PPP1R16A

Chr 8

protein phosphatase 1 regulatory subunit 16A

Also known as: MYPT3

NCBI Gene: 84988 ENSG00000160972 UniProt: Q96I34 OMIM: 609172

The protein functions as a myosin phosphatase targeting subunit that directs protein phosphatase 1 to specific substrates including myosin light chains, regulating muscle contraction and intracellular movement. Mutations in PPP1R16A cause autosomal recessive intellectual disability with microcephaly and seizures, typically presenting in early childhood. The gene shows moderate constraint to loss-of-function variation, suggesting some intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

Myosin light chain kinase and phosphatase (MLCP) complexes control the phosphorylation states of regulatory myosin light chains, which is crucial for muscle and intracellular movement. MLCPs typically contain a catalytic protein phosphatase 1 (PP1c) subunit, a myosin phosphatase targeting (MYPT) subunit, and another smaller subunit. The protein encoded by this gene represents an MYPT subunit, which is responsible for directing PP1c to its intended targets. However, while the phosphorylation of other MYPT members results in PP1c inactivation, phosphorylation of the encoded protein by protein kinase A results in PP1c activation. [provided by RefSeq, Jan 2020]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.65

Clinical Summary— PPP1R16A

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Population Constraint (gnomAD)

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

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ClinVar Variants

98 VUS of 113 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.65LOEUF

pLI 0.004

Z-score 2.81

OE 0.36 (0.21–0.65)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.13Z-score

OE missense 0.98 (0.89–1.07)

320 obs / 326.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.21–0.65)

0≤0.351.4

Missense OE?0.98 (0.89–1.07)

0≤0.61.4

Synonymous OE?1.31

0≤1.21.6

LoF obs/exp: 8 / 22.3Missense obs/exp: 320 / 326.5Syn Z: -2.97

This gene — mechanism propensity

0.7033th %ile

GOF

0.80top 10%

LOF

0.3067th %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

113 submitted variants in ClinVar

ClinVar

Classification Summary

VUS98

Likely Benign8

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	98	0	98
Likely Benign	6	2	8
Benign	0	0	0
Total	104	2	106

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

View in ClinVar →

55 pathogenic / likely-pathogenic (of 72) ClinVar copy-number / structural variants overlap PPP1R16A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →