PPP1R21

Chr 2AR

protein phosphatase 1 regulatory subunit 21

Also known as: CCDC128, FERRY2, Fy-2, KLRAQ1, NEDHFBA

NCBI Gene: 129285 ENSG00000162869 UniProt: Q6ZMI0 OMIM: 618159

PPP1R21 encodes a component of the FERRY complex that binds mRNA and mediates endosomal transport of specific mRNAs and ribosomes to early endosomes. Mutations cause autosomal recessive neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities. The gene shows low constraint to loss-of-function variants (pLI nearly zero), consistent with its recessive inheritance pattern.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalitiesMIM #619383

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities · AR · ClinGen 2026

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.69

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — PPP1R21

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.69LOEUF

pLI 0.000

Z-score 3.37

OE 0.49 (0.36–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-1.92Z-score

OE missense 1.27 (1.18–1.37)

506 obs / 398.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.49 (0.36–0.69)

0≤0.351.4

Missense OE?1.27 (1.18–1.37)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 25 / 50.9Missense obs/exp: 506 / 398.3Syn Z: -0.99

Background carrier burden — how many people carry a rare variant somewhere in PPP1R21?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 56

1,276 rare PASS variants

Rare truncating (LoF)

1 in 1,700

150 rare PASS variants

Rare synonymous (reference)

1 in 170

415 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PPP1R21. 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 81	1 in 1,700
South Asian	~43k	1 in 46	1 in 2,400
Remaining (unassigned)	~30k	1 in 49	1 in 840
European (Finnish)	~27k	1 in 150	1 in 2,000
Admixed American	~22k	1 in 43	1 in 1,400
African / African American	~21k	1 in 50	1 in 730
East Asian	~20k	1 in 64	1 in 2,100
Ashkenazi Jewish	~13k	1 in 220	1 in 680
Middle Eastern	~2,884	1 in 42	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.