KLHL24

Chr 3ARAD

kelch like family member 24

Also known as: CMH29, DRE1, EBS6, EBSSH, KRIP6

NCBI Gene: 54800 ENSG00000114796 UniProt: Q6TFL4 OMIM: 611295

The protein encoded by this gene is a ubiquitin ligase substrate receptor and is regulated by autoubiquitination. Variations in the translation initiation codon of this gene have been found, which result in an N-terminally truncated but more stable protein due to loss of the autoubiquitination function. The more stable mutant protein causes an increased ubiquitin and degradation of keratin 14, which leads to skin fragility and the potentially life-threatening disease epidermolysis bullosa. The encoded protein is also involved in the regulation of kainate receptors. [provided by RefSeq, Mar 2017]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 0.652 OMIM phenotypes

Clinical Summary— KLHL24

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Gene-Disease Validity (ClinGen)

hypertrophic cardiomyopathy · ARModerate

Moderate evidence — consider for supplementary testing

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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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ClinVar Variants

15 unique Pathogenic / Likely Pathogenic· 66 VUS of 140 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — KLHL24

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.65LOEUF

pLI 0.002

Z-score 2.86

OE 0.37 (0.22–0.65)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.88Z-score

OE missense 0.56 (0.50–0.63)

190 obs / 339.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.37 (0.22–0.65)

0≤0.351.4

Missense OE?0.56 (0.50–0.63)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 9 / 24.2Missense obs/exp: 190 / 339.5Syn Z: 0.05

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateKLHL24-related epidermolysis bullosa simplex, generalised intermediate, with or without cardiomyopathyOTHERAD

This gene — mechanism propensity

0.6937th %ile

GOF

0.6638th %ile

LOF

0.3164th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

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.

Literature Evidence

GOFGain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 34292882 ↗

ClinVar Variant Classifications

140 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic4

VUS66

Likely Benign12

Benign23

Conflicting3

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	7	2	0	11
Likely Pathogenic	2	2	0	0	4
VUS	2	64	0	0	66
Likely Benign	0	0	1	11	12
Benign	0	1	16	6	23
Conflicting	—				3
Total	6	74	19	17	119

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

View in ClinVar →

37 pathogenic / likely-pathogenic (of 43) ClinVar copy-number / structural variants overlap KLHL24 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →