PSMD2

Chr 3

proteasome 26S subunit ubiquitin receptor, non-ATPase 2

Also known as: P97, RPN1, S2, TRAP2

NCBI Gene: 5708 ENSG00000175166 UniProt: Q13200 OMIM: 606223

The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core 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. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase 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 one of the non-ATPase subunits of the 19S regulator lid. In addition to participation in proteasome function, this subunit may also participate in the TNF signalling pathway since it interacts with the tumor necrosis factor type 1 receptor. A pseudogene has been identified on chromosome 1. Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jul 2013]

OMIM Research

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.10

Clinical Summary— PSMD2

⚡

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.

📋

ClinVar Variants

78 VUS of 106 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.10LOEUF

pLI 1.000

Z-score 6.17

OE 0.02 (0.01–0.10)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.09Z-score

OE missense 0.61 (0.56–0.67)

308 obs / 502.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.10)

0≤0.351.4

Missense OE?0.61 (0.56–0.67)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 1 / 46.3Missense obs/exp: 308 / 502.8Syn Z: -0.17

This gene — mechanism propensity

0.3793th %ile

GOF

0.4381th %ile

LOF

0.68top 10%

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

LOFprediction above median · LOEUF 0.10

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

106 submitted variants in ClinVar

ClinVar

Classification Summary

VUS78

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	78	0	78
Likely Benign	0	1	1
Benign	0	0	0
Total	78	1	79

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

View in ClinVar →

42 pathogenic / likely-pathogenic (of 49) ClinVar copy-number / structural variants overlap PSMD2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →