quality
mucosa of stomach	UBERON:0001199	72.48	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	71.66	gold quality
pancreas	UBERON:0001264	70.87	gold quality
ventricular zone	UBERON:0003053	70.62	gold quality
islet of Langerhans	UBERON:0000006	70.21	gold quality
body of uterus	UBERON:0009853	70.06	gold quality
upper lobe of lung	UBERON:0008948	69.29	gold quality
lower esophagus muscularis layer	UBERON:0035833	69.24	gold quality
lower esophagus	UBERON:0013473	69.22	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	69.15	gold quality
upper lobe of left lung	UBERON:0008952	68.91	gold quality
adult organism	UBERON:0007023	68.87	gold quality
ganglionic eminence	UBERON:0004023	68.10	gold quality
lung	UBERON:0002048	67.98	gold quality
right lung	UBERON:0002167	67.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-109979	yes	496.10
E-MTAB-9388	yes	14.27
E-ANND-3	yes	8.82

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): POU5F1

miRNA regulators (miRDB)

100 targeting USP44, 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-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-568	99.98	69.86	2084
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3658	99.96	73.87	4379
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650

Literature-anchored findings (GeneRIF, showing 25)

• a dynamic balance of ubiquitination by the APC and deubiquitination by USP44 contributes to the generation of the switch-like transition controlling anaphase entry (PMID:17443180)
• These data are consistent with an important role for USP44 in regulating Cdc20-APC/C activity and suggest that high levels of this enzyme may contribute to the pathogenesis of T-cell leukemias. (PMID:21853124)
• Data identify Cdc20, USP44, and Wee1 as relevant Fcp1 targets. (PMID:22692537)
• findings implicate USP44 in negative regulation of the RNF8/RNF168 pathway (PMID:23615962)
• USP44 is epigenetically inactivated in colorectal adenomas, but this alone is not sufficient to cause aneuploidy in colorectal neoplasia. (PMID:24837038)
• USP44+ Cancer Stem Cell Subclones Contribute to Breast Cancer Aggressiveness by Promoting Vasculogenic Mimicry (PMID:26232424)
• USP44 contributes to N-CoR functions in regulating gene expression and is required for efficient invasiveness of triple-negative breast cancer cells. (PMID:27880911)
• USP44 protein was widely expressed in most of the tumor samples and no clear association could be established between its expression and DNA ploidy status or tumor size (PMID:28492742)
• These data imply a complex picture where regulating factors such as OCT4 may interact with other epigenetic mechanisms to regulate USP44 expression in pluripotent stem cells and testes. (PMID:28520534)
• In summary, we report that the combination of USP44 expression and DNA ploidy status might serve as an independent prognostic marker in gastric cancer. (PMID:28544703)
• USP44 promotes the tumorigenesis of prostate cancer cells partly by stabilizing EZH2. (PMID:30622230)
• USP44 inhibited AKT signaling by stabilizing PTEN in non-small cell lung cancer cells. (PMID:31197957)
• identified USP44 as a positive regulator of MITA; USP44 is recruited to MITA following DNA virus infection and removes K48-linked polyubiquitin moieties from MITA at K236, therefore prevents MITA from proteasome mediated degradation; findings suggest that USP44 plays a specific and critical role in the regulation of innate immune response against DNA viruses (PMID:31968013)
• Ubiquitin-specific protease-44 inhibits the proliferation and migration of cells via inhibition of JNK pathway in clear cell renal cell carcinoma. (PMID:32164618)
• USP44 suppresses proliferation and enhances apoptosis in colorectal cancer cells by inactivating the Wnt/beta-catenin pathway via Axin1 deubiquitination. (PMID:32285989)
• Existence of circFOXO3-miR-143-3p-USP44 axis in GC cells was confirmed by RNA-binding protein immunoprecipitation, luciferase reporter assay, and an RNA pull-down experiments. All the data indicate that circFOXO3 promotes GC cell proliferation and migration by upregulating USP44 expression via targeting of miR-143-3p. (PMID:32445925)
• The deubiquitinase USP44 promotes Treg function during inflammation by preventing FOXP3 degradation. (PMID:32644293)
• USP44 hypermethylation promotes cell proliferation and metastasis in breast cancer. (PMID:32956592)
• CRADD and USP44 mutations in intellectual disability, mild lissencephaly, brain atrophy, developmental delay, strabismus, behavioural problems and skeletal anomalies. (PMID:33647455)
• USP44 regulates irradiation-induced DNA double-strand break repair and suppresses tumorigenesis in nasopharyngeal carcinoma. (PMID:35079021)
• USP44 accelerates the growth of T-cell acute lymphoblastic leukemia through interacting with WDR5 and repressing its ubiquitination. (PMID:36483601)
• Integrated network findings reveal ubiquitin-specific protease 44 overexpression suppresses tumorigenicity of liver cancer. (PMID:37204480)
• MAD2 activates IGF1R/PI3K/AKT pathway and promotes cholangiocarcinoma progression by interfering USP44/LIMA1 complex. (PMID:37752233)
• RNA-binding protein NOVA1 promotes acute T-lymphocyte leukemia progression by stabilizing USP44 mRNA. (PMID:37816258)
• USP44 Overexpression Drives a MYC-Like Gene Expression Program in Neuroblastoma through Epigenetic Reprogramming. (PMID:38775808)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	usp44	ENSDARG00000089861
mus_musculus	Usp44	ENSMUSG00000020020
rattus_norvegicus	Usp44	ENSRNOG00000005637

Paralogs (71): USP2 (ENSG00000036672), USP28 (ENSG00000048028), USP36 (ENSG00000055483), USP13 (ENSG00000058056), USP33 (ENSG00000077254), USP40 (ENSG00000085982), USP48 (ENSG00000090686), USP14 (ENSG00000101557), USP11 (ENSG00000102226), USP10 (ENSG00000103194), USP31 (ENSG00000103404), USP42 (ENSG00000106346), USP5 (ENSG00000111667), USP4 (ENSG00000114316), USP9Y (ENSG00000114374), USP34 (ENSG00000115464), USP35 (ENSG00000118369), USP45 (ENSG00000123552), USP22 (ENSG00000124422), USP9X (ENSG00000124486), USP6 (ENSG00000129204), USP29 (ENSG00000131864), USP26 (ENSG00000134588), USP30 (ENSG00000135093), USP15 (ENSG00000135655), USP37 (ENSG00000135913), USP20 (ENSG00000136878), USP8 (ENSG00000138592), USP3 (ENSG00000140455), USP21 (ENSG00000143258), USP43 (ENSG00000154914), USP25 (ENSG00000155313), USP16 (ENSG00000156256), USP24 (ENSG00000162402), USP1 (ENSG00000162607), USP49 (ENSG00000164663), USP38 (ENSG00000170185), USP50 (ENSG00000170236), USP47 (ENSG00000170242), USP32 (ENSG00000170832)

Protein

Protein identifiers

Ubiquitin carboxyl-terminal hydrolase 44 — Q9H0E7 (reviewed: Q9H0E7)

Alternative names: Deubiquitinating enzyme 44, Ubiquitin thioesterase 44, Ubiquitin-specific-processing protease 44

All UniProt accessions (4): Q9H0E7, F8VRI7, F8VRW0, F8VVD6

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinase that plays a key regulatory role in the spindle assembly checkpoint or mitotic checkpoint by preventing premature anaphase onset. Acts by specifically mediating deubiquitination of CDC20, a negative regulator of the anaphase promoting complex/cyclosome (APC/C). Deubiquitination of CDC20 leads to stabilize the MAD2L1-CDC20-APC/C ternary complex (also named mitotic checkpoint complex), thereby preventing premature activation of the APC/C. Promotes association of MAD2L1 with CDC20 and reinforces the spindle assembly checkpoint. Also promotes the deubiquitination of histone H2A and H2B. Recruited to RNF8/RNF168-ubiquitinated chromatin surrounding double stranded breaks (DSBs), promotes hydrolysis of such ubiquitin conjugates, thus negatively regulating protein recruitment to damaged chromatin. Participates in nucleotide excision repair (NER) pathway by deubiquitinating DDB2 to prevent its premature degradation so it can remain on damaged chromatin. Promotes FOXP3 stabilization through ‘Lys-48’-linked deubiquitination leading to increased stability and increased regulatory T-cell lineage stability. Also plays a positive role in innate immune response to DNA viruses by deubiquitinating STING1, selectively removing its ‘Lys-48’-linked polyubiquitin chains and stabilizing it.

Subunit / interactions. Interacts with the N-CoR components TBL1X and TBL1XR1.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Expressed in testis. Expressed at high levels in T-cell acute lymphoblastic leukemia.

Post-translational modifications. Dephosphorylated by CTDP1. Ubiquitinated; undergoes both ‘Lys-48’- and ‘Lys-63’-linked polyubiquitination and is degraded by the proteasome.

Induction. Transcriptionally regulated by POU5F1/OCT4 in embryonic stem cells and embryonal carcinoma cells. Induced by TGF-beta during regulatory T-cells differentiation.

Similarity. Belongs to the peptidase C19 family. USP44 subfamily.

RefSeq proteins (5): NP_001035862, NP_001265322, NP_001334865, NP_001334866, NP_115523* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001394	Peptidase_C19_UCH	Domain
IPR001607	Znf_UBP	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR018200	USP_CS	Conserved_site
IPR028889	USP	Domain
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050185	Ub_carboxyl-term_hydrolase	Family

Pfam: PF00443, PF02148

UniProt features (26 total): binding site 12, modified residue 4, sequence variant 3, active site 2, chain 1, domain 1, zinc finger region 1, mutagenesis site 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H0E7-F1	72.63	0.37

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 (2): 282 (nucleophile); 636 (proton acceptor)

Ligand- & substrate-binding residues (12): 41; 44; 49; 56; 60; 66; 79; 82; 7; 9; 29; 32

Post-translational modifications (4): 169, 239, 269, 401

Mutagenesis-validated functional residues (1):

Position	Phenotype
282	abolishes deubiquitinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5689880	Ub-specific processing proteases

MSigDB gene sets: 209 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_CHROMOSOME_SEPARATION, CHX10_01, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_NUCLEOTIDE_EXCISION_REPAIR, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_ORGANELLE_FISSION, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_REGULATION_OF_CHROMOSOME_SEGREGATION

GO Biological Process (15): nucleotide-excision repair (GO:0006289), chromosome segregation (GO:0007059), regulation of cell cycle process (GO:0010564), protein deubiquitination (GO:0016579), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), regulatory T cell differentiation (GO:0045066), negative regulation of mitotic metaphase/anaphase transition (GO:0045841), cell division (GO:0051301), regulation of mitotic cell cycle spindle assembly checkpoint (GO:0090266), antiviral innate immune response (GO:0140374), negative regulation of ubiquitin protein ligase activity (GO:1904667), immune system process (GO:0002376), proteolysis (GO:0006508), innate immune response (GO:0045087), positive regulation of mitotic metaphase/anaphase transition (GO:0045842)

GO Molecular Function (8): cysteine-type deubiquitinase activity (GO:0004843), zinc ion binding (GO:0008270), deubiquitinase activity (GO:0101005), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitotic spindle (GO:0072686)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of mitotic metaphase/anaphase transition	3
cellular anatomical structure	3
cell cycle process	2
metaphase/anaphase transition of mitotic cell cycle	2
DNA repair	1
regulation of cell cycle	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
T cell differentiation	1
negative regulation of mitotic nuclear division	1
negative regulation of mitotic cell cycle phase transition	1
negative regulation of metaphase/anaphase transition of cell cycle	1
negative regulation of mitotic sister chromatid separation	1
cellular process	1
regulation of mitotic nuclear division	1
mitotic spindle assembly checkpoint signaling	1
regulation of mitotic sister chromatid separation	1
regulation of mitotic sister chromatid segregation	1
regulation of mitotic spindle checkpoint	1
innate immune response	1
defense response to virus	1
negative regulation of ubiquitin-protein transferase activity	1
ubiquitin protein ligase activity	1
regulation of ubiquitin protein ligase activity	1
biological_process	1
protein metabolic process	1
immune response	1
defense response to symbiont	1
positive regulation of mitotic nuclear division	1
positive regulation of mitotic sister chromatid separation	1
positive regulation of mitotic cell cycle phase transition	1
positive regulation of metaphase/anaphase transition of cell cycle	1
cysteine-type peptidase activity	1
deubiquitinase activity	1
transition metal ion binding	1
ubiquitin-like protein peptidase activity	1
binding	1
hydrolase activity	1

Protein interactions and networks

STRING

1154 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP44	CDC20	Q12834	802
USP44	K7ESF6	K7ESF6	773
USP44	ZNF501	Q96CX3	773
USP44	ZNF436	Q9C0F3	773
USP44	ZNF629	Q9UEG4	773
USP44	ZNF569	Q5MCW4	772
USP44	ZNF44	P15621	756
USP44	WEE1	P30291	718
USP44	H2BC21	Q16778	644
USP44	ZUP1	Q96AP4	642
USP44	OTUB1	Q96FW1	613
USP44	USP39	Q53GS9	571
USP44	USP25	Q9UHP3	559
USP44	CDK1	P06493	558
USP44	USP26	Q9BXU7	542

IntAct

8 interactions, top by confidence:

A	B	Type	Score
USP44	CETN2	psi-mi:“MI:0915”(physical association)	0.690
USP44	CETN2	psi-mi:“MI:0914”(association)	0.690
USP44	FOXP3	psi-mi:“MI:0915”(physical association)	0.460
FOXP3	USP44	psi-mi:“MI:0403”(colocalization)	0.460
USP49	ANKRD28	psi-mi:“MI:0914”(association)	0.350

BioGRID (228): CETN2 (Affinity Capture-MS), CETN2 (Affinity Capture-MS), TBL1XR1 (Affinity Capture-MS), TBL1X (Affinity Capture-MS), PSMC4 (Affinity Capture-MS), HDAC3 (Affinity Capture-MS), PSMC1 (Affinity Capture-MS), PSMC2 (Affinity Capture-MS), PSMC5 (Affinity Capture-MS), NCOR1 (Affinity Capture-MS), NCOR2 (Affinity Capture-MS), USP44 (Affinity Capture-MS), TBL1X (Affinity Capture-Western), TBL1XR1 (Affinity Capture-Western), NCOR1 (Affinity Capture-Western)

ESM2 similar proteins: A0JM59, A2BGT0, A5PJS6, A5PMR2, A5PN09, A6QNM7, A7Z056, B1AY15, B1WBD7, D2HBJ8, E1C213, E7F6T8, E9QG68, O88974, P52479, Q0V9G5, Q14694, Q15047, Q1RMU2, Q28CN3, Q2KJ09, Q2NL57, Q3KR59, Q5R5Z6, Q5RED8, Q5REG5, Q5XGZ2, Q5ZJN4, Q66H62, Q6NTR6, Q6P549, Q70CQ3, Q70CQ4, Q70EK9, Q7ZUM8, Q7ZXR7, Q80TQ2, Q8BW70, Q8C0R0, Q8C2S0

Diamond homologs: A0A8I6GM68, D2HBJ8, F1QCV2, O17323, O27262, O30107, P28606, P38748, P53973, P56523, P56524, P72702, P83038, Q09440, Q0V9G5, Q20296, Q2QWU2, Q3JUN4, Q54QE6, Q569C4, Q57955, Q5A960, Q5R902, Q5XGZ2, Q613L4, Q6NTR6, Q6NZM9, Q6P3E7, Q6P9L4, Q70CQ1, Q70I53, Q7Z569, Q7ZUM8, Q80ZH1, Q8C2B3, Q8C2S0, Q8GXJ1, Q8LRK8, Q8RX28, Q8WUI4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	83
Likely benign	8
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

1616 predictions. Top by Δscore:

Variant	Effect	Δscore
12:95520990:T:C	donor_gain	1.0000
12:95520998:T:TA	donor_gain	1.0000
12:95518352:CC:C	acceptor_gain	0.9900
12:95518353:CC:C	acceptor_gain	0.9900
12:95520995:ACCT:A	donor_gain	0.9900
12:95520996:CCTC:C	donor_gain	0.9900
12:95520999:C:A	donor_gain	0.9900
12:95521027:AGTGC:A	donor_gain	0.9900
12:95521043:T:TA	donor_gain	0.9900
12:95521048:T:A	donor_gain	0.9900
12:95521063:C:CT	donor_gain	0.9900
12:95521117:C:CA	donor_gain	0.9900
12:95528718:A:C	donor_gain	0.9900
12:95534325:AA:A	acceptor_gain	0.9900
12:95534327:CTAAA:C	acceptor_loss	0.9900
12:95546893:TAGGC:T	donor_gain	0.9900
12:95546894:AGGCA:A	donor_gain	0.9900
12:95518260:C:CT	acceptor_gain	0.9800
12:95518351:ACCCT:A	acceptor_loss	0.9800
12:95518352:CCCTA:C	acceptor_loss	0.9800
12:95518353:CCTAG:C	acceptor_loss	0.9800
12:95518354:C:CA	acceptor_loss	0.9800
12:95518355:T:A	acceptor_loss	0.9800
12:95520991:CTATA:C	donor_loss	0.9800
12:95520992:TATAC:T	donor_loss	0.9800
12:95520993:ATAC:A	donor_loss	0.9800
12:95520994:TACCT:T	donor_loss	0.9800
12:95520995:A:AT	donor_loss	0.9800
12:95520996:C:A	donor_loss	0.9800
12:95520997:C:A	donor_loss	0.9800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000112244 (12:95520443 G>C), RS1000144613 (12:95536670 C>G), RS1000181518 (12:95518688 C>T), RS1000202280 (12:95543089 A>AC), RS1000232224 (12:95520789 A>G), RS1000335458 (12:95548964 TG>T,TGG), RS1000387939 (12:95549114 G>A), RS1000399333 (12:95548901 C>T), RS1000410694 (12:95549057 G>A), RS1000436749 (12:95549381 A>G), RS1000531868 (12:95530933 G>A), RS1000590804 (12:95544991 T>C), RS1000638949 (12:95524656 T>G), RS1000659030 (12:95543478 C>A,T), RS1000691286 (12:95525056 G>A,T)

Disease associations

OMIM: gene MIM:610993 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart disease	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital heart disease	Limited	AD

Mondo (1): congenital heart disease (MONDO:0005453)

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001308_4	Response to anti-depressant treatment in major depressive disorder	3.000000e-07
GCST003985_1	Breast size	1.000000e-13
GCST004795_5	Brain volume in infants (white matter)	1.000000e-06
GCST007615_34	C-reactive protein levels	1.000000e-16
GCST009379_340	Type 2 diabetes	4.000000e-08
GCST010396_182	Gut microbiota (bacterial taxa, hurdle binary method)	3.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006322	antidepressant-induced sexual dysfunction
EFO:0008370	infant white matter volume measurement
EFO:0004458	C-reactive protein measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	3
Valproic Acid	affects expression, decreases expression	3
bisphenol A	decreases methylation, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
kojic acid	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Arbutin	decreases expression	1
Arsenic	increases methylation	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Carbamazepine	affects expression	1
Cisplatin	increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Silicon Dioxide	increases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tretinoin	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression	1
Zinc Sulfate	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function
NCT01827059	PHASE2	UNKNOWN	Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE