ULK2

Chr 17

unc-51 like autophagy activating kinase 2

Also known as: ATG1B, Unc51.2

NCBI Gene: 9706 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

This gene encodes a protein that is similar to a serine/threonine kinase in C. elegans which is involved in axonal elongation. The structure of this protein is similar to the C. elegans protein in that both proteins have an N-terminal kinase domain, a central proline/serine rich (PS) domain, and a C-terminal (C) domain. The gene is located within the Smith-Magenis syndrome region on chromosome 17. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Dec 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.59

Clinical Summary— ULK2

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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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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.