MAML2

Summary

MAML2 (mastermind like transcriptional coactivator 2, HGNC:16259) is a protein-coding gene on chromosome 11q21, encoding Mastermind-like protein 2 (Q8IZL2). Acts as a transcriptional coactivator for NOTCH proteins.

The protein encoded by this gene is a member of the Mastermind-like family of proteins. All family members are proline and glutamine-rich, and contain a conserved basic domain that binds the ankyrin repeat domain of the intracellular domain of the Notch receptors (ICN1-4) in their N-terminus, and a transcriptional activation domain in their C-terminus. This protein binds to an extended groove that is formed by the interaction of CBF1, Suppressor of Hairless, LAG-1 (CSL) with ICN, and positively regulates Notch signaling. High levels of expression of this gene have been observed in several B cell-derived lymphomas. Translocations resulting in fusion proteins with both CRTC1 and CRTC3 have been implicated in the development of mucoepidermoid carcinomas, while a translocation event with CXCR4 has been linked with chronic lymphocytic leukemia (CLL). Copy number variation in the polyglutamine tract has been observed.

Source: NCBI Gene 84441 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (No Known Disease Relationship, ClinGen)
• GWAS associations: 16
• Clinical variants (ClinVar): 154 total
• Cancer driver (intOGen): ambiguous (mixed evidence) across 3 cancer types
• MANE Select transcript: NM_032427

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16259
Approved symbol	MAML2
Name	mastermind like transcriptional coactivator 2
Location	11q21
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1819, MAM3
Ensembl gene	ENSG00000184384
Ensembl biotype	protein_coding
OMIM	607537
Entrez	84441

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000524717

RefSeq mRNA: 1 — MANE Select: NM_032427 NM_032427

CCDS: CCDS44714

Canonical transcript exons

ENST00000524717 — 5 exons

Exon	Start	End
ENSE00001290465	95991520	95991723
ENSE00001312273	95985531	95985642
ENSE00001771343	96091892	96093517
ENSE00002141976	96341383	96343195
ENSE00002161130	95976598	95979963

Expression profiles

Bgee: expression breadth ubiquitous, 238 present calls, max score 94.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.2924 / max 615.6560, expressed in 1706 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121916	21.7968	1683
121908	3.3579	870
121917	1.0339	370
121912	0.7182	390
121913	0.6899	302
121915	0.4128	191
121910	0.3285	147
121907	0.3277	144
121909	0.2752	132
121914	0.2022	87

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of paranasal sinus	UBERON:0005030	94.01	gold quality
cartilage tissue	UBERON:0002418	93.93	gold quality
mammary duct	UBERON:0001765	93.73	gold quality
epithelium of mammary gland	UBERON:0003244	93.63	gold quality
skin of hip	UBERON:0001554	91.94	gold quality
parietal pleura	UBERON:0002400	91.30	gold quality
bronchial epithelial cell	CL:0002328	91.02	gold quality
bronchus	UBERON:0002185	90.56	gold quality
visceral pleura	UBERON:0002401	90.39	gold quality
mammary gland	UBERON:0001911	90.29	gold quality
thoracic mammary gland	UBERON:0005200	90.25	gold quality
renal medulla	UBERON:0000362	89.67	gold quality
kidney epithelium	UBERON:0004819	89.54	gold quality
ileal mucosa	UBERON:0000331	89.07	gold quality
layer of synovial tissue	UBERON:0007616	89.06	gold quality
upper leg skin	UBERON:0004262	88.98	gold quality
epithelial cell of pancreas	CL:0000083	88.91	silver quality
oviduct epithelium	UBERON:0004804	88.84	gold quality
tibia	UBERON:0000979	88.48	gold quality
decidua	UBERON:0002450	88.42	gold quality
epithelium of nasopharynx	UBERON:0001951	87.74	gold quality
cerebellar vermis	UBERON:0004720	87.62	gold quality
superficial temporal artery	UBERON:0001614	87.49	gold quality
lower lobe of lung	UBERON:0008949	86.92	gold quality
synovial joint	UBERON:0002217	86.40	gold quality
pigmented layer of retina	UBERON:0001782	86.36	gold quality
placenta	UBERON:0001987	86.15	gold quality
pancreatic ductal cell	CL:0002079	85.88	gold quality
stromal cell of endometrium	CL:0002255	85.42	gold quality
upper arm skin	UBERON:0004263	85.32	silver quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	72.52
E-CURD-119	yes	66.72
E-HCAD-25	yes	25.08
E-ANND-3	yes	8.28
E-MTAB-11011	no	556.45
E-MTAB-7249	no	161.70

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
HES1	Activation
NOTCH1	Activation

miRNA regulators (miRDB)

107 targeting MAML2, 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-3924	100.00	72.09	2394
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-4698	99.84	71.41	4303

Literature-anchored findings (GeneRIF, showing 40)

• Identification of new human proteins defines a family that consists of positive regulators for notch signaling (PMID:12386158)
• cloning and functional analyses of the t(11;19) fusion oncogene t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. (PMID:12539049)
• cloning of a novel fusion gene in mucoepidermoid carcinomas & benign Warthin’s tumors; the fusion, which results from a translocation, creates a chimeric gene in which exon 1 of a novel gene designated WAMTP1 is linked to exons 2-5 of MAML2 [WAMPT1] (PMID:14720503)
• The MECT1-MAML2 fusion transcript may be specific to mucoepidermoid carcinoma and associated with a distinct mucoepidermoid carcinoma subset that exhibits favorable clinicopathologic features and an indolent clinical course. (PMID:16818685)
• The present and previous observations indicate that the CRTC1-MAML2 fusion is etiologically linked to benign and low-grade malignant tumors originating from diverse exocrine glands rather than being linked to a separate tumor entity. (PMID:17334997)
• CRTC1/MAML2 transcript may be detected in both low and high grade mucoepidermoid carcinoma (MEC), that fusion negative tumors may define a subset of biologically aggressive MEC’s tumors (PMID:17437281)
• MAML2 involving a chimeric gene might contribute to carcinogenesis in multiple neoplasms by the disruption of NOTCH signaling. (PMID:17551948)
• study reports for the first time a CRTC3-MAML2 fusion gene in a mucoepidermoid carcinoma, as determined by RT-PCR and sequencing. (PMID:18050304)
• The presence of the t(11;19)(q21;p13) rearrangement favors a diagnosis of mucoepidermoid carcinoma. (PMID:18206539)
• MAML2 and MECT1 fusion product can be detected by fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction analysis performed on low- and high-grade primary bronchopulmonary mucoepidermoid carcinoma (PMID:19269006)
• Mucoepidermoid carcinomas are often characterized by the fusion gene CRTC1-MAML2. The mean expression level of an embryonic stem cell marker, HMGA2 was studied and found to be higher in fusion negative than in positive tumors. (PMID:19521953)
• CRTC1-MAML2 fusion was associated with favorable clinicopathologic tumor features and was useful in predicting the overall survival of patients with salivary gland mucoepidermoid carcinoma (PMID:19531414)
• Mucoepidermoid carcinomas possessing CRTC3-MAML2 fusion may be associated with favorable clinicopathological features and patients may be younger than those with CRTC1-MAML2 fusion or those with no detectable gene fusion. (PMID:19749740)
• MECT1/MAML2 translocation status may be important prognostically in salivary mucoepidermoid carcinomas, but it does not seem to override traditional clinicopathologic parameters. (PMID:20588178)
• We report an example of intraosseous mucoepidermoid carcinoma with positive TORC1/MAML2 gene fusion transcript and discuss the clinical implications. (PMID:20625861)
• The t(11;19) translocation and its CRTC1/MAML1 fusion transcript have been identified in mucoepidermoid carcinomas at different sites and are believed to be associated with the development of a subset of these tumors. (PMID:21074686)
• in line with the essential role of MAML proteins for assembly and activity of the NOTCH transcriptional complex (NTC), we show that MAML-derived small-peptide constructs block NOTCH activity and disrupt NTC formation in vitro (PMID:21119597)
• mucoepidermoid carcinoma of the salivary glands positive for CRTC1-MAML2 or CRTC3-MAML2 fusion formed a favourable tumour subset that was distinct from fusion-negative cases (PMID:21668476)
• The presence of MAML2 rearrangement can be used as supportive evidence to distinguish oncocytic mucoepidermoid carcinoma from other oncocytic lesions. (PMID:21777943)
• presence of small subpopulation of cells carrying MAML2 rearrangement in areas of squamous metaplasia in WT could predispose lesions to malignant transformation in mucoepidermoid carcinoma and could represent molecular link between the 2 entities. (PMID:22582766)
• The lack of significant correlation with histologic grade or pathologic stage implies that the previously reported prognostic value of the MAML2 translocation may be an artifact of misclassification of MEC as other tumors. (PMID:22833306)
• The presence of the MAML2 gene split defines a distinct mucoepidermoid carcinoma subset that is associated clinicopathologically with favorable tumor features. (PMID:23035786)
• high-grade salivary mucoepidermoid carcinoma comprises a heterogeneous group of tumours in terms of molecular pathogenesis, in particular MAML2 fusion status (PMID:23855785)
• aberrantly activated AREG-EGFR signaling is required for CRTC1-MAML2-positive MEC cell growth and survival, suggesting that EGFR-targeted therapies will benefit patients with advanced, unresectable CRTC1-MAML2-positive MEC. (PMID:23975434)
• Metaplastic Warthin tumor and metaplastic pleomorphic adenoma of salivary glands did not harbor CRTC1-MAML2 and CRTC3-MAML2 fusion transcripts, respectively, or MAML2 gene rearrangement. (PMID:24121173)
• using FISH to identify MAML2 rearrangement is a valuable diagnostic tool in the evaluation of thymic malignancies, specifically, distinguishing mucoepidermoid carcinoma from squamous cell carcinoma and adenosquamous carcinoma. (PMID:24134933)
• Lacrimal and salivary gland PAs and Ca-ex-PAs have similar genomic profiles and frequently overexpress the PLAG1 oncoprotein. Copy number gains involving 9p23-p22.3 (NFIB) and 22q12-qter (PDGFB) may be of importance for disease progression. (PMID:24468654)
• The high sensitivity and specificity of MAML2 rearrangement for central mucoepidermoid carcinoma points to its utility as a diagnostic adjunct in separating mucinous cystic lesions of the gnathic bones. (PMID:24647913)
• MAML2 rearrangement appears frequent in PMEC and specific with this tumor. Both the presence of MAML2 rearrangement and absence of FLT1 tend to confer a favorable clinical outcome. (PMID:24714697)
• Translocation t(11;19)(q14-21;p12-13) in patients with Salivary mucoepidermoid carcinoma was reported , which results in fusion between exons 1 and 2 of MAML2 on chromosome 11q21.Fusion positive, MAML2 re-arrangements are present in 50-70 % of MECs. (PMID:24771140)
• The rearrangement between MAML2 and CXCR4, created by a t(2;11)(q22.1;q21) translocation, results in a new fusion gene in which a portion of CXCR4 is linked to the MAML2 gene. (PMID:24855209)
• Malignant mucoepidermoid salivary gland tumors can arise from a recurrent t (11, 19)(q21;p13.1) translocation that generates an unusual chimeric CRTC1/MAML2 oncoprotein. (PMID:25071166)
• We identified MAML2 rearrangements in five of nine odontogenic cysts lined by mucus-secreting cells (PMID:25123064)
• SNPs in Notch pathway genes may be predictors of cutaneous melanoma disease-specific survival. (PMID:25953768)
• The molecular basis underlying CRTC1-MAML2 oncogenic functions were identified in mucoepidermoid carcinoma cells. (PMID:26503699)
• Detection of the CRTC1/MAML2 fusion transcript provides useful information for MEC diagnosis but is not associated with differences in survival outcomes. (PMID:26796488)
• MAML2 rearrangement is common and specific for MEC, which makes it a useful diagnostic tool. MAML2 rearrangement also predicts a favorable prognosis. (PMID:27068311)
• This condensed chromatin structure is associated with binding of DNMT3B and decreased occupancy of OCT1 transcription factor at MAML2 enhancer, suggesting a role of DNMT3B in increasing methylation of MAML2 after stilbenoid treatment. (PMID:27207652)
• revealing neither correlation between the cellular composition and CRTC1-MAML2 fusions nor presence of CRTC3-MAML2 fusions in cutaneous hidradenoma (PMID:27402217)
• we demonstrated that MDM2 is frequently overexpressed in clear cell carcinomas, and that MDM2 overexpression is associated with poor prognosis. (PMID:27659536)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000112977
mus_musculus	Maml2	ENSMUSG00000031925
rattus_norvegicus	Maml2	ENSRNOG00000005879

Paralogs (2): MAML1 (ENSG00000161021), MAML3 (ENSG00000196782)

Protein

Protein identifiers

Mastermind-like protein 2 — Q8IZL2 (reviewed: Q8IZL2)

All UniProt accessions (1): Q8IZL2

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1. Potentiates activation by NOTCH3 and NOTCH4 more efficiently than MAML1 or MAML3.

Subunit / interactions. Interacts through its N-terminal region with the ankyrin repeat region of the Notch proteins NOTCH1, NOTCH2, NOTCH3 and NOTCH4. Forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa.

Subcellular location. Nucleus speckle.

Tissue specificity. Widely expressed with high levels detected in placenta, salivary gland and skeletal muscle.

Disease relevance. A chromosomal aberration involving MAML2 is found in mucoepidermoid carcinomas, benign Warthin tumors and clear cell hidradenomas. Translocation t(11;19)(q21;p13) with CRTC1. The fusion protein consists of the N-terminus of CRTC1 joined to the C-terminus of MAML2. The reciprocal fusion protein consisting of the N-terminus of MAML2 joined to the C-terminus of CRTC1 has been detected in a small number of mucoepidermoid carcinomas.

Domain organisation. The C-terminal domain is required for transcriptional activation.

Similarity. Belongs to the mastermind family.

RefSeq proteins (1): NP_115803* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019082	Mastermind-like_N	Domain
IPR046369	MAML1-3	Family
IPR046370	MAML_N_sf	Homologous_superfamily
IPR048452	MAML2_TAD	Domain

Pfam: PF09596, PF20804

UniProt features (29 total): compositionally biased region 14, region of interest 8, sequence conflict 3, chain 1, site 1, modified residue 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IZL2-F1	46.21	0.04

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): 171–172 (breakpoint for translocation to form the crtc1-maml2 and maml2-crtc1 fusion proteins)

Post-translational modifications (1): 175

Function

Pathways and Gene Ontology

Reactome pathways

31 pathways

ID	Pathway
R-HSA-1912408	Pre-NOTCH Transcription and Translation
R-HSA-210744	Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells
R-HSA-2122947	NOTCH1 Intracellular Domain Regulates Transcription
R-HSA-2197563	NOTCH2 intracellular domain regulates transcription
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-350054	Notch-HLH transcription pathway
R-HSA-8941856	RUNX3 regulates NOTCH signaling
R-HSA-9013508	NOTCH3 Intracellular Domain Regulates Transcription
R-HSA-9013695	NOTCH4 Intracellular Domain Regulates Transcription
R-HSA-9793380	Formation of paraxial mesoderm
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)
R-HSA-1266738	Developmental Biology
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-186712	Regulation of beta-cell development
R-HSA-1912422	Pre-NOTCH Expression and Processing
R-HSA-1980143	Signaling by NOTCH1
R-HSA-1980145	Signaling by NOTCH2
R-HSA-212436	Generic Transcription Pathway
R-HSA-2644602	Signaling by NOTCH1 PEST Domain Mutants in Cancer
R-HSA-2644603	Signaling by NOTCH1 in Cancer
R-HSA-2894858	Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878159	Transcriptional regulation by RUNX3
R-HSA-9012852	Signaling by NOTCH3
R-HSA-9013694	Signaling by NOTCH4

MSigDB gene sets: 193 (showing top): CREL_01, REACTOME_SIGNALING_BY_NOTCH, NFKB_Q6, NFKB_C, MYLLYKANGAS_AMPLIFICATION_HOT_SPOT_23, GGGNNTTTCC_NFKB_Q6_01, IRF_Q6, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN, OSMAN_BLADDER_CANCER_DN, TGGAAA_NFAT_Q4_01, PID_NOTCH_PATHWAY, GOCC_NUCLEAR_SPECK, GOCC_NUCLEAR_BODY, GOCC_RIBONUCLEOPROTEIN_GRANULE, REACTOME_REGULATION_OF_BETA_CELL_DEVELOPMENT

GO Biological Process (3): Notch signaling pathway (GO:0007219), positive regulation of transcription of Notch receptor target (GO:0007221), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (2): transcription coactivator activity (GO:0003713), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear speck (GO:0016607)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Signaling by NOTCH	3
Pre-NOTCH Expression and Processing	1
Regulation of beta-cell development	1
Signaling by NOTCH1	1
Signaling by NOTCH2	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Generic Transcription Pathway	1
Transcriptional regulation by RUNX3	1
Signaling by NOTCH3	1
Signaling by NOTCH4	1
Gastrulation	1
Differentiation of T cells	1
Signal Transduction	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of DNA-templated transcription	2
cell surface receptor signaling pathway	1
Notch signaling pathway	1
positive regulation of transcription by RNA polymerase II	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
transcription coregulator activity	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

1164 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAML2	RBPJ	Q06330	999
MAML2	NOTCH1	P46531	995
MAML2	NOTCH4	Q99466	859
MAML2	GNLY	P09325	833
MAML2	JAG1	P78504	792
MAML2	NOTCH3	Q9UM47	787
MAML2	CRTC1	Q6UUV9	784
MAML2	ANK1	P16157	760
MAML2	ANK3	Q12955	741
MAML2	ANK2	Q01484	741
MAML2	JAG2	Q9Y219	734
MAML2	DLL1	O00548	734
MAML2	SRRT	Q9BXP5	697
MAML2	DLL4	Q9NR61	686
MAML2	EP300	Q09472	679

IntAct

8 interactions, top by confidence:

A	B	Type	Score
MAML2	NOTCH1	psi-mi:“MI:0915”(physical association)	0.500
MAML2	NOTCH1	psi-mi:“MI:0914”(association)	0.500
NEDD4	MAML2	psi-mi:“MI:0407”(direct interaction)	0.440
MAML2	NOTCH1	psi-mi:“MI:0915”(physical association)	0.370
MAML2	DIABLO	psi-mi:“MI:0915”(physical association)	0.370
MAML2	MB	psi-mi:“MI:0914”(association)	0.350
	MAML2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (19): MAML2 (Affinity Capture-Western), MAML2 (Affinity Capture-Western), RBPJ (Affinity Capture-Western), MAML2 (Two-hybrid), MAML2 (Affinity Capture-RNA), MAML2 (Negative Genetic), MAML2 (Affinity Capture-MS), SYNC (Affinity Capture-MS), MB (Affinity Capture-MS), MAML1 (Affinity Capture-Western), MAML2 (Two-hybrid), MAML2 (Protein-peptide), MAML2 (Affinity Capture-MS), MAML2 (Proximity Label-MS), MAML2 (Proximity Label-MS)

ESM2 similar proteins: A0A3Q7JC00, A0JM64, A0JNC2, A2VE44, A4IHD9, B2C6R6, B5DE09, B8BCZ8, E7F1H9, F4JT98, O09000, O57539, P78364, Q0WVM7, Q15596, Q17BA4, Q2NLB0, Q3TCX3, Q5RDA3, Q5TP13, Q5ZL54, Q61026, Q64028, Q6GP15, Q6K271, Q6NS15, Q6PEH8, Q71SY5, Q7XYY2, Q7ZVN7, Q80TM6, Q8C7E9, Q8CHY6, Q8HXM1, Q8IZL2, Q8VCB2, Q8W234, Q90WJ3, Q924H2, Q940A7

Diamond homologs: A5D7F6, Q13495, Q6T264, Q8IZL2, P0C6A2, Q92585, Q96JK9

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
RBPJ	up-regulates	MAML2	binding
MAML2	“up-regulates quantity by expression”	NOTCH	“transcriptional regulation”
NOTCH	up-regulates	MAML2	binding
MAML2	“up-regulates quantity by expression”	NOTCH1	“transcriptional regulation”
MAML2	“up-regulates quantity by expression”	HES1	“transcriptional regulation”
NOTCH4	up-regulates	MAML2	binding

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: ambiguous (mixed evidence) across 3 cancer types — AML, LUSC, VULVA.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	134
Likely benign	7
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

3977 predictions. Top by Δscore:

Variant	Effect	Δscore
11:95985644:T:C	acceptor_gain	1.0000
11:95991721:ATCC:A	acceptor_loss	1.0000
11:95991722:TC:T	acceptor_gain	1.0000
11:95991722:TCC:T	acceptor_loss	1.0000
11:95991723:CC:C	acceptor_gain	1.0000
11:95991724:C:CC	acceptor_gain	1.0000
11:95991725:T:G	acceptor_loss	1.0000
11:96136317:A:C	acceptor_gain	1.0000
11:95985524:CACTT:C	donor_loss	0.9900
11:95985525:ACTT:A	donor_loss	0.9900
11:95985526:CTTA:C	donor_loss	0.9900
11:95985527:TTA:T	donor_loss	0.9900
11:95985528:TAC:T	donor_loss	0.9900
11:95985529:A:AC	donor_gain	0.9900
11:95985530:C:A	donor_loss	0.9900
11:95985530:C:CC	donor_gain	0.9900
11:95985642:CCT:C	acceptor_gain	0.9900
11:95985643:C:CC	acceptor_gain	0.9900
11:95985644:T:TC	acceptor_gain	0.9900
11:95985656:A:C	acceptor_gain	0.9900
11:95991719:TGATC:T	acceptor_gain	0.9900
11:95991724:C:T	acceptor_gain	0.9900
11:95993618:C:CT	donor_gain	0.9900
11:96057646:T:A	donor_gain	0.9900
11:96095483:C:CA	donor_gain	0.9900
11:96136309:A:C	acceptor_gain	0.9900
11:96136315:A:C	acceptor_gain	0.9900
11:96136317:A:AC	acceptor_gain	0.9900
11:96136326:A:C	acceptor_gain	0.9900
11:96177072:A:C	acceptor_gain	0.9900

AlphaMissense

7629 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:95978993:C:A	W1142C	1.000
11:95978993:C:G	W1142C	1.000
11:95978995:A:G	W1142R	1.000
11:95978995:A:T	W1142R	1.000
11:96092724:A:G	L436P	1.000
11:96092724:A:T	L436H	1.000
11:96093093:A:G	L313P	1.000
11:96093105:A:G	L309P	1.000
11:96093114:A:G	L306P	1.000
11:96341669:A:G	L76P	1.000
11:96341745:G:C	H51D	1.000
11:96341753:C:G	R48P	1.000
11:96341757:A:G	C47R	1.000
11:96341765:A:C	I44S	1.000
11:96341765:A:T	I44N	1.000
11:96341768:C:G	R43P	1.000
11:96341774:C:G	R41P	1.000
11:96341777:A:G	L40P	1.000
11:96341777:A:T	L40H	1.000
11:95978967:A:C	I1151S	0.999
11:95978967:A:G	I1151T	0.999
11:95978976:A:G	L1148P	0.999
11:95978976:A:T	L1148H	0.999
11:95978991:A:G	M1143T	0.999
11:95978994:C:G	W1142S	0.999
11:95979021:A:G	L1133S	0.999
11:95979024:A:G	L1132S	0.999
11:96093054:A:G	L326P	0.999
11:96093093:A:T	L313Q	0.999
11:96093102:A:G	F310S	0.999

dbSNP variants (sampled 300 via entrez): RS1000004929 (11:96217132 A>G), RS1000018005 (11:96333118 T>A), RS1000028235 (11:96341989 G>A), RS1000036091 (11:96297330 T>A,C), RS1000036314 (11:96072732 T>A,C), RS1000044039 (11:95990863 A>G), RS1000052535 (11:96004725 T>C), RS1000058152 (11:96114252 C>G), RS1000072801 (11:96162760 T>C), RS1000082556 (11:96169314 G>A), RS1000090772 (11:96299698 T>C), RS1000091425 (11:96268747 T>C), RS1000100884 (11:96051241 A>G), RS1000109034 (11:96247581 C>T), RS1000135476 (11:96004474 C>A)

Disease associations

OMIM: gene MIM:607537 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart disease	No Known Disease Relationship	Unknown

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital heart disease	No Known Disease Relationship	UD

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

Orphanet (0):

HPO phenotypes

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

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000323_10	Response to treatment for acute lymphoblastic leukemia	8.000000e-06
GCST001728_12	Ulcerative colitis	1.000000e-08
GCST001819_8	Corneal astigmatism	2.000000e-06
GCST001885_5	Height	8.000000e-09
GCST002566_13	Response to chemotherapy in breast cancer hypertensive cases (cumulative dose) (bevacizumab)	6.000000e-06
GCST003126_5	Influenza A (H1N1) severity	6.000000e-07
GCST003226_5	Pelvic organ prolapse	1.000000e-06
GCST004133_30	Ulcerative colitis	7.000000e-07
GCST004136_24	Methadone dose in opioid dependence	6.000000e-06
GCST004348_18	Non-glioblastoma glioma	4.000000e-10
GCST004579_2	Waist-to-hip circumference ratio (alcohol intake interaction)	2.000000e-06
GCST008595_103	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	8.000000e-09
GCST009677_3	Keratoconus	1.000000e-07
GCST012490_499	Femur bone mineral density x serum urate levels interaction	3.000000e-08
GCST90002383_41	Hematocrit	2.000000e-09
GCST90002384_296	Hemoglobin	8.000000e-10

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0005944	cumulative dose response to bevacizumab
EFO:0007743	influenza A severity measurement
EFO:0007907	methadone dose measurement
EFO:0004343	waist-hip ratio
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0004531	urate measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin 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

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, decreases expression, decreases methylation	4
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression, decreases expression	3
trichostatin A	affects cotreatment, increases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
entinostat	decreases expression, affects cotreatment	2
(+)-JQ1 compound	decreases expression	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Cisplatin	affects cotreatment, decreases expression	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Valproic Acid	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
methylmercuric chloride	decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	affects methylation	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
abrine	increases expression	1
dorsomorphin	increases expression, affects cotreatment, decreases expression	1

Cellosaurus cell lines

16 cell lines: 15 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0455	NCI-H292	Cancer cell line	Female
CVCL_A464	NCI-H3118	Cancer cell line	Female
CVCL_B409	Hut292DM	Cancer cell line	Female
CVCL_B7H4	HCM-MEC010	Cancer cell line	Female
CVCL_D7FF	NCI-H292-Luc	Cancer cell line	Female
CVCL_D7U2	Ubigene A-549 MAML2 KO	Cancer cell line	Male
CVCL_D8PR	Ubigene HCT 116 MAML2 KO	Cancer cell line	Male
CVCL_D9J2	Ubigene HEK293 MAML2 KO	Transformed cell line	Female
CVCL_E0GZ	Ubigene HeLa MAML2 KO	Cancer cell line	Female
CVCL_E0ZT	Ubigene NCI-H292 EPCAM KO	Cancer cell line	Female

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