PSMD12

Chr 17AD

proteasome 26S subunit, non-ATPase 12

Also known as: Rpn5, STISS, p55

NCBI Gene: 5718 ENSG00000197170 UniProt: O00232 OMIM: 604450

This protein is a non-ATPase subunit of the 26S proteasome's 19S regulator that cleaves peptides through ATP/ubiquitin-dependent degradation. Heterozygous loss-of-function mutations cause Stankiewicz-Isidor syndrome through an autosomal dominant inheritance pattern. The high pLI score (0.999) and low LOEUF score (0.162) indicate the gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the likely pathogenic mechanism.

OMIM ResearchSummary from RefSeq, OMIM

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 a non-ATPase subunit of the 19S regulator. A pseudogene has been identified on chromosome 3. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.161 OMIM phenotype

Clinical Summary— PSMD12

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Gene-Disease Validity (ClinGen)

Stankiewicz-Isidor syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

33 unique Pathogenic / Likely Pathogenic· 106 VUS of 174 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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?

0.16LOEUF

pLI 1.000

Z-score 4.85

OE 0.03 (0.01–0.16)

Highly constrained

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

Missense Constraint?

1.87Z-score

OE missense 0.66 (0.58–0.76)

163 obs / 245.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.16)

0≤0.351.4

Missense OE?0.66 (0.58–0.76)

0≤0.61.4

Synonymous OE?0.77

0≤1.21.6

LoF obs/exp: 1 / 29.3Missense obs/exp: 163 / 245.5Syn Z: 1.70

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongPSMD12-related global developmental delay with or without multiple malformations (Stankiewicz-Isidor syndrome)LOFAD

This gene — mechanism propensity

0.4487th %ile

GOF

0.3986th %ile

LOF

0.61top 25%

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

LOF1 literature citation · 100% of P/LP variants are LoF · LOEUF 0.16

Literature Evidence

LOFThe mutations in 3 patients were found by trio-based whole-exome sequencing and confirmed by Sanger sequencing; the mutation in the fourth patient was found by exome sequencing. Studies of 1 patient's cells showed decreased amounts of full-length PSMD12, consistent with haploinsufficiency1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 28132691 ↗

ClinVar Variant Classifications

174 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21

Likely Pathogenic12

VUS106

Likely Benign9

Benign5

Conflicting2

Pathogenic

Likely Pathogenic

106

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	21	0	0	0	21
Likely Pathogenic	12	0	0	0	12
VUS	2	100	4	0	106
Likely Benign	0	3	1	5	9
Benign	0	1	1	3	5
Conflicting	—				2
Total	35	104	6	8	155

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap PSMD12 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →