PPP1R21
protein-codingprotein phosphatase 1 regulatory subunit 21, the group of Protein phosphatase 1 regulatory subunits
Gene summary
Enables mRNA binding activity and protein-macromolecule adaptor activity. Involved in regulation of intracellular mRNA localization. Located in early endosome. Is active in early endosome membrane. [provided by Alliance of Genome Resources, Jun 2026]
- CCDC128
- KLRAQ1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~74.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0859165
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0859165
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0859165
Submitter: ClinGen
The *PPP1R21* gene is located on chromosome 2p16.3 and encodes the protein phosphatase 1 regulatory subunit 21. *PPP1R21* was first reported in relation to autosomal recessive neurodevelopmental disorder with hypotonia, facial dysmorphism and brain abnormalities (NEDHFBA) in 2018 Rehman et al. (PMID: 30520571). NEDHFBA is characterized by distinct facial dysmorphisms, intellectual disability, hypotonia, severe developmental delay and brain abnormalities. To date, 17 homozygous variants (including 4 nonsense, 8 frameshift, 2 missense and 3 splicing variants) have been reported in 18 probands across 5 publications and are included in this curation (PMID 29808498; 30520571; 32985083; 36692708; 38356149). The mechanism of pathogenicity appears to be biallelic loss of function. Currently, there is limited experimental evidence to support the gene-disease association but other PP1 subunits have been linked to disease. In summary, there is definitive evidence to support the relationship between *PPP1R21* and autosomal recessive NEDHFBA. This gene-disease pair was originally evaluated by the ClinGen Syndromic Disorders GCEP on 10/24/2023. It was re-evaluated on 3/12/2026. As a result of this reevaluation, the classification increased from Strong to Definitive with the addition of a new publication documenting human genetic evidence for *PPP1R21* and autosomal recessive NEDHFBA raising the total reports to 24 individuals (PMID: 38356149). (SOP Version 12).
Inheritance Pattern: AR
Disease ID:MONDO:0859165
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PPP1R21 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001135629.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 24 | 1 | 27 | ||
| missense | 2 | 154 | 11 | 167 | ||
| nonsense | 6 | 3 | 3 | 12 | ||
| start loss | 0 | |||||
| frameshift | 6 | 3 | 9 | |||
| splice donor/acceptor (+/-2bp) | 4 | 6 | 10 | |||
| Total | 14 | 10 | 165 | 35 | 1 | 225 |
Highest pathogenic variant AF is 0.000012556426
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001129101.1 | 22 | MANE Select | |
| Ensembl | ENSP00000294952.8 | 22 | MANE Select | |
| RefSeq | NP_001180404.1 | 20 | Standard | |
| RefSeq | NP_694539.1 | 21 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Cellular Component
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000294952
- Coding exons
- 22
- Length
- 74789
- Individuals with no LoFs
- 125699
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 48
- Defined
- 125747
- p
- 0.000191
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.92 | 506 | 398 | 1.27 | 0.0000200 | 5109 |
| Missense (PolyPhen) | 182 | 166.69 | 1.0918 | 2199 | ||
| Synonymous | -0.991 | 163 | 148 | 1.10 | 0.00000759 | 1441 |
| Loss of Function | 3.37 | 25 | 50.9 | 0.491 | 0.00000277 | 604 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00029 | 0.00029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.00019 | 0.00018 | rare |
| European (Non-Finnish) | 0.00023 | 0.00023 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
Intolerance Scores
- RVIS EVS
- -1.01
- RVIS percentile EVS
- 8.16
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.114
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |