MECP2

Chr XX-linkedXLRXLD

methyl-CpG binding protein 2

Also known as: AUTSX3, MRX16, MRX79, MRXS13, MRXSL, PPMX, RS, RTS

NCBI Gene: 4204 ENSG00000169057 UniProt: P51608

DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

Primary Disease Associations & Inheritance

{Autism susceptibility, X-linked 3}MIM #300496

X-linked

Encephalopathy, neonatal severeMIM #300673

XLR

Intellectual developmental disorder, X-linked syndromic 13MIM #300055

XLR

Intellectual developmental disorder, X-linked syndromic, Lubs typeMIM #300260

XLR

Rett syndromeMIM #312750

XLD

Rett syndrome, atypicalMIM #312750

XLD

Rett syndrome, preserved speech variantMIM #312750

XLD

UniProtAngelman syndrome

UniProtAutism, X-linked 3

672

ClinVar variants

247

Pathogenic / LP

0.89

pLI score

Active trials

Clinical Summary— MECP2

🧬

Gene-Disease Validity (ClinGen)

Rett syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.89) — some intolerance to loss-of-function variants.

📋

ClinVar Variants

247 Pathogenic / Likely Pathogenic· 229 VUS of 672 total submissions

💊

Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

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.

0.41LOEUF

pLI 0.894

Z-score 2.89

OE 0.09 (0.03–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

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.

-1.21Z-score

OE missense 1.23 (1.11–1.35)

281 obs / 229.3 exp

Tolerant

Tolerant to missense variation

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.0.09 (0.03–0.41)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.23 (1.11–1.35)

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.2.03

0≤1.21.6

LoF obs/exp: 1 / 11.7Missense obs/exp: 281 / 229.3Syn Z: -7.95

ClinVar Variant Classifications

672 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic183

Likely Pathogenic64

VUS229

Likely Benign169

Benign20

Conflicting7

183

Pathogenic

Likely Pathogenic

229

VUS

169

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	88	7	88	0	183
Likely Pathogenic	35	21	8	0	64
VUS	9	163	52	5	229
Likely Benign	0	16	45	108	169
Benign	0	6	9	5	20
Conflicting	—				7
Total	132	213	202	118	672

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

View in ClinVar →

Protein Context — Lollipop Plot

MECP2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

MECP2-related duplication syndrome

definitive

Monoallelic X HemizygousUndeterminedIncreased Gene Product Level

Dev. Disorders

G2P ↗

whole partial gene duplication

MECP2-related Rett syndrome

definitive

Monoallelic X HeterozygousLoss Of FunctionAbsent Gene Product

Dev. Disorders

G2P ↗

MECP2-related encephalopathy neonatal severe

definitive

Monoallelic X HemizygousLoss 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

METHYL-CpG-BINDING PROTEIN 2; MECP2

MIM #300005 · *

{Autism susceptibility, X-linked 3}

MIM #300496