PRAMEF12

Chr 1

PRAME family member 12

NCBI Gene: 390999 ENSG00000116726 UniProt: O95522

The protein is predicted to function as a ubiquitin-like ligase-substrate adaptor in the Cul2-RING ubiquitin ligase complex, facilitating proteasome-mediated protein degradation in the cytoplasm. PRAMEF12 is extremely loss-of-function intolerant (pLI ~1.0), suggesting mutations would likely cause severe disease, though no established clinical phenotype has been reported to date. The inheritance pattern for potential PRAMEF12-related disorders has not been determined.

ResearchSummary from RefSeq

Predicted to enable ubiquitin-like ligase-substrate adaptor activity. Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Predicted to be part of Cul2-RING ubiquitin ligase complex. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.26

Clinical Summary— PRAMEF12

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

76 VUS of 84 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.26LOEUF

pLI 0.000

Z-score 0.95

OE 0.70 (0.41–1.26)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.13Z-score

OE missense 1.20 (1.09–1.32)

301 obs / 250.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.70 (0.41–1.26)

0≤0.351.4

Missense OE?1.20 (1.09–1.32)

0≤0.61.4

Synonymous OE?1.48

0≤1.21.6

LoF obs/exp: 8 / 11.5Missense obs/exp: 301 / 250.6Syn Z: -3.88

This gene — mechanism propensity

0.73top 25%

GOF

0.6637th %ile

LOF

0.1697th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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

84 submitted variants in ClinVar

ClinVar

Classification Summary

VUS76

Likely Benign7

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	75	1	76
Likely Benign	5	2	7
Benign	0	0	0
Total	80	3	83

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 46) ClinVar copy-number / structural variants overlap PRAMEF12 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →