MSL2

Chr 3AD

MSL complex subunit 2

Also known as: KBHS, MSL-2, MSL2L1, RNF184

NCBI Gene: 55167 ENSG00000174579 UniProt: Q9HCI7 OMIM: 614802

MSL2 encodes a non-catalytic component of the MSL histone acetyltransferase complex that mediates histone H4 acetylation and acts as an E3 ubiquitin ligase for histone H2B, playing essential roles in chromatin regulation, gene dosage compensation, and DNA damage response. Mutations cause Karayol-Borroto-Haghshenas neurodevelopmental syndrome with autosomal dominant inheritance. The gene shows significant constraint against loss-of-function variants (LOEUF 0.481), reflecting its critical role in cellular function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Enables histone H2B ubiquitin ligase activity. Involved in DNA damage response and protein monoubiquitination. Located in nucleus. Part of MSL complex. Is active in chromatin. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Karayol-Borroto-Haghshenas neurodevelopmental syndromeMIM #620985

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Karayol-Borroto-Haghshenas neurodevelopmental syndrome; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.48

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.48LOEUF

pLI 0.624

Z-score 3.03

OE 0.19 (0.08–0.48)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.00Z-score

OE missense 0.68 (0.61–0.76)

210 obs / 309.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.19 (0.08–0.48)

0≤0.351.4

Missense OE?0.68 (0.61–0.76)

0≤0.61.4

Synonymous OE?1.27

0≤1.21.6

LoF obs/exp: 3 / 16.1Missense obs/exp: 210 / 309.1Syn Z: -2.27

Background carrier burden — how many people carry a rare variant somewhere in MSL2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

568 rare PASS variants

Rare truncating (LoF)

1 in 150,000

5 rare PASS variants

Rare synonymous (reference)

1 in 160

310 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MSL2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 110	≈ 1 in 140,000
South Asian	~43k	1 in 190	none seen
Remaining (unassigned)	~30k	1 in 130	none seen
European (Finnish)	~27k	1 in 340	none seen
Admixed American	~22k	1 in 160	≈ 1 in 22,000
African / African American	~21k	1 in 150	none seen
East Asian	~20k	1 in 130	none seen
Ashkenazi Jewish	~13k	1 in 1,100	none seen
Middle Eastern	~2,884	1 in 210	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓