PSME4

Chr 2

proteasome activator subunit 4

Also known as: Blm10, PA200, hBlm10

NCBI Gene: 23198 ENSG00000068878 UniProt: Q14997 OMIM: 607705

This protein recognizes acetylated histones and activates the proteasome to promote ATP- and ubiquitin-independent degradation of core histones during spermatogenesis and DNA damage response. Mutations cause autosomal recessive developmental and epileptic encephalopathy with microcephaly. The gene is highly constrained against loss-of-function variants, indicating intolerance to protein disruption.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable peptidase activator activity. Predicted to be involved in DNA repair; proteasomal ubiquitin-independent protein catabolic process; and sperm DNA condensation. Located in nucleoplasm. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.18

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.18LOEUF

pLI 1.000

Z-score 8.89

OE 0.11 (0.07–0.18)

Highly constrained

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

Missense Constraint?

2.27Z-score

OE missense 0.79 (0.75–0.84)

757 obs / 954.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.11 (0.07–0.18)

0≤0.351.4

Missense OE?0.79 (0.75–0.84)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 13 / 116.6Missense obs/exp: 757 / 954.3Syn Z: -1.29

Background carrier burden — how many people carry a rare variant somewhere in PSME4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 44

2,173 rare PASS variants

Rare truncating (LoF)

1 in 1,700

158 rare PASS variants

Rare synonymous (reference)

1 in 54

926 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PSME4. 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 50	1 in 1,600
South Asian	~43k	1 in 34	1 in 1,200
Remaining (unassigned)	~30k	1 in 41	1 in 6,000
European (Finnish)	~27k	1 in 110	1 in 2,000
Admixed American	~22k	1 in 49	1 in 1,200
African / African American	~21k	1 in 40	≈ 1 in 4,300
East Asian	~20k	1 in 38	1 in 1,300
Ashkenazi Jewish	~13k	1 in 160	1 in 1,600
Middle Eastern	~2,884	1 in 65	≈ 1 in 1,400

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): 39 of 46 coding exons well covered in gnomAD exomes; exons 4, 6, 12, 21, 22 and 2 more marginal. Genomes: all 46.? see exons ↓