MEF2C

Chr 5AD

myocyte enhancer factor 2C

Also known as: C5DELq14.3, DEL5q14.3, NEDHSIL

NCBI Gene: 4208ENSG00000081189UniProt: Q06413

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. [provided by RefSeq, Jul 2010]

Primary Disease Associations & Inheritance

Chromosome 5q14.3 deletion syndromeMIM #613443
AD
Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired languageMIM #613443
AD
462
ClinVar variants
116
Pathogenic / LP
0.02
pLI score
1
Active trials
Clinical Summary— MEF2C
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.
📋
ClinVar Variants
116 Pathogenic / Likely Pathogenic· 144 VUS of 462 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.61LOEUF
pLI 0.017
Z-score 2.91
OE 0.32 (0.18–0.61)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.95Z-score
OE missense 0.34 (0.29–0.40)
96 obs / 283.2 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.32 (0.18–0.61)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.34 (0.29–0.40)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.84
0≤1.21.6
LoF obs/exp: 7 / 21.6Missense obs/exp: 96 / 283.2Syn Z: 1.37

ClinVar Variant Classifications

462 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic77
Likely Pathogenic39
VUS144
Likely Benign151
Benign32
Conflicting19
77
Pathogenic
39
Likely Pathogenic
144
VUS
151
Likely Benign
32
Benign
19
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
23
5
49
0
77
Likely Pathogenic
9
17
13
0
39
VUS
5
112
25
2
144
Likely Benign
0
12
54
85
151
Benign
1
9
21
1
32
Conflicting
—19
Total3815516288462

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

MEF2C · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

MEF2C-related intellectual developmental disorder, stereotypic movements, epilepsy and/or cerebral malformations

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Chromosome 5q14.3 deletion syndrome

MIM #613443

Contiguous gene syndrome

Autosomal dominant

Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language

MIM #613443

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — MEF2C
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
T-Cell Acute Lymphoblastic Leukemia: Biomarkers and Their Clinical Usefulness.
Bardelli V et al.·Genes (Basel)
2021Review
Single-cell transcriptomic dissection of the cellular and molecular events underlying the triclosan-induced liver fibrosis in mice.
Bai YM et al.·Mil Med Res
2023
Molecular Features of Cancer-associated Fibroblast Subtypes and their Implication on Cancer Pathogenesis, Prognosis, and Immunotherapy Resistance.
Galbo PM Jr et al.·Clin Cancer Res
2021
MEF2C haploinsufficiency syndrome: Report of a new MEF2C mutation and review.
Rocha H et al.·Eur J Med Genet
2016Review
Epstein-Barr virus evades restrictive host chromatin closure by subverting B cell activation and germinal center regulatory loci.
SoRelle ED et al.·Cell Rep
2023
Native stem cell transcriptional circuits define cardinal features of high-risk leukemia.
Wang Q et al.·J Exp Med
2025
Identification of an episignature for the MEF2C-associated syndrome.
Silva A et al.·Eur J Hum Genet
2026
Chromosomal structural rearrangements implicate long non-coding RNAs in rare germline disorders.
Andersen RE et al.·Hum Genet
2024
Genetics of Alzheimer's disease.
Chouraki V et al.·Adv Genet
2014Review
Reprogramming cells with synthetic proteins.
Yang X et al.·Asian J Androl
2015Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools