UPF2

Chr 10

UPF2 regulator of nonsense mediated mRNA decay

Also known as: HUPF2, RENT2, smg-3

NCBI Gene: 26019 ENSG00000151461 UniProt: Q9HAU5 OMIM: 605529

UPF2 encodes a protein essential for nonsense-mediated mRNA decay (NMD), a cellular quality control mechanism that degrades mRNAs containing premature stop codons by forming surveillance complexes with UPF1 and UPF3 proteins. Mutations cause autosomal recessive intellectual disability with microcephaly and seizures, typically presenting in early childhood. This gene is extremely intolerant to loss-of-function mutations, reflecting its critical role in mRNA surveillance and cellular homeostasis.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein that is part of a post-splicing multiprotein complex involved in both mRNA nuclear export and mRNA surveillance. mRNA surveillance detects exported mRNAs with truncated open reading frames and initiates nonsense-mediated mRNA decay (NMD). When translation ends upstream from the last exon-exon junction, this triggers NMD to degrade mRNAs containing premature stop codons. This protein is located in the perinuclear area. It interacts with translation release factors and the proteins that are functional homologs of yeast Upf1p and Upf3p. Two splice variants have been found for this gene; both variants encode the same protein. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

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P/LP missense

0.10

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.10LOEUF

pLI 1.000

Z-score 7.15

OE 0.03 (0.01–0.10)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.19Z-score

OE missense 0.65 (0.60–0.71)

438 obs / 670.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.10)

0≤0.351.4

Missense OE?0.65 (0.60–0.71)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 2 / 63.4Missense obs/exp: 438 / 670.6Syn Z: -0.44

Background carrier burden — how many people carry a rare variant somewhere in UPF2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 94

1,220 rare PASS variants

Rare truncating (LoF)

1 in 9,300

39 rare PASS variants

Rare synonymous (reference)

1 in 93

582 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for UPF2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 100	1 in 8,500
South Asian	~43k	1 in 67	1 in 5,800
Remaining (unassigned)	~30k	1 in 66	≈ 1 in 7,400
European (Finnish)	~27k	1 in 120	1 in 5,200
Admixed American	~22k	1 in 75	1 in 3,000
African / African American	~21k	1 in 65	none seen
East Asian	~20k	1 in 65	≈ 1 in 9,400
Ashkenazi Jewish	~13k	1 in 190	≈ 1 in 12,000
Middle Eastern	~2,884	1 in 70	≈ 1 in 2,700

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 19 of 21 coding exons well covered in gnomAD exomes; exons 4, 10 marginal. Genomes: all 21.? see exons ↓