EPC2

Chr 2

enhancer of polycomb 2

Also known as: EPC-LIKE

NCBI Gene: 26122 ENSG00000135999 OMIM: 611000

The EPC2 protein is part of the NuA4 histone acetyltransferase complex and regulates DNA double-strand break repair via homologous recombination and cell cycle progression. Mutations cause autosomal dominant neurodevelopmental disorders with intellectual disability and developmental delay. This gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.16), indicating that haploinsufficiency is likely not tolerated in the general population.

OMIM ResearchSummary from RefSeq, UniProt

Involved in positive regulation of double-strand break repair via homologous recombination and regulation of cell cycle. Part of NuA4 histone acetyltransferase complex and nucleosome. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.16

Clinical Summary— EPC2

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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

1 unique Pathogenic / Likely Pathogenic· 75 VUS of 93 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.16LOEUF

pLI 1.000

Z-score 5.53

OE 0.05 (0.02–0.16)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.70Z-score

OE missense 0.62 (0.56–0.69)

251 obs / 403.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.16)

0≤0.351.4

Missense OE?0.62 (0.56–0.69)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 2 / 39.6Missense obs/exp: 251 / 403.6Syn Z: -0.45

This gene — mechanism propensity

0.2898th %ile

GOF

0.2597th %ile

LOF

0.86top 5%

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

LOFprediction above median · LOEUF 0.16

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

93 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS75

Benign5

Pathogenic

VUS

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	1
Likely Pathogenic	0	0	0	0
VUS	75	0	0	75
Likely Benign	0	0	0	0
Benign	0	1	4	5
Total	75	2	4	81

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap EPC2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →