MSL2

Chr 3

MSL complex subunit 2

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

NCBI Gene: 55167 ENSG00000174579 UniProt: Q9HCI7

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.

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]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.48

Clinical Summary— MSL2

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.62) — some intolerance to loss-of-function variants.

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ClinVar Variants

14 unique Pathogenic / Likely Pathogenic· 74 VUS of 104 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMSL2-related developmental disorderLOFAD

This gene — mechanism propensity

0.2698th %ile

GOF

0.1999th %ile

LOF

0.77top 5%

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

LOFprediction above median · 79% of P/LP variants are LoF · LOEUF 0.48

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

104 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic7

VUS74

Likely Benign6

Benign2

Conflicting3

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	2	1	0	7
Likely Pathogenic	7	0	0	0	7
VUS	12	62	0	0	74
Likely Benign	0	3	0	3	6
Benign	0	1	1	0	2
Conflicting	—				3
Total	23	68	2	3	99

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap MSL2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →