PPM1L

Chr 3

protein phosphatase, Mg2+/Mn2+ dependent 1L

Also known as: PP2C-epsilon, PP2CE, PPM1-LIKE

NCBI Gene: 151742 ENSG00000163590 UniProt: Q5SGD2 OMIM: 611931

The protein encoded by this gene is a magnesium or manganese-requiring phosphatase that is involved in several signaling pathways. The encoded protein downregulates apoptosis signal-regulating kinase 1, a protein that initiates a signaling cascade that leads to apoptosis when cells are subjected to cytotoxic stresses. This protein also is an endoplasmic reticulum transmembrane protein that helps regulate ceramide transport from the endoplasmic reticulum to the Golgi apparatus. Finally, this gene may be involved in adiposity since it is upregulated in adipose tissues. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

OMIM Research

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

—

P/LP missense

0.54

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.54LOEUF

pLI 0.473

Z-score 2.80

OE 0.21 (0.09–0.54)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.06Z-score

OE missense 0.60 (0.51–0.69)

123 obs / 206.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.21 (0.09–0.54)

0≤0.351.4

Missense OE?0.60 (0.51–0.69)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 3 / 14.5Missense obs/exp: 123 / 206.4Syn Z: -0.19

Background carrier burden — how many people carry a rare variant somewhere in PPM1L?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 260

355 rare PASS variants

Rare truncating (LoF)

1 in 1,800

51 rare PASS variants

Rare synonymous (reference)

1 in 150

192 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PPM1L. 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 260	1 in 3,100
South Asian	~43k	1 in 520	1 in 1,900
Remaining (unassigned)	~30k	1 in 180	1 in 1,700
European (Finnish)	~27k	1 in 440	1 in 5,300
Admixed American	~22k	1 in 210	1 in 1,100
African / African American	~21k	1 in 320	≈ 1 in 9,300
East Asian	~20k	1 in 380	≈ 1 in 20,000
Ashkenazi Jewish	~13k	≈ 1 in 3,300	none seen
Middle Eastern	~2,884	1 in 320	≈ 1 in 940

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): All 4 coding exons well covered in gnomAD exomes and genomes.? see exons ↓