PRKAB2

Chr 1

protein kinase AMP-activated non-catalytic subunit beta 2

NCBI Gene: 5565 ENSG00000131791 UniProt: O43741 OMIM: 602741

The protein serves as a non-catalytic regulatory subunit of AMP-activated protein kinase (AMPK), an energy sensor that monitors cellular energy status and regulates metabolic pathways by phosphorylating key enzymes involved in fatty acid and cholesterol biosynthesis. Mutations cause Wolff-Parkinson-White syndrome with intellectual disability and other abnormalities, inherited in an autosomal recessive pattern. The gene shows high constraint against loss-of-function variants (LOEUF 0.485), indicating that complete protein loss is poorly tolerated.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a regulatory 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. This subunit may be a positive regulator of AMPK activity. It is highly expressed in skeletal muscle and thus may have tissue-specific roles. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2013]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.48

Clinical Summary— PRKAB2

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Gene-Disease Validity (ClinGen)

congenital heart disease · UDDisputed

Disputed — evidence questions this relationship

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.73) — some intolerance to loss-of-function variants.

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ClinVar Variants

20 VUS of 26 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PRKAB2

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.48LOEUF

pLI 0.726

Z-score 2.82

OE 0.15 (0.06–0.48)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.50Z-score

OE missense 0.65 (0.55–0.77)

97 obs / 148.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.15 (0.06–0.48)

0≤0.351.4

Missense OE?0.65 (0.55–0.77)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 2 / 13.0Missense obs/exp: 97 / 148.4Syn Z: 0.38

This gene — mechanism propensity

0.6356th %ile

GOF

0.3986th %ile

LOF

0.58top 25%

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

26 submitted variants in ClinVar

ClinVar

Classification Summary

VUS20

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	20	20
Likely Benign	0	0
Benign	0	0
Total	20	20

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

View in ClinVar →

288 pathogenic / likely-pathogenic (of 302) ClinVar copy-number / structural variants overlap PRKAB2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →