MEF2C

Summary

MEF2C (myocyte enhancer factor 2C, HGNC:6996) is a protein-coding gene on chromosome 5q14.3, encoding Myocyte-specific enhancer factor 2C (Q06413). Transcription activator which binds specifically to the MEF2 element present in the regulatory regions of many muscle-specific genes. It is haploinsufficient (ClinGen: sufficient evidence).

This locus encodes a member of the MADS box transcription enhancer factor 2 (MEF2) family of proteins, which play a role in myogenesis. The encoded protein, MEF2 polypeptide C, has both trans-activating and DNA binding activities. This protein may play a role in maintaining the differentiated state of muscle cells. Mutations and deletions at this locus have been associated with severe cognitive disability, stereotypic movements, epilepsy, and cerebral malformation. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 4208 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 103
• Clinical variants (ClinVar): 632 total — 85 pathogenic, 44 likely-pathogenic
• Phenotypes (HPO): 48
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity little evidence
• Transcription factor: yes — 97 downstream targets (CollecTRI)
• MANE Select transcript: NM_002397

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6996
Approved symbol	MEF2C
Name	myocyte enhancer factor 2C
Location	5q14.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000081189
Ensembl biotype	protein_coding
OMIM	600662
Entrez	4208

Gene structure

Transcript identifiers

Ensembl transcripts: 117 — 94 protein_coding, 19 protein_coding_CDS_not_defined, 4 retained_intron

ENST00000340208, ENST00000424173, ENST00000437473, ENST00000502831, ENST00000502983, ENST00000503075, ENST00000503554, ENST00000503955, ENST00000504921, ENST00000506554, ENST00000506716, ENST00000507984, ENST00000508569, ENST00000508610, ENST00000509349, ENST00000509373, ENST00000510942, ENST00000510980, ENST00000511086, ENST00000513252, ENST00000514015, ENST00000514028, ENST00000515093, ENST00000515715, ENST00000625585, ENST00000625674, ENST00000626391, ENST00000627170, ENST00000627659, ENST00000627717, ENST00000628656, ENST00000629612, ENST00000629847, ENST00000631026, ENST00000635837, ENST00000635898, ENST00000636061, ENST00000636143, ENST00000636294, ENST00000636336, ENST00000636349, ENST00000636517, ENST00000636541, ENST00000636998, ENST00000637048, ENST00000637167, ENST00000637231, ENST00000637372, ENST00000637481, ENST00000637506, ENST00000637531, ENST00000637663, ENST00000637664, ENST00000637732, ENST00000637754, ENST00000637801, ENST00000707127, ENST00000860108, ENST00000860109, ENST00000860110, ENST00000860111, ENST00000860112, ENST00000860113, ENST00000860114, ENST00000860115, ENST00000860116, ENST00000860117, ENST00000860118, ENST00000860119, ENST00000860120, ENST00000860121, ENST00000860122, ENST00000860123, ENST00000860124, ENST00000860125, ENST00000860126, ENST00000860127, ENST00000860128, ENST00000860129, ENST00000860130, ENST00000860131, ENST00000860132, ENST00000860133, ENST00000860134, ENST00000860135, ENST00000929471, ENST00000944370, ENST00000944371, ENST00000944372, ENST00000944373, ENST00000944374, ENST00000944375, ENST00000944376, ENST00000944377, ENST00000944378, ENST00000944379, ENST00000944380, ENST00000944381, ENST00000944382, ENST00000944383, ENST00000944384, ENST00000944385, ENST00000944386, ENST00000944387, ENST00000944388, ENST00000944389, ENST00000944390, ENST00000944391, ENST00000944392, ENST00000944393, ENST00000944394, ENST00000944395, ENST00000944396, ENST00000944397, ENST00000944398, ENST00000944399, ENST00000944400

RefSeq mRNA: 36 — MANE Select: NM_002397 NM_001131005, NM_001193347, NM_001193348, NM_001193349, NM_001193350, NM_001308002, NM_001363581, NM_001364329, NM_001364330, NM_001364331, NM_001364332, NM_001364333, NM_001364334, NM_001364335, NM_001364336, NM_001364337, NM_001364338, NM_001364339, NM_001364340, NM_001364341, NM_001364342, NM_001364343, NM_001364344, NM_001364345, NM_001364346, NM_001364347, NM_001364348, NM_001364349, NM_001364350, NM_001364352, NM_001364353, NM_001364354, NM_001364355, NM_001364356, NM_001364357, NM_002397

CCDS: CCDS47244, CCDS47245, CCDS54877, CCDS54878, CCDS78030, CCDS78034, CCDS87313, CCDS93738, CCDS93740

Canonical transcript exons

ENST00000504921 — 11 exons

Exon	Start	End
ENSE00000870640	88729218	88729347
ENSE00000870642	88731729	88731901
ENSE00001427522	88823735	88823930
ENSE00001631499	88730211	88730234
ENSE00002266008	88717117	88722925
ENSE00002383329	88804598	88804801
ENSE00003462732	88728493	88728628
ENSE00003468224	88751857	88752043
ENSE00003533951	88749070	88749117
ENSE00003627872	88761185	88761328
ENSE00003900091	88882955	88883184

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 99.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 83.8040 / max 10176.7125, expressed in 1523 samples.

FANTOM5 promoters (26 alternative TSS)

Promoter ID	TPM avg	Samples expressed
62499	62.0272	1333
62500	12.0579	1204
62501	2.5634	656
62502	2.2181	727
62507	1.0302	356
62503	0.5885	182
62493	0.4586	142
62495	0.4166	63
62489	0.3735	155
62510	0.2763	97

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	99.75	gold quality
gluteal muscle	UBERON:0002000	99.66	gold quality
biceps brachii	UBERON:0001507	99.52	gold quality
cortical plate	UBERON:0005343	99.52	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.51	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.47	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.45	gold quality
vastus lateralis	UBERON:0001379	99.24	gold quality
quadriceps femoris	UBERON:0001377	99.14	gold quality
triceps brachii	UBERON:0001509	99.14	gold quality
orbitofrontal cortex	UBERON:0004167	98.99	gold quality
frontal pole	UBERON:0002795	98.96	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.90	gold quality
deltoid	UBERON:0001476	98.88	gold quality
skeletal muscle tissue	UBERON:0001134	98.81	gold quality
adrenal tissue	UBERON:0018303	98.68	gold quality
calcaneal tendon	UBERON:0003701	98.63	gold quality
diaphragm	UBERON:0001103	98.62	gold quality
body of tongue	UBERON:0011876	98.58	gold quality
primary visual cortex	UBERON:0002436	98.55	gold quality
occipital lobe	UBERON:0002021	98.50	gold quality
tibia	UBERON:0000979	98.47	gold quality
superior frontal gyrus	UBERON:0002661	98.44	gold quality
tibialis anterior	UBERON:0001385	98.43	gold quality
periodontal ligament	UBERON:0008266	97.90	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.76	gold quality
muscle tissue	UBERON:0002385	97.62	gold quality
monocyte	CL:0000576	97.57	gold quality
sural nerve	UBERON:0015488	97.50	gold quality
parietal lobe	UBERON:0001872	97.38	gold quality

Single-cell (SCXA)

Detected in 29 experiment(s), a significant marker in 28.

Experiment	Marker?	Max mean expression
E-GEOD-124472	yes	1332.35
E-GEOD-75140	yes	1165.49
E-GEOD-75688	yes	733.10
E-GEOD-114530	yes	579.07
E-HCAD-5	yes	514.68
E-MTAB-9388	yes	487.66
E-HCAD-4	yes	128.05
E-CURD-122	yes	111.64
E-HCAD-10	yes	63.18
E-HCAD-35	yes	62.94
E-MTAB-10287	yes	50.86
E-MTAB-10553	yes	45.15
E-MTAB-6701	yes	44.51
E-HCAD-25	yes	36.65
E-MTAB-8410	yes	35.06

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

97 targets.

Target	Regulation
ADAM2
ADSS1	Unknown
AMPD1	Activation
ASCL1
BCO1	Activation
BGLAP	Activation
BMP10
BMP2	Unknown
BMP4
CALR	Activation
CAT
CDKL5	Unknown
CKM	Activation
COL2A1	Activation
CPT1A
CPT1B	Activation
CSRP3	Unknown
CTNNA3	Activation
CTNNB1
DES	Activation
DLX5	Unknown
DLX6	Unknown
EIF3K
EP300
FOS
FPGT-TNNI3K	Activation
FRZB	Activation
FSD1
GRIN1
GTF2IRD1

JASPAR motifs

Motif	Name	Family
MA0497.1	MEF2C	Regulators of differentiation
MA0497.2	MEF2C	Regulators of differentiation

JASPAR matrix evidence (PMIDs): PMID:7559475

Upstream regulators (CollecTRI, top): AR, CBX5, FOXH1, FOXJ3, GATA4, GATA5, GFI1B, HDAC7, HEY1, HIPK2, HOXA10, HOXA9, ISL1, JAZF1, LYL1, MECP2, MEF2A, MEF2C, MYCN, MYOD1, MYOG, NKX2-5, NRL, RPE65, SIRT1, SMAD3, STAT5A, STAT5B, TAL1, TBX20, TWIST1

miRNA regulators (miRDB)

334 targeting MEF2C, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4668-3P	100.00	68.74	2635
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-188-3P	100.00	68.76	1240
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4715-3P	99.98	66.03	670

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 1 (little evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Individuals possessing more susceptible XRCC1 Gln-Gln genotypes were more likely to reveal p53 overexpression. Susceptible XRCC1 genotypes may modulate the mutation of the p53 gene among VCM-exposed workers. (PMID:12010862)
• Fibrosis in radiotherapy-treated breast neoplasms tends to be higher in patients being polymorphic in XRCC1 when compared to patients with wildtype genotype. (PMID:20170971)
• MEF2C carboxy terminus (aa 387-473) deletion enhances transcriptional activation. AA 312-367 coupled with aa 1-86 activates transcription. Deletion of aa 312-350 decreases transcription. (PMID:11744164)
• The C-terminal region in MEF2C contains signals that are necessary to localize the histone deacetylase 4/MEF2 complex to the nucleus. (PMID:11792813)
• The DNA-binding TEA domain of transcription factor TEF-1 interacts with the MADS/MEF2 domain of MEF2C. (PMID:12061776)
• upregulation of expression by C-terminus of myogenin (PMID:12135755)
• The skeletal muscle-specific transcription cofactor vestigial-like 2 interacts with the C-terminal domain of MEF2C. (PMID:12376544)
• myogenin and myocyte enhancer factor-2 expression are triggered by membrane hyperpolarization during human myoblast differentiation (PMID:15084602)
• MEF2C is acetylated by p300 both in vitro and in vivo, which enhances its DNA binding activity, transcriptional activity, and myogenic differentiation. (PMID:15831463)
• A conserved pattern of alternative splicing in vertebrate MEF2 (myocyte enhancer factor 2) genes generates an acidic activation domain in MEF2 proteins selectively in tissues where MEF2 target genes are highly expressed. (MEF2) (PMID:15834131)
• data show a dosage-dependent cardiomyopathic phenotype and a progressive reduction in ventricular performance associated with MEF2A or MEF2C overexpression (PMID:16469744)
• Phosphorylation of MEF2C at S396 aids sumoylation at K391, which recruits yet unidentified corepressors to inhibit transcription. Sumoylation motifs with a phosphorylated serine or an acidic residue at the +5 position might be more efficiently sumoylated. (PMID:16478538)
• Study demonstrates that human intestinal cell BCMO1 expression is dependent on the functional cooperation between peroxisome proliferator-activated receptor-gamma and myocyte enhancer factor 2 isoforms. (PMID:16504037)
• Overexpression of MEF2C is associated with hepatocellular carcinoma (PMID:17611778)
• Results show the altered interaction between the different variants in the PGC-1alpha gene and MEF2C may attribute to the susceptibility to type 2 diabetes in the southern Chinese population. (PMID:18067759)
• In T-ALL cell lines, MEF2C is activated by NKX2-5 at both the RNA and protein levels. MEF2C consistently inhibits expression of NR4A1/NUR77, which regulates apoptosis via BCL2 transformation. (PMID:18079734)
• Thus, ERK5 phosphorylation contributes to MEF2C activation and subsequent HASMC hypertrophy induced by Ang II (PMID:19011954)
• the association of the 482G/A polymorphism of the PGC-1alpha gene with type 2 diabetes and the quantitative and qualitative binding force changes between the PGC-1alpha domain mutant and MEF2C (PMID:19065516)
• MEF2 proteins are an important component in Galpha13-mediated angiogenesis. (PMID:19093215)
• These results strongly suggest that haploinsufficiency of MEF2C is responsible for severe mental retardation with stereotypic movements, seizures and/or cerebral malformations. (PMID:19592390)
• MEF2C is involved in the effect of insulin on skeletal muscle in type 2 diabetes. (PMID:19720801)
• Studies indicate that MAML1 functions as a coactivator for the tumor suppressor p53, MEF2C, beta-catenin and Notch signaling. (PMID:19751190)
• Muscle-growth geene MEF2C gene expression is enhanced by essential amino acid ingestion. (PMID:19828686)
• These deletions further support that haploinsufficiency of MEF2C is responsible for severe mental retardation, seizures, and hypotonia. (PMID:20333642)
• we present two additional patients with severe mental retardation, autism spectrum disorder and epilepsy, carrying a very small deletion encompassing the MEF2C gene. (PMID:20412115)
• Data indicate that MEF2C missense de novo mutations in severe mental retardation showed diminished MECP2 and CDKL5 expression. (PMID:20513142)
• Binding sequences for the Mef2 family of transcription factors were enriched in the AR-bound regions, and data show that several Mef2c-dependent genes are direct targets of AR, suggesting a functional interaction between Mef2c and AR in skeletal muscle. (PMID:20610535)
• RNA-binding protein Muscleblind-like 3 (MBNL3) disrupts myocyte enhancer factor 2 (Mef2) {beta}-exon splicing (PMID:20709755)
• NKX2-1, NKX2-2, and MEF2C define oncogenic pathways in T cell acute lymphoblastic leukemia (T-ALL). (PMID:21481790)
• knockdown of bone-specific transcription factors, Runx2 and osterix by shRNAi knockdown of Mef2c, suggests that Mef2c lies upstream of these two important factors in the cascade of gene expression in osteoblasts. (PMID:21652706)
• MEF2C is a transcriptional regulator of homeostasis in rod photoreceptor cells (PMID:21849497)
• Data report that forced expression of constitutively active MEF2C (MEF2CA) generates significantly greater numbers of neurons with dopaminergic properties in vitro. (PMID:21901155)
• suggest that PRL-3 functions downstream of the VEGF/MEF2C pathway in endothelial cells and may play an important role in tumor angiogenesis (PMID:22073279)
• a novel signaling cascade that links RhoA-mediated calcium sensitivity to MEF2-dependent myocardin expression in VSMCs through a mechanism involving p38 MAPK, PP1alpha, and CPI-17. (PMID:22275376)
• The present study investigated the effect of heart failure aetiology on Ca(+2) handling proteins and NFAT1, MEF2C and GATA4 (transcription factors) in the same cardiac tissue. (PMID:22363514)
• Mutations in MEF2C are probably a very rare cause of Rett syndrome. (PMID:22449245)
• 15 bp-deletion and C-insertion in the 5’UTR region of MEF2C could affect hypertrophic cardiomyopathy, potentially by affecting expression of MEF2C. (PMID:22718505)
• genetic association study in population of 1,012 Han women in China: Data suggest that an SNP in MEF2C (rs1366594) is associated with bone mineral density of lumbar spine and hip joint in aging women. (PMID:22798246)
• Allele frequencies of three Alu insertions that are located in MEF2C (two of them) and TAX1BP1 genes significantly differ between cohorts of healthy donors and ALL(acute lymphoblastic leukemia) patients. (PMID:22997707)
• A targeted search for MEF2C mutations could be applied to patients with a severe intellectual deficiency associated with absence of language and hypotonia, strabismus, and epilepsy. (PMID:23001426)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mef2cb	ENSDARG00000009418
danio_rerio	mef2ca	ENSDARG00000029764
mus_musculus	Mef2c	ENSMUSG00000005583
rattus_norvegicus	Mef2c	ENSRNOG00000033134

Paralogs (4): MEF2A (ENSG00000068305), SRF (ENSG00000112658), MEF2D (ENSG00000116604), MEF2B (ENSG00000213999)

Protein

Protein identifiers

Myocyte-specific enhancer factor 2C — Q06413 (reviewed: Q06413)

Alternative names: Myocyte enhancer factor 2C

All UniProt accessions (22): Q06413, A0A0D9SET2, A0A0D9SFD0, A0A0D9SFV9, A0A0D9SG58, A0A0D9SGF3, A0A0D9SGI5, A0A0R4J2G5, A0A1B0GTW4, A0A1B0GV32, A0A1B0GVI4, A0A9L9PYA3, D6R942, D6RB91, D6RC63, D6RCM6, D6RG14, D6RG21, D6RJ95, D6RJA7, D6RJG6, D8L7E9

UniProt curated annotations — full annotation on UniProt →

Function. Transcription activator which binds specifically to the MEF2 element present in the regulatory regions of many muscle-specific genes. Controls cardiac morphogenesis and myogenesis, and is also involved in vascular development. Enhances transcriptional activation mediated by SOX18. Plays an essential role in hippocampal-dependent learning and memory by suppressing the number of excitatory synapses and thus regulating basal and evoked synaptic transmission. Crucial for normal neuronal development, distribution, and electrical activity in the neocortex. Necessary for proper development of megakaryocytes and platelets and for bone marrow B-lymphopoiesis. Required for B-cell survival and proliferation in response to BCR stimulation, efficient IgG1 antibody responses to T-cell-dependent antigens and for normal induction of germinal center B-cells. May also be involved in neurogenesis and in the development of cortical architecture. Isoforms that lack the repressor domain are more active than isoform 1.

Subunit / interactions. Forms a complex with class II HDACs in undifferentiating cells. On myogenic differentiation, HDACs are released into the cytoplasm allowing MEF2s to interact with other proteins for activation. Interacts with EP300 in differentiating cells; the interaction acetylates MEF2C leading to increased DNA binding and activation. Interacts with HDAC7 and CARM1. Interacts with HDAC4 and HDAC9; the interaction with HDACs represses transcriptional activity. Interacts with LPIN1. Interacts with MYOCD. Interacts with AKAP13. Interacts with FOXK1; the interaction inhibits MEF2C transactivation activity. Interacts (via N-terminus) with HABP4; this interaction decreases DNA-binding activity of MEF2C in myocardial cells in response to mechanical stress. Interacts with JPH2; interaction specifically takes place with the Junctophilin-2 N-terminal fragment cleavage product of JPH2. Interacts (via MADS box) with SOX18. Interacts with PHF7; the interaction promotes MEF2C binding to its transcription targets.

Subcellular location. Nucleus. Cytoplasm. Sarcoplasm.

Tissue specificity. Expressed in brain and skeletal muscle.

Post-translational modifications. Phosphorylation on Ser-59 enhances DNA binding activity. Phosphorylation on Ser-396 is required for Lys-391 sumoylation and inhibits transcriptional activity. Acetylated by p300 on several sites in diffentiating myocytes. Acetylation on Lys-4 increases DNA binding and transactivation. Sumoylated on Lys-391 with SUMO2 but not by SUMO1 represses transcriptional activity. Proteolytically cleaved in cerebellar granule neurons, probably by caspase 7, following neurotoxicity. Preferentially cleaves the CDK5-mediated hyperphosphorylated form which leads to neuron apoptosis and transcriptional inactivation.

Disease relevance. Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (NEDHSIL) [MIM:613443] An autosomal dominant disorder characterized by impaired intellectual development, absent speech, hypotonia, poor eye contact and stereotypic movements. Dysmorphic features include high broad forehead with variable small chin, short nose with anteverted nares, large open mouth, upslanted palpebral fissures and prominent eyebrows. Some patients have seizures. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The beta domain, missing in a number of isoforms, is required for enhancement of transcriptional activity.

Similarity. Belongs to the MEF2 family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q06413-1	1	yes
Q06413-2	2, Muscle
Q06413-3	3, hMEF2C-delta32, Brain
Q06413-4	4
Q06413-5	5
Q06413-6	6

RefSeq proteins (36): NP_001124477, NP_001180276, NP_001180277, NP_001180278, NP_001180279, NP_001294931, NP_001350510, NP_001351258, NP_001351259, NP_001351260, NP_001351261, NP_001351262, NP_001351263, NP_001351264, NP_001351265, NP_001351266, NP_001351267, NP_001351268, NP_001351269, NP_001351270, NP_001351271, NP_001351272, NP_001351273, NP_001351274, NP_001351275, NP_001351276, NP_001351277, NP_001351278, NP_001351279, NP_001351281, NP_001351282, NP_001351283, NP_001351284, NP_001351285, NP_001351286, NP_002388* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002100	TF_MADSbox	Domain
IPR022102	HJURP_C	Domain
IPR033896	MEF2-like_N	Domain
IPR036879	TF_MADSbox_sf	Homologous_superfamily

Pfam: PF00319, PF12347

UniProt features (59 total): modified residue 19, mutagenesis site 19, region of interest 5, splice variant 5, compositionally biased region 3, sequence variant 2, chain 1, domain 1, site 1, DNA-binding region 1, cross-link 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q06413-F1	56.80	0.20

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): 432–433 (cleavage)

Post-translational modifications (20): 4, 59, 98, 106, 110, 116, 119, 222, 228, 234, 239, 240, 252, 264, 293, 300, 396, 419, 445, 391

Mutagenesis-validated functional residues (19):

Position	Phenotype
116	reduced acetylation. further reduction in acetylation; when associated with r-119. complete loss of acetylation, 15% les
119	reduced acetylation. further reduction in acetylation; when associated with r-119. complete loss of acetylation, 15% les
234	reduced acetylation. complete loss of acetylation, 15% less transactivation activity and slightly reduced dna binding; w
239	reduced acetylation. complete loss of acetylation, 15% less transactivation activity and slightly reduced dna binding; w
252	reduced acetylation. complete loss of acetylation, 15% less transactivation activity and slightly reduced dna binding; w
264	reduced acetylation. complete loss of acetylation, 15% less transactivation activity and slightly reduced dna binding; w
271	no effect on transcriptional activation.
272	reduced transcriptional activation. completely abolishes transcriptional activation; when associated with n-273 and n-27
273	reduced transcriptional activation. completely abolishes transcriptional activation; when associated with q-272 and n-27
275	reduced transcriptional activation. completely abolishes transcriptional activation; when associated with q-272 and n-27
293	abolishes mapk14-mediated phosphorylation. no effect on mapk7-mediated phosphorylation; when associated with a-300.
300	abolishes mapk14-mediated phosphorylation. no effect on mapk7-mediated phosphorylation; when associated with a-293.
387	no change in transactivational activation for isoforms with or without the beta domain.
391	abolishes sumoylation.
396	abolishes sumoylation. enhanced transcriptional activity.
396	no change in transactivational activation for isoforms with or without the beta domain.
396	no effect on sumoylation. no effect on transcriptional activity.
419	no effect on mapk14-mediated phosphorylation. abolishes mapk7-mediated phosphorylation and reduces transactivation activ
432	abolishes cleavage by caspase 7.

Function

Pathways and Gene Ontology

Reactome pathways

45 pathways

ID	Pathway
R-HSA-198753	ERK/MAPK targets
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-525793	Myogenesis
R-HSA-9022707	MECP2 regulates transcription factors
R-HSA-9707616	Heme signaling
R-HSA-9733709	Cardiogenesis
R-HSA-9931509	Expression of BMAL (ARNTL), CLOCK, and NPAS2
R-HSA-1266738	Developmental Biology
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1592230	Mitochondrial biogenesis
R-HSA-162582	Signal Transduction
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-166166	MyD88-independent TLR4 cascade
R-HSA-166520	Signaling by NTRKs
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168142	Toll Like Receptor 10 (TLR10) Cascade
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade
R-HSA-168176	Toll Like Receptor 5 (TLR5) Cascade
R-HSA-168179	Toll Like Receptor TLR1:TLR2 Cascade
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade
R-HSA-168188	Toll Like Receptor TLR6:TLR2 Cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168898	Toll-like Receptor Cascades
R-HSA-181438	Toll Like Receptor 2 (TLR2) Cascade
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-198725	Nuclear Events (kinase and transcription factor activation)
R-HSA-212436	Generic Transcription Pathway

MSigDB gene sets: 1126 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_DENDRITE_DEVELOPMENT, GOBP_REGULATION_OF_CELL_ACTIVATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_SKELETAL_MUSCLE_TISSUE_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT

GO Biological Process (85): negative regulation of transcription by RNA polymerase II (GO:0000122), MAPK cascade (GO:0000165), blood vessel development (GO:0001568), osteoblast differentiation (GO:0001649), neuron migration (GO:0001764), B cell homeostasis (GO:0001782), heart looping (GO:0001947), endochondral ossification (GO:0001958), blood vessel remodeling (GO:0001974), chondrocyte differentiation (GO:0002062), germinal center formation (GO:0002467), regulation of germinal center formation (GO:0002634), response to ischemia (GO:0002931), primary heart field specification (GO:0003138), secondary heart field specification (GO:0003139), outflow tract morphogenesis (GO:0003151), sinoatrial valve morphogenesis (GO:0003185), cardiac ventricle formation (GO:0003211), regulation of DNA-templated transcription (GO:0006355), apoptotic process (GO:0006915), humoral immune response (GO:0006959), nervous system development (GO:0007399), heart development (GO:0007507), muscle organ development (GO:0007517), skeletal muscle tissue development (GO:0007519), muscle cell fate determination (GO:0007521), learning or memory (GO:0007611), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), neural crest cell differentiation (GO:0014033), myotube differentiation (GO:0014902), cell differentiation (GO:0030154), neuron differentiation (GO:0030182), platelet formation (GO:0030220), negative regulation of ossification (GO:0030279), melanocyte differentiation (GO:0030318), positive regulation of bone mineralization (GO:0030501), positive regulation of B cell proliferation (GO:0030890), cellular response to trichostatin A (GO:0035984), B cell proliferation (GO:0042100)

GO Molecular Function (15): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), minor groove of adenine-thymine-rich DNA binding (GO:0003680), DNA-binding transcription factor activity (GO:0003700), histone deacetylase binding (GO:0042826), protein heterodimerization activity (GO:0046982), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), DNA-binding transcription factor binding (GO:0140297), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515), protein dimerization activity (GO:0046983)

GO Cellular Component (9): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), sarcoplasm (GO:0016528), nuclear speck (GO:0016607), protein-containing complex (GO:0032991), postsynapse (GO:0098794)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Toll-like Receptor Cascades	5
Developmental Biology	2
Toll Like Receptor 4 (TLR4) Cascade	2
Nuclear Events (kinase and transcription factor activation)	1
MAPK targets/ Nuclear events mediated by MAP kinases	1
Mitochondrial biogenesis	1
Transcriptional Regulation by MECP2	1
Cellular responses to stress	1
Circadian clock	1
Immune System	1
Organelle biogenesis and maintenance	1
Toll Like Receptor TLR1:TLR2 Cascade	1
Toll Like Receptor TLR6:TLR2 Cascade	1
Signaling by Receptor Tyrosine Kinases	1
Toll Like Receptor 2 (TLR2) Cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
cell differentiation	2
heart field specification	2
transcription cis-regulatory region binding	2
cytoplasm	2
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
intracellular signaling cassette	1
vasculature development	1
anatomical structure development	1
ossification	1
cell migration	1
generation of neurons	1
lymphocyte homeostasis	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
replacement ossification	1
endochondral bone morphogenesis	1
tissue remodeling	1
cartilage development	1
adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
anatomical structure formation involved in morphogenesis	1
germinal center formation	1
regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
regulation of anatomical structure morphogenesis	1
response to stress	1
heart morphogenesis	1
anatomical structure morphogenesis	1
sinoatrial valve development	1
heart valve morphogenesis	1
cardiac chamber formation	1
cardiac ventricle morphogenesis	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1

Protein interactions and networks

STRING

3952 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MEF2C	NKX2-5	P52952	970
MEF2C	GATA4	P43694	968
MEF2C	TBX5	Q99593	914
MEF2C	MYOG	P15173	907
MEF2C	HDAC4	P56524	888
MEF2C	CTNNB1	P35222	882
MEF2C	HAND2	P61296	880
MEF2C	HDAC5	Q9UQL6	860
MEF2C	HDAC1	Q13547	855
MEF2C	MYOD1	P15172	847
MEF2C	PPARGC1A	Q9UBK2	818
MEF2C	HDAC9	Q9UKV0	818
MEF2C	MYOCD	Q8IZQ8	809
MEF2C	MYF5	P13349	762
MEF2C	NR2F2	P24468	759

IntAct

49 interactions, top by confidence:

A	B	Type	Score
HDAC4	MEF2C	psi-mi:“MI:0915”(physical association)	0.560
MEF2C	HDAC5	psi-mi:“MI:0915”(physical association)	0.550
MEF2C	HDAC9	psi-mi:“MI:0915”(physical association)	0.550
MEF2C	MYLK2	psi-mi:“MI:0915”(physical association)	0.540
MYLK2	MEF2C	psi-mi:“MI:0217”(phosphorylation reaction)	0.540
HDAC4	NCOR1	psi-mi:“MI:0914”(association)	0.530
CACNA1C	MEF2C	psi-mi:“MI:0915”(physical association)	0.500
MEF2C	CACNA1C	psi-mi:“MI:0915”(physical association)	0.500
MEF2C	Hdac5	psi-mi:“MI:0915”(physical association)	0.490
Hdac5	MEF2C	psi-mi:“MI:0915”(physical association)	0.490
MEF2C	HDAC4	psi-mi:“MI:0403”(colocalization)	0.490
UBE3A	MEF2C	psi-mi:“MI:0915”(physical association)	0.460
UBE3A	MEF2C	psi-mi:“MI:0403”(colocalization)	0.460
KPNA4	MEF2C	psi-mi:“MI:0407”(direct interaction)	0.440
MEF2C	EP300	psi-mi:“MI:0915”(physical association)	0.400
Mylk2	MEF2C	psi-mi:“MI:0915”(physical association)	0.400
MEF2C	PLA2G12A	psi-mi:“MI:0915”(physical association)	0.370
MEF2A	REV3L	psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
HIPK2	MAP3K7	psi-mi:“MI:0914”(association)	0.350
CACNA1C	SYT5	psi-mi:“MI:0914”(association)	0.350
CACNA1C	IGLL5	psi-mi:“MI:0914”(association)	0.350
MEF2A	PTPN5	psi-mi:“MI:0914”(association)	0.350
MEF2B	MEF2A	psi-mi:“MI:0914”(association)	0.350
HDAC5	TBL1X	psi-mi:“MI:0914”(association)	0.350
HDAC7	HDAC3	psi-mi:“MI:0914”(association)	0.350

BioGRID (62): MEF2C (Biochemical Activity), MEF2C (Affinity Capture-Western), SKP2 (Affinity Capture-Western), MEF2C (Affinity Capture-MS), MEF2C (Reconstituted Complex), MEF2C (Affinity Capture-MS), MEF2C (Affinity Capture-Western), HDAC4 (Reconstituted Complex), HDAC4 (Reconstituted Complex), EP300 (Phenotypic Enhancement), EP300 (Reconstituted Complex), MEF2C (Two-hybrid), SP1 (Two-hybrid), MEF2C (Affinity Capture-Western), SOX18 (Reconstituted Complex)

ESM2 similar proteins: A0A096MJY4, A0A486WWJ9, A2ICN5, A2VDZ3, A4UTP7, A8WL06, B7ZR65, H2LBU8, O89038, P10071, P40791, P55197, P55879, Q02078, Q03413, Q03414, Q06413, Q0VGT2, Q14814, Q2KIA0, Q2MJT0, Q32NP8, Q4VYR7, Q5IS56, Q5R444, Q5REW7, Q5U4X3, Q60929, Q61602, Q63943, Q6DFF5, Q6DIF3, Q6F2E7, Q7ZY13, Q8BUR3, Q8CFN5, Q91660, Q91661, Q9DE25, Q9EPK5

Diamond homologs: A0A096MJY4, A0A217EJJ0, A0A3Q7EKL1, A2IB53, A2ICN5, A2VDZ3, A4UTP7, A9YDN6, B0XYE0, B4YPV4, B4YPW6, D7KQR8, D7KWY6, D7SMN6, F6I457, G4MWZ7, I1GN76, O22328, O55087, O65874, O89038, P0C5B0, P0C5B1, P0DI14, P29381, P29385, P29386, P35631, P38128, P40791, Q02078, Q02080, Q03413, Q03414, Q03489, Q06413, Q0J466, Q10CQ1, Q12224, Q14814

SIGNOR signaling

58 interactions.

A	Effect	B	Mechanism
MAML1	up-regulates	MEF2C	binding
CABIN1	down-regulates	MEF2C
CDK4	down-regulates	MEF2C	binding
CDK4	down-regulates	MEF2C
MAPK14	“up-regulates activity”	MEF2C	phosphorylation
CyclinD/CDK4	down-regulates	MEF2C	binding
MEF2C	up-regulates	Skeletal_muscle_differentiation
EP300	up-regulates	MEF2C	binding
MYLK2	“up-regulates activity”	MEF2C	phosphorylation
Calcineurin	up-regulates	MEF2C
NKX2-5	“up-regulates quantity by expression”	MEF2C	“transcriptional regulation”
MEF2C	“up-regulates quantity by expression”	MECP2	“transcriptional regulation”
MEF2C	“up-regulates quantity by expression”	CDKL5	“transcriptional regulation”
GFI1B	“up-regulates quantity by expression”	MEF2C	“transcriptional regulation”
STAT5A	“down-regulates quantity by repression”	MEF2C	“transcriptional regulation”
LYL1	“up-regulates quantity by expression”	MEF2C	“transcriptional regulation”
TAL1	“up-regulates quantity by expression”	MEF2C	“transcriptional regulation”
HOXA9	“down-regulates quantity by repression”	MEF2C	“transcriptional regulation”
HOXA10	“down-regulates quantity by repression”	MEF2C	“transcriptional regulation”
MYCN	“down-regulates quantity by repression”	MEF2C	“transcriptional regulation”
MYLK3	“up-regulates activity”	MEF2C	phosphorylation
MEF2C	“up-regulates quantity by expression”	CTNNA3	“transcriptional regulation”
MEF2C	“up-regulates quantity by expression”	α-Catenin	“transcriptional regulation”
PP2B	up-regulates	MEF2C
HIPK2	“down-regulates activity”	MEF2C	phosphorylation
MAPK11	“up-regulates activity”	MEF2C	phosphorylation
MEF2C	“up-regulates quantity by expression”	JUN	“transcriptional regulation”
MAPK7	up-regulates	MEF2C	phosphorylation
MEF2C	“up-regulates activity”	MYOD1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 38 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Notch-HLH transcription pathway	7	89.2×	9e-11
NOTCH1 Intracellular Domain Regulates Transcription	8	59.5×	9e-11
Constitutive Signaling by NOTCH1 PEST Domain Mutants	8	49.2×	2e-10
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	8	49.2×	2e-10
MAP kinase activation	5	48.2×	3e-06
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	9	41.2×	9e-11
Interleukin-17 signaling	5	39.6×	7e-06
Toll Like Receptor 10 (TLR10) Cascade	5	33.7×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
epigenetic regulation of gene expression	6	65.7×	2e-07
heart development	5	11.2×	4e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	85
Likely pathogenic	44
Uncertain significance	190
Likely benign	213
Benign	41

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070269	NC_000005.9:g.(?87776690)(88119605_?)del	Pathogenic
1070711	NM_002397.5(MEF2C):c.559dup (p.Thr187fs)	Pathogenic
1072396	NC_000005.9:g.(?88027526)(88027738_?)del	Pathogenic
1202675	NM_002397.5(MEF2C):c.-8C>T	Pathogenic
1214083	NM_002397.5(MEF2C):c.259-1G>A	Pathogenic
1272069	NM_002397.5(MEF2C):c.220G>T (p.Glu74Ter)	Pathogenic
1272071	NM_002397.5(MEF2C):c.-26C>T	Pathogenic
1272072	NM_002397.5(MEF2C):c.-66A>T	Pathogenic
1331547	NM_002397.5(MEF2C):c.638-2A>G	Pathogenic
1412055	NC_000005.9:g.(?88047654)(88047880_?)del	Pathogenic
149177	GRCh38/hg38 5q14.3(chr5:88766676-88808855)x1	Pathogenic
158888	NM_002397.5(MEF2C):c.833del (p.Leu277_Leu278insTer)	Pathogenic
167287	NM_002397.5(MEF2C):c.926dup (p.Gly310fs)	Pathogenic
1685944	NM_002397.5(MEF2C):c.44G>C (p.Arg15Pro)	Pathogenic
1703661	GRCh37/hg19 5q14.3(chr5:88065061-88406446)	Pathogenic
1805133	NM_002397.5(MEF2C):c.908del (p.Leu303fs)	Pathogenic
1805734	NM_002397.5(MEF2C):c.939_940del (p.Ala314fs)	Pathogenic
1992493	NC_000005.10:g.88731902del	Pathogenic
2001170	NM_002397.5(MEF2C):c.468del (p.Tyr157fs)	Pathogenic
2007342	NM_002397.5(MEF2C):c.999_1000del (p.Ser334fs)	Pathogenic
206134	NM_002397.5(MEF2C):c.766C>T (p.Arg256Ter)	Pathogenic
2091785	NM_002397.5(MEF2C):c.881del (p.Pro294fs)	Pathogenic
2169514	NM_002397.5(MEF2C):c.79G>A (p.Gly27Arg)	Pathogenic
218315	NM_002397.5(MEF2C):c.9A>T (p.Arg3Ser)	Pathogenic
2317249	NM_002397.5(MEF2C):c.204_208del (p.Lys68fs)	Pathogenic
2424428	NC_000005.9:g.(?88100395)(88100638_?)del	Pathogenic
2424429	NC_000005.9:g.(?88100395)(88119605_?)del	Pathogenic
2424430	NC_000005.9:g.(?88056982)(88119605_?)del	Pathogenic
253415	GRCh37/hg19 5q14.3(chr5:88018116-88183698)x1	Pathogenic
253672	GRCh37/hg19 5q14.3(chr5:88056500-88183698)x1	Pathogenic

SpliceAI

2572 predictions. Top by Δscore:

Variant	Effect	Δscore
5:88722616:T:TA	donor_gain	1.0000
5:88722653:T:A	donor_gain	1.0000
5:88728488:CTTA:C	donor_loss	1.0000
5:88728489:TTA:T	donor_loss	1.0000
5:88728490:TAC:T	donor_loss	1.0000
5:88728491:A:AC	donor_gain	1.0000
5:88728491:AC:A	donor_gain	1.0000
5:88728491:ACC:A	donor_gain	1.0000
5:88728492:C:CC	donor_gain	1.0000
5:88728492:CC:C	donor_gain	1.0000
5:88728492:CCC:C	donor_gain	1.0000
5:88728624:GTACT:G	acceptor_gain	1.0000
5:88728625:TACT:T	acceptor_gain	1.0000
5:88728627:CT:C	acceptor_gain	1.0000
5:88728629:C:CC	acceptor_gain	1.0000
5:88728630:T:C	acceptor_loss	1.0000
5:88728634:T:C	acceptor_gain	1.0000
5:88728634:T:TC	acceptor_gain	1.0000
5:88728641:A:AC	acceptor_gain	1.0000
5:88728641:A:C	acceptor_gain	1.0000
5:88729212:ACT:A	donor_loss	1.0000
5:88729213:CTCA:C	donor_loss	1.0000
5:88729214:TCA:T	donor_loss	1.0000
5:88729215:CA:C	donor_loss	1.0000
5:88729216:A:AC	donor_gain	1.0000
5:88729216:A:T	donor_loss	1.0000
5:88729217:C:CG	donor_gain	1.0000
5:88729343:TGATT:T	acceptor_gain	1.0000
5:88729344:GATT:G	acceptor_gain	1.0000
5:88729345:ATT:A	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000001992 (5:88752826 A>G), RS1000017293 (5:88769976 G>A), RS1000028879 (5:88842915 T>G), RS1000029734 (5:88883674 C>G), RS1000055661 (5:88722125 C>T), RS1000059902 (5:88843282 C>A,T), RS1000092370 (5:88777469 T>C), RS1000099625 (5:88880005 G>A), RS1000126439 (5:88821152 A>G), RS1000152011 (5:88825462 T>C), RS1000162016 (5:88730128 T>C), RS1000179962 (5:88791217 T>A), RS1000202288 (5:88836184 A>C), RS1000243576 (5:88759169 T>C), RS1000252382 (5:88783367 G>A)

Disease associations

OMIM: gene MIM:600662 | disease phenotypes: MIM:613443

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language	Definitive	Autosomal dominant
complex neurodevelopmental disorder	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (9): neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (MONDO:0013266), neurodevelopmental disorder (MONDO:0700092), autism spectrum disorder (MONDO:0005258), intellectual disability (MONDO:0001071), 5q14.3 microdeletion syndrome (MONDO:0016456), frontotemporal dementia (MONDO:0017276), epilepsy (MONDO:0005027), syndromic intellectual disability (MONDO:0000508), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (6): 5q14.3 microdeletion syndrome (Orphanet:228384), Brain abnormalities-severe developmental delay-facial dysmorphism-intellectual disability syndrome (Orphanet:664410), Frontotemporal dementia (Orphanet:282), Rare genetic syndromic intellectual disability (Orphanet:183763), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000180	Lobulated tongue
HP:0000194	Open mouth
HP:0000219	Thin upper lip vermilion
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000331	Short chin
HP:0000337	Broad forehead
HP:0000348	High forehead
HP:0000369	Low-set ears
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000574	Thick eyebrow
HP:0000582	Upslanted palpebral fissure
HP:0000609	Optic nerve hypoplasia
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development
HP:0000817	Reduced eye contact
HP:0000954	Single transverse palmar crease
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001344	Absent speech
HP:0001770	Toe syndactyly
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002198	Dilated fourth ventricle
HP:0002335	Agenesis of cerebellar vermis

GWAS associations

103 associations (top):

Study	Trait	p-value
GCST000107_9	Tonometry	3.000000e-06
GCST000495_5	Bone mineral density (hip)	1.000000e-13
GCST000817_176	Height	2.000000e-18
GCST000847_4	Retinal vascular caliber	7.000000e-16
GCST001050_4	Bone mineral density	8.000000e-10
GCST001050_6	Bone mineral density	1.000000e-07
GCST001335_14	Mean platelet volume	2.000000e-09
GCST001337_26	Platelet count	1.000000e-09
GCST001859_3	Thiazide-induced adverse metabolic effects in hypertensive patients	5.000000e-07
GCST001962_1	Bone mineral density	9.000000e-09
GCST002071_1	Retinal arteriolar caliber	2.000000e-12
GCST002245_14	Alzheimer’s disease (late onset)	3.000000e-08
GCST002276_2	Bone mineral density	7.000000e-18
GCST002539_58	Schizophrenia	5.000000e-09
GCST002647_123	Height	6.000000e-24
GCST002702_117	Height	3.000000e-10
GCST003139_16	Glomerular filtration rate in chronic kidney disease	7.000000e-06
GCST003139_5	Glomerular filtration rate in chronic kidney disease	5.000000e-06
GCST003403_1	Vascular endothelial growth factor levels	1.000000e-11
GCST003654_9	Bone mineral density (Ward’s triangle area)	3.000000e-06
GCST003992_48	Photic sneeze reflex	7.000000e-12
GCST004364_13	Intelligence	1.000000e-08
GCST004364_32	Intelligence	1.000000e-08
GCST004562_123	Waist circumference adjusted for body mass index	7.000000e-11
GCST004562_164	Waist circumference adjusted for body mass index	3.000000e-08
GCST004562_21	Waist circumference adjusted for body mass index	5.000000e-06
GCST004562_98	Waist circumference adjusted for body mass index	6.000000e-06
GCST004563_100	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	2.000000e-10
GCST004563_237	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	8.000000e-08
GCST004564_12	Waist circumference adjusted for BMI in active individuals	8.000000e-06

EFO canonical traits (28, from GWAS)

EFO ID	Trait name
EFO:0004731	eye measurement
EFO:0004309	platelet count
EFO:0004530	triglyceride measurement
EFO:0007785	femoral neck bone mineral density
EFO:0007887	autosomal dominant compelling helio-ophthalmic outburst syndrome
EFO:0004337	intelligence
EFO:0007789	BMI-adjusted waist circumference
EFO:0008002	physical activity measurement
EFO:0004305	erythrocyte count
EFO:0007985	platelet crit
EFO:0007984	platelet component distribution width
EFO:0004527	mean corpuscular hemoglobin
EFO:0004784	self reported educational attainment
EFO:0009180	rosacea severity measurement
EFO:0004340	body mass index
EFO:0007702	hip bone mineral density
EFO:0009592	social interaction measurement
EFO:0004318	smoking behavior
EFO:0008328	chronotype measurement
EFO:0009695	household income
EFO:0008111	diet measurement
EFO:0006781	coffee consumption measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007989	monocyte percentage of leukocytes
EFO:0010701	mean reticulocyte volume
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D057180	Frontotemporal Dementia	C10.228.140.380.266.299; C10.574.950.300.299; C18.452.845.800.300.299; F03.615.400.380.299
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	8
bisphenol A	affects cotreatment, increases expression	3
trichostatin A	affects cotreatment, increases expression	3
Tretinoin	decreases expression, increases expression	3
dorsomorphin	decreases reaction, increases phosphorylation, affects cotreatment, increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Arsenic	affects expression, affects methylation	2
Benzo(a)pyrene	decreases expression, decreases methylation, affects methylation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
TAK-243	increases sumoylation	1
methylmercuric chloride	decreases expression	1
methylselenic acid	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
acadesine	decreases expression	1
sodium arsenite	decreases expression	1
aflatoxin B2	decreases methylation	1
KN 62	increases phosphorylation, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
platycodin D	decreases reaction, increases phosphorylation	1
rofecoxib	affects expression	1
monomethylarsonous acid	increases expression	1
STO 609	decreases reaction, increases phosphorylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
incobotulinumtoxinA	decreases expression	1
Resveratrol	increases expression	1

Cellosaurus cell lines

7 cell lines: 4 cancer cell line, 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A4C2	SEES3-1V human MEF2C, clone1	Embryonic stem cell	Male
CVCL_A4C3	SEES3-1V human MEF2C, clone2	Embryonic stem cell	Male
CVCL_A4C4	SEES3-1V human MEF2C, clone3	Embryonic stem cell	Male
CVCL_B8KC	Abcam HCT 116 MEF2C KO	Cancer cell line	Male
CVCL_B9ML	Abcam A-549 MEF2C KO	Cancer cell line	Male
CVCL_D2GC	Abcam MCF-7 MEF2C KO	Cancer cell line	Female
CVCL_E0HW	Ubigene HeLa MEF2C KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
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
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder