PPP1CB

Chr 2AD

protein phosphatase 1 catalytic subunit beta

Also known as: HEL-S-80p, MP, NSLH2, PP-1B, PP1B, PP1Cbeta, PP1Cdelta, PP1beta

NCBI Gene: 5500 ENSG00000213639 UniProt: P62140 OMIM: 600590

The protein is a catalytic subunit of protein phosphatase 1 that dephosphorylates numerous cellular targets and is essential for cell division, glycogen metabolism, muscle contractility, synaptic plasticity, and MAPK pathway regulation. Mutations cause Noonan syndrome-like disorder with loose anagen hair 2 with autosomal dominant inheritance. This gene is highly constrained against loss-of-function variants (pLI 0.999, LOEUF 0.147), indicating that functional copies are critical for normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is one of the three catalytic subunits of protein phosphatase 1 (PP1). PP1 is a serine/threonine specific protein phosphatase known to be involved in the regulation of a variety of cellular processes, such as cell division, glycogen metabolism, muscle contractility, protein synthesis, and HIV-1 viral transcription. Mouse studies suggest that PP1 functions as a suppressor of learning and memory. Two alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.151 OMIM phenotype

VCEP Guidelines: RASopathyReleased

View Specifications ClinGen Panel

Clinical Summary— PPP1CB

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Gene-Disease Validity (ClinGen)

Noonan syndrome-like disorder with loose anagen hair · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

14 unique Pathogenic / Likely Pathogenic· 96 VUS of 373 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.15LOEUF

pLI 0.999

Z-score 4.18

OE 0.00 (0.00–0.15)

Highly constrained

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

Missense Constraint?

4.33Z-score

OE missense 0.09 (0.06–0.14)

17 obs / 181.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.15)

0≤0.351.4

Missense OE?0.09 (0.06–0.14)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 0 / 20.3Missense obs/exp: 17 / 181.0Syn Z: 0.94

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePPP1CB-related rasopathy with developmental delay, short stature, and sparse slow-growing hairOTHERAD

This gene — mechanism propensity

0.3793th %ile

GOF

0.3689th %ile

LOF

0.75top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.15

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

373 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic10

VUS96

Likely Benign226

Benign22

Conflicting6

Pathogenic

Likely Pathogenic

VUS

226

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	4	0	0	4
Likely Pathogenic	0	10	0	0	10
VUS	5	77	12	2	96
Likely Benign	0	0	115	111	226
Benign	0	0	20	2	22
Conflicting	—				6
Total	5	91	147	115	364

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap PPP1CB — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →