PRAMEF17

Chr 1

PRAME family member 17

NCBI Gene: 391004 ENSG00000204479 UniProt: Q5VTA0

The protein is predicted to function as a ubiquitin ligase adaptor in the Cul2-RING complex, facilitating proteasome-mediated protein degradation in the cytoplasm. This gene is not well-established as a cause of human disease, with extremely low constraint against loss-of-function variants (pLI near zero) and high tolerance to haploinsufficiency (LOEUF 1.95). Clinical significance of PRAMEF17 variants in pediatric neurological disorders remains unclear.

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 1.95

Clinical Summary— PRAMEF17

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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

45 VUS of 56 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?

1.95LOEUF

pLI 0.000

Z-score -1.50

OE 1.70 (0.94–1.95)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.43Z-score

OE missense 1.11 (0.96–1.28)

133 obs / 119.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.70 (0.94–1.95)

0≤0.351.4

Missense OE?1.11 (0.96–1.28)

0≤0.61.4

Synonymous OE?1.23

0≤1.21.6

LoF obs/exp: 9 / 5.3Missense obs/exp: 133 / 119.8Syn Z: -1.24

This gene — mechanism propensity

0.7034th %ile

GOF

0.6541th %ile

LOF

0.2385th %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

56 submitted variants in ClinVar

ClinVar

Classification Summary

VUS45

Likely Benign10

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	45	0	45
Likely Benign	9	1	10
Benign	0	0	0
Total	54	1	55

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

View in ClinVar →

25 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap PRAMEF17 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →