PSMB4

Chr 1AR

proteasome 20S subunit beta 4

Also known as: HN3, HsN3, PRAAS3, PROS-26, PROS26

NCBI Gene: 5692 ENSG00000159377 UniProt: P28070 OMIM: 602177

PSMB4 encodes a non-catalytic beta subunit of the 20S proteasome core complex, which degrades intracellular proteins to maintain cellular protein homeostasis and generate MHC class I antigenic peptides. Mutations cause proteasome-associated autoinflammatory syndrome 3, an autosomal recessive disorder involving immune system dysfunction. The gene shows relatively low constraint to loss-of-function variants, consistent with recessive inheritance patterns.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. The core structure is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.791 OMIM phenotype

Clinical Summary— PSMB4

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 154 VUS of 297 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.79LOEUF

pLI 0.003

Z-score 2.18

OE 0.42 (0.24–0.79)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.47Z-score

OE missense 0.90 (0.78–1.03)

142 obs / 158.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.42 (0.24–0.79)

0≤0.351.4

Missense OE?0.90 (0.78–1.03)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 7 / 16.6Missense obs/exp: 142 / 158.5Syn Z: 0.12

This gene — mechanism propensity

0.7227th %ile

GOF

0.5464th %ile

LOF

0.3067th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

297 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS154

Likely Benign107

Benign11

Conflicting5

Pathogenic

154

VUS

107

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	1	0	0	2
Likely Pathogenic	0	0	0	0	0
VUS	6	139	8	1	154
Likely Benign	0	5	58	44	107
Benign	0	0	8	3	11
Conflicting	—				5
Total	7	145	74	48	279

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

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16 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap PSMB4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →