KLHL22

Chr 22

kelch like family member 22

Also known as: KELCHL

NCBI Gene: 84861ENSG00000099910UniProt: Q53GT1

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]

458
ClinVar variants
343
Pathogenic / LP
0.42
pLI score
0
Active trials
Clinical Summary— KLHL22
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.
📋
ClinVar Variants
343 Pathogenic / Likely Pathogenic· 101 VUS of 458 total submissions
Some data sources returned errors (1)

clinvar: 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?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.22 (0.12–0.44)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.66 (0.60–0.73)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 6 / 27.2Missense obs/exp: 267 / 403.2Syn Z: 0.17

ClinVar Variant Classifications

458 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic323
Likely Pathogenic20
VUS101
Likely Benign3
Benign2
Conflicting2
323
Pathogenic
20
Likely Pathogenic
101
VUS
3
Likely Benign
2
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
323
0
323
Likely Pathogenic
0
0
20
0
20
VUS
0
65
36
0
101
Likely Benign
0
1
1
1
3
Benign
0
0
2
0
2
Conflicting
—2
Total0663821451

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

View in ClinVar →

Protein Context — Lollipop Plot

KLHL22 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
KELCH-LIKE 22; KLHL22
MIM #618020 · *
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
COLEC10 inhibits the stemness of hepatocellular carcinoma by suppressing the activity of β-catenin signaling.
Cai MN et al.·Cell Oncol (Dordr)
2024
Modulation of the tumor microenvironment by the ubiquitin-proteasome system in colorectal cancer.
Wang X et al.·J Transl Med
2025Review
An Enhanced Random Forests Approach to Predict Heart Failure From Small Imbalanced Gene Expression Data.
Chicco D et al.·IEEE/ACM Trans Comput Biol Bioinform
2021
Accurate diagnosis of spinal muscular atrophy and 22q11.2 deletion syndrome using limited deoxynucleotide triphosphates and high-resolution melting.
Zhang X et al.·BMC Genomics
2018
Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance.
Woodward KJ et al.·Mol Genet Genomic Med
2019Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools