MBD5

Chr 2AD

methyl-CpG binding domain protein 5

Also known as: C2DELq23.1, DEL2Q23.1, MRD1

NCBI Gene: 55777ENSG00000204406UniProt: Q9P267OMIM: 611472

The protein binds specifically to methylated DNA and interacts with the polycomb repressive complex PR-DUB to regulate histone deubiquitination. Haploinsufficiency causes autosomal dominant intellectual developmental disorder characterized by microcephaly, intellectual disabilities, severe speech impairment, and seizures. The pathogenic mechanism involves loss of function mutations leading to reduced gene expression.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismADLOEUF 0.141 OMIM phenotype
Clinical Summary— MBD5
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Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
33 unique Pathogenic / Likely Pathogenic· 338 VUS of 500 total submissions
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — MBD5
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.14LOEUF
pLI 1.000
Z-score 6.04
OE 0.04 (0.02–0.14)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint
0.86Z-score
OE missense 0.91 (0.86–0.97)
710 obs / 777.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.04 (0.02–0.14)
0≤0.351.4
Missense OE0.91 (0.86–0.97)
0≤0.61.4
Synonymous OE1.05
0≤1.21.6
LoF obs/exp: 2 / 46.4Missense obs/exp: 710 / 777.1Syn Z: -0.61
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongMBD5-related intellectual developmental disorderLOFAD
DN
0.2897th %ile
GOF
0.1999th %ile
LOF
0.85top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 76% of P/LP variants are LoF · LOEUF 0.14

Literature Evidence

LOFMBD5 haploinsufficiency is a neurodevelopmental disorder characterized by developmental delay / intellectual disability, severe speech impairment, seizures, sleep disturbances, and abnormal behaviors.PMID:27786435

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18
Likely Pathogenic15
VUS338
Likely Benign106
Conflicting7
18
Pathogenic
15
Likely Pathogenic
338
VUS
106
Likely Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
0
5
0
18
Likely Pathogenic
12
0
3
0
15
VUS
3
316
16
3
338
Likely Benign
0
9
22
75
106
Benign
0
0
0
0
0
Conflicting
—7
Total283254678484

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

View in ClinVar →

Protein Context — Lollipop Plot

MBD5 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Haploinsufficiency of MBD5 and MBD6 impairs mitochondrial respiration through chromatin-mediated gene regulation.
Meguro-Horike M et al.·Biochem Biophys Res Commun
2026
A Novel Intronic Mutation in MBD5 Results in Autosomal Dominant Intellectual Disability Type 1 due to Abnormal Splicing.
Jiang H et al.·Mol Genet Genomic Med
2025Open Access
A Unique Case of MBD5 and CCM2 Deletions Leading to a Severe Neurological Phenotype With Prolonged Status Epilepticus.
Silva S et al.·Clin Genet
2025
Zebrafish Mbd5 binds to RNA m5C and regulates histone deubiquitylation and gene expression in development metabolism and behavior.
Guo J et al.·Nucleic Acids Res
2024Open AccessFunctional
A Novel Genetic Variant in MBD5 Associated with Severe Epilepsy and Intellectual Disability: Potential Implications on Neural Primary Cilia.
Martins M et al.·Int J Mol Sci
2023Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients