MBD5

Chr 2AD

methyl-CpG binding domain protein 5

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

NCBI Gene: 55777 ENSG00000204406 UniProt: Q9P267 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the methyl-CpG-binding domain (MBD) family. The MBD consists of about 70 residues and is the minimal region required for a methyl-CpG-binding protein binding specifically to methylated DNA. In addition to the MBD domain, this protein contains a PWWP domain (Pro-Trp-Trp-Pro motif), which consists of 100-150 amino acids and is found in numerous proteins that are involved in cell division, growth and differentiation. Mutations in this gene cause an autosomal dominant type of cognitive disability. The encoded protein interacts with the polycomb repressive complex PR-DUB which catalyzes the deubiquitination of a lysine residue of histone 2A. Haploinsufficiency of this gene is associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures. Alternatively spliced transcript variants have been found, but their full-length nature is not determined. [provided by RefSeq, Jul 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

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

144 unique Pathogenic / Likely Pathogenic· 916 VUS of 1834 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 OE?0.04 (0.02–0.14)

0≤0.351.4

Missense OE?0.91 (0.86–0.97)

0≤0.61.4

Synonymous OE?1.05

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

This gene — mechanism propensity

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 · 81% of P/LP variants are LoF · LOEUF 0.14 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFMBD5 haploinsufficiency is a neurodevelopmental disorder characterized by developmental delay / intellectual disability, severe speech impairment, seizures, sleep disturbances, and abnormal behaviors.1

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

References

1.PMID 27786435 ↗

ClinVar Variant Classifications

1834 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic101

Likely Pathogenic43

VUS916

Likely Benign577

Benign38

Conflicting142

101

Pathogenic

Likely Pathogenic

916

VUS

577

Likely Benign

Benign

142

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	82	1	18	0	101
Likely Pathogenic	35	5	3	0	43
VUS	9	878	21	8	916
Likely Benign	0	136	89	352	577
Benign	0	9	25	4	38
Conflicting	—				142
Total	126	1,029	156	364	1,817

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

View in ClinVar →

70 pathogenic / likely-pathogenic (of 109) ClinVar copy-number / structural variants overlap MBD5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →