PPP1R12A

Chr 12AD

protein phosphatase 1 regulatory subunit 12A

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Key regulator of protein phosphatase 1C (PPP1C). Mediates binding to myosin. As part of the PPP1C complex, involved in dephosphorylation of PLK1. Capable of inhibiting HIF1AN-dependent suppression of HIF1A activity

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Genitourinary and/or/brain malformation syndromeMIM #618820

Clinical highlights

Gene–disease validity (ClinGen)

Strong · genitourinary and/or brain malformation syndrome · AD · ClinGen 2021

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.13

LOEUF· LoF intol.

LOF

Mechanism· G2P

Some data sources returned errors (1)

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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

Background carrier burden — how many people carry a rare variant somewhere in PPP1R12A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 63

1,027 rare PASS variants

Rare truncating (LoF)

1 in 1,400

69 rare PASS variants

Rare synonymous (reference)

1 in 100

467 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PPP1R12A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 92	1 in 1,400
South Asian	~43k	1 in 50	1 in 1,100
Remaining (unassigned)	~30k	1 in 61	≈ 1 in 7,400
European (Finnish)	~27k	1 in 360	1 in 2,000
Admixed American	~22k	1 in 53	1 in 1,000
African / African American	~21k	1 in 74	1 in 1,700
East Asian	~20k	1 in 85	1 in 2,000
Ashkenazi Jewish	~13k	1 in 210	≈ 1 in 4,200
Middle Eastern	~2,884	1 in 75	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 15 of 25 coding exons well covered in gnomAD exomes; exons 6, 11, 12, 15, 19 and 5 more marginal. Genomes: all 25.? see exons ↓