ARPP21

Chr 3

cAMP regulated phosphoprotein 21

Also known as: ARPP-21, R3HDM3, RCS, TARPP

NCBI Gene: 10777 ENSG00000172995 UniProt: Q9UBL0

The protein is a cAMP-regulated phosphoprotein enriched in the caudate nucleus and cerebellar cortex that may inhibit calmodulin-dependent enzymes such as calcineurin in neurons and regulate dopamine effects in the basal ganglia. Mutations cause autosomal recessive neurodevelopmental disorders affecting the brain. The gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely not tolerated.

ResearchSummary from RefSeq, UniProt

This gene encodes a cAMP-regulated phosphoprotein. The encoded protein is enriched in the caudate nucleus and cerebellar cortex. A similar protein in mouse may be involved in regulating the effects of dopamine in the basal ganglia. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

ResearchGenerating clinical summary…

Clinical highlights

Gene–disease validity (ClinGen)

Limited · amyotrophic lateral sclerosis · AD · ClinGen 2025

not for standalone diagnostic reporting

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.44

LOEUF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.44LOEUF

pLI 0.012

Z-score 4.60

OE 0.28 (0.18–0.44)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.26Z-score

OE missense 0.97 (0.89–1.04)

432 obs / 447.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.28 (0.18–0.44)

0≤0.351.4

Missense OE?0.97 (0.89–1.04)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 13 / 47.1Missense obs/exp: 432 / 447.5Syn Z: 0.83

Background carrier burden — how many people carry a rare variant somewhere in ARPP21?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 57

1,158 rare PASS variants

Rare truncating (LoF)

1 in 1,700

138 rare PASS variants

Rare synonymous (reference)

1 in 110

396 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ARPP21. 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 87	1 in 2,200
South Asian	~43k	1 in 39	1 in 2,200
Remaining (unassigned)	~30k	1 in 55	1 in 740
European (Finnish)	~27k	1 in 220	1 in 1,800
Admixed American	~22k	1 in 61	1 in 2,200
African / African American	~21k	1 in 51	1 in 410
East Asian	~20k	1 in 83	1 in 630
Ashkenazi Jewish	~13k	1 in 200	≈ 1 in 4,300
Middle Eastern	~2,884	1 in 39	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 19 coding exons well covered in gnomAD exomes; exons 5, 7, 8, 13 marginal. Genomes: all 19.? see exons ↓