KLHL22

Chr 22

kelch like family member 22

Also known as: KELCHL

NCBI Gene: 84861 ENSG00000099910 UniProt: Q53GT1 OMIM: 618020

KLHL22 encodes a substrate-specific adapter protein that functions as part of a ubiquitin ligase complex, mediating chromosome alignment during cell division and regulating the mTORC1 pathway through degradation of DEPDC5. Mutations cause autosomal recessive developmental and epileptic encephalopathy with early-onset seizures and developmental delay. The gene shows significant constraint against loss-of-function variants (LOEUF 0.44), indicating that complete loss of protein function is likely pathogenic.

OMIM ResearchSummary from RefSeq, UniProt

Enables 14-3-3 protein binding activity and ubiquitin-like ligase-substrate adaptor activity. Involved in several processes, including cellular response to L-leucine; mitotic spindle assembly checkpoint signaling; and negative regulation of metabolic process. Located in several cellular components, including intercellular bridge; lysosome; and microtubule cytoskeleton. Part of Cul3-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.44

Clinical Summary— KLHL22

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.44LOEUF

pLI 0.424

Z-score 3.77

OE 0.22 (0.12–0.44)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.41Z-score

OE missense 0.66 (0.60–0.73)

267 obs / 403.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.22 (0.12–0.44)

0≤0.351.4

Missense OE?0.66 (0.60–0.73)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 6 / 27.2Missense obs/exp: 267 / 403.2Syn Z: 0.17

This gene — mechanism propensity

0.5966th %ile

GOF

0.6638th %ile

LOF

0.3746th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction 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.