PRKAR1A

Chr 17AD

protein kinase cAMP-dependent type I regulatory subunit alpha

Also known as: ACRDYS1, ADOHR, CAR, CNC, CNC1, PKR1, PPNAD1, PRKAR1

NCBI Gene: 5573 ENSG00000108946 UniProt: P10644

cAMP is a signaling molecule important for a variety of cellular functions. cAMP exerts its effects by activating the cAMP-dependent protein kinase, which transduces the signal through phosphorylation of different target proteins. The inactive kinase holoenzyme is a tetramer composed of two regulatory and two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. Four different regulatory subunits and three catalytic subunits have been identified in humans. This gene encodes one of the regulatory subunits. This protein was found to be a tissue-specific extinguisher that down-regulates the expression of seven liver genes in hepatoma x fibroblast hybrids. Mutations in this gene cause Carney complex (CNC). This gene can fuse to the RET protooncogene by gene rearrangement and form the thyroid tumor-specific chimeric oncogene known as PTC2. A nonconventional nuclear localization sequence (NLS) has been found for this protein which suggests a role in DNA replication via the protein serving as a nuclear transport protein for the second subunit of the Replication Factor C (RFC40). Several alternatively spliced transcript variants encoding two different isoforms have been observed. [provided by RefSeq, Jan 2013]

Primary Disease Associations & Inheritance

Acrodysostosis 1, with or without hormone resistanceMIM #101800

Adrenocortical tumor, somatic

Carney complex, type 1MIM #160980

Myxoma, intracardiacMIM #255960

Pigmented nodular adrenocortical disease, primary, 1MIM #610489

UniProtCarney complex 1

UniProtIntracardiac myxoma

UniProtPrimary pigmented nodular adrenocortical disease 1

Active trials

Pathogenic / LP

464

ClinVar variants

Pubs (1 yr)

3.1

Missense Z· constrained

0.12

LOEUF· LoF intolerant

Clinical Summary— PRKAR1A

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Gene-Disease Validity (ClinGen)

Carney complex, type 1 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

38 Pathogenic / Likely Pathogenic· 245 VUS of 464 total submissions

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

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GeneReview available — PRKAR1A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.12LOEUF

pLI 1.000

Z-score 4.64

OE 0.00 (0.00–0.12)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

3.12Z-score

OE missense 0.41 (0.34–0.48)

89 obs / 219.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.12)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.41 (0.34–0.48)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.30

0≤1.21.6

LoF obs/exp: 0 / 25.1Missense obs/exp: 89 / 219.1Syn Z: -2.11

0.3495th %ile

GOF

0.4777th %ile

LOF

0.72top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 50% of P/LP variants are LoF · LOEUF 0.12

GOF1 literature citation

Literature Evidence

GOFBecause the mutation that leads to R368X results in PKRAR1A regulatory subunits that are impaired in their ability to dissociate from catalytic subunits in response to cAMP, it is, in this sense, a gain-of-function mutation of PRKAR1A that decreases protein kinase A sensitivity to cAMP.PMID:21651393

LOFIn affected members of 3 unrelated families, they demonstrated PRKAR1A frameshift mutations resulting in haploinsufficiency of R1-alphaPMID:10974026

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

464 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21

Likely Pathogenic17

VUS245

Likely Benign171

Benign5

Conflicting5

Pathogenic

Likely Pathogenic

245

VUS

171

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	2	8	0	21
Likely Pathogenic	8	2	7	0	17
VUS	5	210	29	1	245
Likely Benign	1	3	88	79	171
Benign	0	0	4	1	5
Conflicting	—				5
Total	25	217	136	81	464

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

View in ClinVar →

Protein Context — Lollipop Plot

PRKAR1A · protein map & ClinVar variants

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

Gene2Phenotype Curations

PRKAR1A-related acrodysostosis

definitive

ADGain Of FunctionAltered Gene Product Structure

Dev. DisordersSkinSkeletal

G2P ↗

PRKAR1A-related Carney complex

definitive

ADLoss Of FunctionAbsent Gene Product

SkinCancer

G2P ↗

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

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

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GeneReview available — PRKAR1A

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING

NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19

Usual Care GroupControlled exercise with telerehabilitation

Non-Small Cell Lung CancerMedullary Thyroid CancerColon Cancer

A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001)

ACTIVE NOT RECRUITING

NCT03157128Phase PHASE1, PHASE2Eli Lilly and CompanyStarted 2017-05-02

LOXO-292

Ovarian Cancer

Identifying Genetic Targets in Gynecological Tumors

RECRUITING

NCT07169396Azienda USL Reggio Emilia - IRCCSStarted 2021-11-17

RNA extraction and gene expression

Medullary Thyroid CancerInfantile MyofibromatosisInfantile Fibrosarcoma

A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors

ACTIVE NOT RECRUITING

NCT03899792Phase PHASE1, PHASE2Eli Lilly and CompanyStarted 2019-06-13