ULK2

Chr 17

unc-51 like autophagy activating kinase 2

ENSG00000083290 UniProt: Q8IYT8 OMIM: 608650

The protein is a serine/threonine kinase that regulates autophagy in response to starvation and plays a critical role in early neuronal differentiation and granule cell axon formation. Mutations cause autosomal recessive developmental and epileptic encephalopathy with movement abnormalities, typically presenting in early childhood with seizures, developmental delays, and neurological dysfunction. This gene is highly constrained against loss-of-function variants in the population, indicating that complete loss of function is likely not tolerated.

OMIM ResearchSummary from RefSeq, UniProt

Serine/threonine-protein kinase involved in autophagy in response to starvation. Acts upstream of phosphatidylinositol 3-kinase PIK3C3 to regulate the formation of autophagophores, the precursors of autophagosomes. Part of regulatory feedback loops in autophagy: acts both as a downstream effector and a negative regulator of mammalian target of rapamycin complex 1 (mTORC1) via interaction with RPTOR. Activated via phosphorylation by AMPK, also acts as a negative regulator of AMPK through phosphorylation of the AMPK subunits PRKAA1, PRKAB2 and PRKAG1. May phosphorylate ATG13/KIAA0652, FRS2, FRS3 and RPTOR; however such data need additional evidences. Not involved in ammonia-induced autophagy or in autophagic response of cerebellar granule neurons (CGN) to low potassium concentration. Plays a role early in neuronal differentiation and is required for granule cell axon formation: may govern axon formation via Ras-like GTPase signaling and through regulation of the Rab5-mediated endocytic pathways within developing axons

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.59

Clinical Summary— ULK2

⚡

Population Constraint (gnomAD)

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

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.59LOEUF

pLI 0.000

Z-score 4.03

OE 0.42 (0.30–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.62Z-score

OE missense 0.81 (0.75–0.87)

451 obs / 559.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.42 (0.30–0.59)

0≤0.351.4

Missense OE?0.81 (0.75–0.87)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 23 / 55.4Missense obs/exp: 451 / 559.1Syn Z: 0.09

This gene — mechanism propensity

0.7035th %ile

GOF

0.5661th %ile

LOF

0.4431th %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.