PRAMEF2

Chr 1

PRAME family member 2

Also known as: DJ845O24.3

NCBI Gene: 65122 ENSG00000120952 UniProt: O60811

The protein functions as a ubiquitin-like ligase-substrate adaptor in the Cul2-RING ubiquitin ligase complex, facilitating proteasome-mediated protein degradation in the cytoplasm. This gene is extremely tolerant to loss-of-function variants in the general population, suggesting that complete loss of function may not be pathogenic. No well-established human disease associations have been reported for PRAMEF2 mutations.

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 1.81

Clinical Summary— PRAMEF2

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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

102 VUS of 138 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?

1.81LOEUF

pLI 0.000

Z-score -0.64

OE 1.21 (0.78–1.81)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-3.95Z-score

OE missense 1.74 (1.60–1.89)

392 obs / 225.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.21 (0.78–1.81)

0≤0.351.4

Missense OE?1.74 (1.60–1.89)

0≤0.61.4

Synonymous OE?1.57

0≤1.21.6

LoF obs/exp: 13 / 10.7Missense obs/exp: 392 / 225.3Syn Z: -4.51

This gene — mechanism propensity

0.7132th %ile

GOF

0.6638th %ile

LOF

0.2092th %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

138 submitted variants in ClinVar

ClinVar

Classification Summary

VUS102

Likely Benign30

Benign1

Conflicting4

102

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	0	102	0	0	102
Likely Benign	1	13	1	15	30
Benign	0	1	0	0	1
Conflicting	—				4
Total	1	116	1	15	137

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

View in ClinVar →

29 pathogenic / likely-pathogenic (of 42) ClinVar copy-number / structural variants overlap PRAMEF2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →