PPM1N

Chr 19

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

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…

MultiplemechanismLOEUF 1.43

Clinical Summary— PPM1N

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

74 VUS of 86 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?

1.43LOEUF

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

This gene — mechanism propensity

0.6841th %ile

GOF

0.72top 25%

LOF

0.2777th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

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

86 submitted variants in ClinVar

ClinVar

Classification Summary

VUS74

Likely Benign4

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	1	73	0	74
Likely Benign	0	3	1	4
Benign	0	0	0	0
Total	1	76	1	78

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap PPM1N — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →