PRAMEF6

Chr 1

PRAME family member 6

NCBI Gene: 440561 ENSG00000232423 UniProt: Q5VXH4

The protein functions as a substrate-recognition component of a Cul2-RING E3 ubiquitin ligase complex that targets specific proteins for degradation, including truncated selenoproteins produced by failed translation. PRAMEF6 is extremely tolerant to loss-of-function variants based on population data, and no established human disease associations have been reported for this gene. The gene appears to have low clinical penetrance despite its role in protein quality control pathways.

ResearchSummary from RefSeq, UniProt

Enables ubiquitin-like ligase-substrate adaptor activity. Involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Part of Cul2-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

DNmechanismLOEUF 1.98

Clinical Summary— PRAMEF6

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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

27 VUS of 37 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?

1.98LOEUF

pLI 0.000

Z-score -3.01

OE 2.47 (1.24–1.98)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-2.20Z-score

OE missense 1.81 (1.53–1.97)

107 obs / 59.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?2.47 (1.24–1.98)

0≤0.351.4

Missense OE?1.81 (1.53–1.97)

0≤0.61.4

Synonymous OE?1.65

0≤1.21.6

LoF obs/exp: 12 / 4.9Missense obs/exp: 107 / 59.2Syn Z: -2.45

This gene — mechanism propensity

0.77top 25%

GOF

0.6248th %ile

LOF

0.1895th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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

37 submitted variants in ClinVar

ClinVar

Classification Summary

VUS27

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	27	0	27
Likely Benign	8	2	10
Benign	0	0	0
Total	35	2	37

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 40) ClinVar copy-number / structural variants overlap PRAMEF6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →