PPP1R12A

Chr 12AD

protein phosphatase 1 regulatory subunit 12A

Also known as: GUBS, M130, MBS, MYPT1

NCBI Gene: 4659ENSG00000058272UniProt: O14974

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]

Primary Disease Associations & Inheritance

Genitourinary and/or/brain malformation syndromeMIM #618820
AD
0
Active trials
49
Pathogenic / LP
299
ClinVar variants
9
Pubs (1 yr)
2.6
Missense Z
0.13
LOEUF· LoF intolerant
Clinical Summary— PPP1R12A
🧬
Gene-Disease Validity (ClinGen)
genitourinary and/or brain malformation syndrome · ADStrong

Strong evidence — appropriate for clinical testing

⚡
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.
📋
ClinVar Variants
49 Pathogenic / Likely Pathogenic· 150 VUS of 299 total submissions
📖
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 OE0.05 (0.02–0.13)
0≤0.351.4
Missense OE0.67 (0.61–0.73)
0≤0.61.4
Synonymous OE0.98
0≤1.21.6
LoF obs/exp: 3 / 59.8Missense obs/exp: 342 / 509.5Syn Z: 0.19
LOF
DN
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 · 41% 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

299 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27
Likely Pathogenic22
VUS150
Likely Benign56
Benign27
Conflicting17
27
Pathogenic
22
Likely Pathogenic
150
VUS
56
Likely Benign
27
Benign
17
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
0
18
0
27
Likely Pathogenic
11
4
7
0
22
VUS
2
131
13
4
150
Likely Benign
1
17
21
17
56
Benign
0
7
11
9
27
Conflicting
—17
Total231597030299

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

View in ClinVar →

PPP1R12A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PPP1R12A-related holoprosencephaly spectrum and urogenital malformations

strong
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Loss-of-Function Variant in PPP1R12A -Related Urogenital and/or Brain Malformation Syndrome: Expanded Phenotype of Sex Reversal.
Contreras-Capetillo SN et al.·Am J Med Genet A
2025
PPP1R12A Copy Number Is Associated with Clinical Outcomes of Stage III CRC Receiving Oxaliplatin-Based Chemotherapy.
Zhang C et al.·Mediators Inflamm
2015
Functional analysis of a novel nonsense PPP1R12A variant in a Chinese family with infantile epilepsy.
Tong L et al.·BMC Med Genomics
2024Case report
Expression profiles of PRKG1, SDF2L1 and PPP1R12A are predictive and prognostic factors for therapy response and survival in high-grade serous ovarian cancer.
Benvenuto G et al.·Int J Cancer
2020
Intestinal Atresia in PPP1R12A -Related Urogenital and Brain Malformation Syndrome.
Gomes A et al.·Am J Med Genet A
2025Case report
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients