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

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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Clinical Trials

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

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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 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 OE0.03 (0.01–0.16)

0≤0.351.4

Missense OE0.66 (0.58–0.76)

0≤0.61.4

Synonymous OE0.77

0≤1.21.6

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedPSMD12-related global developmental delay, multiple malformationsLOFAD

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 · 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 haploinsufficiencyPMID:28132691

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