MSL3

Chr X

MSL complex subunit 3

Also known as: MRSXBA, MRXS36, MRXSBA, MSL3L1

NCBI Gene: 10943ENSG00000005302UniProt: Q8N5Y2

This gene encodes a nuclear protein that is similar to the product of the Drosophila male-specific lethal-3 gene. The Drosophila protein plays a critical role in a dosage-compensation pathway, which equalizes X-linked gene expression in males and females. Thus, the human protein is thought to play a similar function in chromatin remodeling and transcriptional regulation, and it has been found as part of a complex that is responsible for histone H4 lysine-16 acetylation. This gene can undergo X inactivation. Alternative splicing results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 2, 7 and 8. [provided by RefSeq, Jul 2010]

Primary Disease Associations & Inheritance

UniProtBasilicata-Akhtar syndrome
234
ClinVar variants
110
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— MSL3
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Gene-Disease Validity (ClinGen)
Basilicata-Akhtar syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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.
📋
ClinVar Variants
110 Pathogenic / Likely Pathogenic· 95 VUS of 234 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.18LOEUF
pLI 0.997
Z-score 3.80
OE 0.00 (0.00–0.18)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
1.93Z-score
OE missense 0.61 (0.53–0.71)
121 obs / 197.4 exp
Tolerant

Mild missense constraint

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.0.00 (0.00–0.18)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.61 (0.53–0.71)
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.0.90
0≤1.21.6
LoF obs/exp: 0 / 16.8Missense obs/exp: 121 / 197.4Syn Z: 0.67

ClinVar Variant Classifications

234 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic94
Likely Pathogenic16
VUS95
Likely Benign25
Benign4
94
Pathogenic
16
Likely Pathogenic
95
VUS
25
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
1
80
0
94
Likely Pathogenic
10
0
6
0
16
VUS
0
74
21
0
95
Likely Benign
0
13
6
6
25
Benign
0
0
2
2
4
Total23881158234

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

View in ClinVar →

Protein Context — Lollipop Plot

MSL3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

MSL3-related intellectual developmental disorder

definitive
Monoallelic X HeterozygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
MSL2 variants lead to a neurodevelopmental syndrome with lack of coordination, epilepsy, specific dysmorphisms, and a distinct episignature.
Karayol R et al.·Am J Hum Genet
2024
Prolonged Follow-Up in a 30-Year-Old Male With a Novel Pathogenic Variant in MSL3 : A Case Report and a Brief Review of the Literature.
Pisanò G et al.·Am J Med Genet A
2025Review
Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder.
Brunet T et al.·Genet Med
2021
De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation.
Basilicata MF et al.·Nat Genet
2018
Construction of a molecular inflammatory predictive model with histone modification-related genes and identification of CAMK2D as a potential response signature to infliximab in ulcerative colitis.
Ye S et al.·Front Immunol
2024Functional
Neurodevelopmental Profile of a Child With X-linked MSL3 Syndrome.
Capawana MR et al.·Cogn Behav Neurol
2025Case report
Epigenetic activation of CD274/PD-L1 by the MSL complex expands its role beyond dosage compensation.
Wen A et al.·Front Immunol
2025
Acquisition of a side population fraction augments malignant phenotype in ovarian cancer.
Yamanoi K et al.·Sci Rep
2019
Characterization of a novel chromo domain gene in xp22.3 with homology to Drosophila msl-3.
Prakash SK et al.·Genomics
1999
Proteome remodeling in the Mycobacterium tuberculosis PknG knockout: Molecular evidence for the role of this kinase in cell envelope biogenesis and hypoxia response.
Lima A et al.·J Proteomics
2021Functional
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools