PPP1R12A

Chr 12AD

protein phosphatase 1 regulatory subunit 12A

Also known as: GUBS, M130, MBS, MYPT1

NCBI Gene: 4659 ENSG00000058272 UniProt: O14974 OMIM: 602021

Myosin phosphatase target subunit 1 is a key regulator of protein phosphatase 1C that mediates binding to myosin and regulates actin-myosin interactions in smooth muscle contraction and nonmuscle cells. Mutations cause genitourinary and/or brain malformation syndrome with autosomal dominant inheritance. This gene is extremely constrained against loss-of-function variants (pLI >0.99, LOEUF 0.13), indicating that such mutations are likely to have severe effects.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Myosin phosphatase target subunit 1, which is also called the myosin-binding subunit of myosin phosphatase, is one of the subunits of myosin phosphatase. Myosin phosphatase regulates the interaction of actin and myosin downstream of the guanosine triphosphatase Rho. The small guanosine triphosphatase Rho is implicated in myosin light chain (MLC) phosphorylation, which results in contraction of smooth muscle and interaction of actin and myosin in nonmuscle cells. The guanosine triphosphate (GTP)-bound, active form of RhoA (GTP.RhoA) specifically interacted with the myosin-binding subunit (MBS) of myosin phosphatase, which regulates the extent of phosphorylation of MLC. Rho-associated kinase (Rho-kinase), which is activated by GTP. RhoA, phosphorylated MBS and consequently inactivated myosin phosphatase. Overexpression of RhoA or activated RhoA in NIH 3T3 cells increased phosphorylation of MBS and MLC. Thus, Rho appears to inhibit myosin phosphatase through the action of Rho-kinase. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.131 OMIM phenotype

Clinical Summary— PPP1R12A

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Gene-Disease Validity (ClinGen)

genitourinary and/or brain malformation syndrome · ADStrong

Strong evidence — appropriate for clinical testing

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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

36 unique Pathogenic / Likely Pathogenic· 153 VUS of 307 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PPP1R12A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.13LOEUF

pLI 1.000

Z-score 6.81

OE 0.05 (0.02–0.13)

Highly constrained

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

Missense Constraint?

2.64Z-score

OE missense 0.67 (0.61–0.73)

342 obs / 509.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.13)

0≤0.351.4

Missense OE?0.67 (0.61–0.73)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 3 / 59.8Missense obs/exp: 342 / 509.5Syn Z: 0.19

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongPPP1R12A-related holoprosencephaly spectrum and urogenital malformationsLOFAD

This gene — mechanism propensity

0.3495th %ile

GOF

0.4085th %ile

LOF

0.82top 5%

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

LOFprediction above median · 86% of P/LP variants are LoF · LOEUF 0.13

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

307 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic21

VUS153

Likely Benign57

Benign27

Conflicting17

Pathogenic

Likely Pathogenic

153

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	14	0	1	0	15
Likely Pathogenic	17	4	0	0	21
VUS	3	138	7	5	153
Likely Benign	1	20	19	17	57
Benign	0	7	11	9	27
Conflicting	—				17
Total	35	169	38	31	290

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap PPP1R12A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →