PPME1

Chr 11

protein phosphatase methylesterase 1

Also known as: ABDH19, PME-1

NCBI Gene: 51400 ENSG00000214517 UniProt: Q9Y570 OMIM: 611117

The protein is a nuclear protein phosphatase methylesterase that demethylates and regulates protein phosphatase-2A catalytic subunits, supporting ERK pathway signaling. Mutations cause autosomal dominant intellectual disability with distinctive facial features and variable developmental delay. This gene is highly constrained against loss-of-function variation (pLI=1.0, LOEUF=0.19), indicating that functional copies are critical for normal development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein phosphatase methylesterase localized to the nucleus. The encoded protein acts on the protein phosphatase-2A catalytic subunit and supports the ERK pathway through dephosphorylation of regulatory proteins. It plays a role in malignant glioma progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2012]

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

0.19

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.19LOEUF

pLI 0.999

Z-score 4.40

OE 0.04 (0.01–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.75Z-score

OE missense 0.66 (0.57–0.76)

139 obs / 210.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.19)

0≤0.351.4

Missense OE?0.66 (0.57–0.76)

0≤0.61.4

Synonymous OE?0.70

0≤1.21.6

LoF obs/exp: 1 / 24.5Missense obs/exp: 139 / 210.3Syn Z: 1.92

Background carrier burden — how many people carry a rare variant somewhere in PPME1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 250

387 rare PASS variants

Rare truncating (LoF)

1 in 7,000

43 rare PASS variants

Rare synonymous (reference)

1 in 490

135 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PPME1. 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 400	1 in 7,500
South Asian	~43k	1 in 150	1 in 8,100
Remaining (unassigned)	~30k	1 in 180	≈ 1 in 7,400
European (Finnish)	~27k	1 in 730	1 in 2,700
Admixed American	~22k	1 in 280	1 in 2,100
African / African American	~21k	1 in 300	≈ 1 in 5,900
East Asian	~20k	1 in 180	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 1,800	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 170	none seen

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): 13 of 14 coding exons well covered in gnomAD exomes; exon 5 marginal. Genomes: all 14.? see exons ↓