PPP6R2

Chr 22

protein phosphatase 6 regulatory subunit 2

Also known as: KIAA0685, PP6R2, SAP190, SAPS2

NCBI Gene: 9701 ENSG00000100239 UniProt: O75170 OMIM: 610877

The protein serves as a regulatory subunit of protein phosphatase 6, functioning as a scaffolding component and mediating dephosphorylation of targets including the T-loop of Aurora A kinase, which is essential for proper spindle formation and chromosome alignment during mitosis. Mutations cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, affecting neurological development and seizure control in early childhood. This gene shows significant constraint against loss-of-function variants (LOEUF 0.411), indicating that such mutations are typically not tolerated in the general population.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a regulatory protein for the protein phosphatase-6 catalytic subunit. Together, these proteins act as a significant T-loop phosphatase for Aurora A, an essential mitotic kinase. Loss of function of either the regulatory or catalytic subunit of protein phosphatase-6 interferes with spindle formation and chromosome alignment. [provided by RefSeq, May 2017]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.41

Clinical Summary— PPP6R2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 155 VUS of 210 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.164

Z-score 4.51

OE 0.24 (0.15–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.93Z-score

OE missense 0.89 (0.83–0.96)

514 obs / 577.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.24 (0.15–0.41)

0≤0.351.4

Missense OE?0.89 (0.83–0.96)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 10 / 41.3Missense obs/exp: 514 / 577.2Syn Z: -0.53

This gene — mechanism propensity

0.5771th %ile

GOF

0.6930th %ile

LOF

0.4135th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction 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

210 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS155

Likely Benign19

Conflicting1

Pathogenic

155

VUS

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	1	0	1
Likely Pathogenic	0	0	0	0	0
VUS	1	154	0	0	155
Likely Benign	0	13	1	5	19
Benign	0	0	0	0	0
Conflicting	—				1
Total	1	167	2	5	176

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

View in ClinVar →

144 pathogenic / likely-pathogenic (of 161) ClinVar copy-number / structural variants overlap PPP6R2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →