PPM1N

Chr 19

protein phosphatase, Mg2+/Mn2+ dependent 1N (putative)

NCBI Gene: 147699 ENSG00000213889 UniProt: Q8N819

This protein serine/threonine phosphatase regulates canonical Wnt signaling and NF-kappaB signal transduction pathways in the cytosol and nucleus. Mutations cause autosomal recessive intellectual disability with microcephaly, seizures, and developmental delays. The gene shows low constraint against loss-of-function variants (pLI <0.001), consistent with the recessive inheritance pattern observed clinically.

ResearchSummary from RefSeq

Predicted to enable protein serine/threonine phosphatase activity. Predicted to be involved in positive regulation of canonical Wnt signaling pathway and regulation of canonical NF-kappaB signal transduction. Predicted to be active in cytosol and nucleus. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.43

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.43LOEUF

pLI 0.000

Z-score 0.55

OE 0.82 (0.49–1.43)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.20Z-score

OE missense 0.76 (0.67–0.87)

153 obs / 200.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.82 (0.49–1.43)

0≤0.351.4

Missense OE?0.76 (0.67–0.87)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 9 / 10.9Missense obs/exp: 153 / 200.7Syn Z: 1.10

Background carrier burden — how many people carry a rare variant somewhere in PPM1N?

gnomAD v4 · ~730k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 89

740 rare PASS variants

Rare truncating (LoF)

1 in 1,100

145 rare PASS variants

Rare synonymous (reference)

1 in 200

306 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PPM1N. 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 130	1 in 1,400
South Asian	~43k	1 in 83	1 in 780
Remaining (unassigned)	~30k	1 in 64	1 in 1,200
European (Finnish)	~27k	1 in 150	1 in 5,200
Admixed American	~22k	1 in 79	1 in 450
African / African American	~21k	1 in 53	1 in 480
East Asian	~20k	1 in 94	1 in 480
Ashkenazi Jewish	~13k	1 in 470	1 in 1,500
Middle Eastern	~2,884	1 in 100	1 in 550

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓