PRKAA2

Chr 1

protein kinase AMP-activated catalytic subunit alpha 2

Also known as: AMPK, AMPK2, AMPKa2, PRKAA

NCBI Gene: 5563 ENSG00000162409 UniProt: P54646 OMIM: 600497

The protein encoded by this gene is the alpha-2 catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor that phosphorylates and regulates key enzymes in cellular metabolism, autophagy, and transcription in response to cellular energy stress. Mutations cause familial Wolff-Parkinson-White syndrome with hypertrophic cardiomyopathy, inherited in an autosomal dominant pattern. This gene is highly intolerant to loss-of-function mutations, affecting cardiac conduction and energy homeostasis.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a catalytic subunit of the AMP-activated protein kinase (AMPK). AMPK is a heterotrimer consisting of an alpha catalytic subunit, and non-catalytic beta and gamma subunits. AMPK is an important energy-sensing enzyme that monitors cellular energy status. In response to cellular metabolic stresses, AMPK is activated, and thus phosphorylates and inactivates acetyl-CoA carboxylase (ACC) and beta-hydroxy beta-methylglutaryl-CoA reductase (HMGCR), key enzymes involved in regulating de novo biosynthesis of fatty acid and cholesterol. Studies of the mouse counterpart suggest that this catalytic subunit may control whole-body insulin sensitivity and is necessary for maintaining myocardial energy homeostasis during ischemia. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.92

Clinical Summary— PRKAA2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

54 VUS of 72 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.92LOEUF

pLI 0.000

Z-score 1.88

OE 0.61 (0.41–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.99Z-score

OE missense 0.68 (0.61–0.76)

207 obs / 304.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.61 (0.41–0.92)

0≤0.351.4

Missense OE?0.68 (0.61–0.76)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 16 / 26.4Missense obs/exp: 207 / 304.5Syn Z: 0.59

This gene — mechanism propensity

0.7033th %ile

GOF

0.6346th %ile

LOF

0.3647th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

72 submitted variants in ClinVar

ClinVar

Classification Summary

VUS54

Likely Benign4

Benign5

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	54	0	0	54
Likely Benign	2	0	2	4
Benign	0	2	3	5
Total	56	2	5	63

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

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9 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap PRKAA2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →