KLHL20

Chr 1AD

kelch like family member 20

Also known as: KHLHX, KLEIP, KLHLX, NEDSZFB

NCBI Gene: 27252 ENSG00000076321 UniProt: Q9Y2M5 OMIM: 617679

The protein functions as a substrate-specific adapter of a BCR E3 ubiquitin ligase complex that regulates protein degradation, Golgi to endosome transport, and neurite outgrowth. Mutations cause a neurodevelopmental disorder with early-onset seizures, facial dysmorphism, and behavioral abnormalities, inherited in an autosomal dominant pattern. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.511), consistent with its role in early neurodevelopment.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the kelch family of proteins, which is characterized by a 44-56 amino acid repeat motif. The kelch motif appears in many different polypeptide contexts and contains multiple potential protein-protein contact sites. Members of this family are present both throughout the cell and extracellularly, with diverse activities. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.511 OMIM phenotype

Clinical Summary— KLHL20

🧬

Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADModerate

Moderate evidence — consider for supplementary testing

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

📋

ClinVar Variants

7 unique Pathogenic / Likely Pathogenic· 62 VUS of 87 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.51LOEUF

pLI 0.009

Z-score 3.73

OE 0.30 (0.18–0.51)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.61Z-score

OE missense 0.47 (0.41–0.53)

168 obs / 361.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.30 (0.18–0.51)

0≤0.351.4

Missense OE?0.47 (0.41–0.53)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 10 / 33.2Missense obs/exp: 168 / 361.2Syn Z: -0.02

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateKLHL20-related developmental disorder with seizuresOTHERAD

This gene — mechanism propensity

0.7230th %ile

GOF

0.6639th %ile

LOF

0.3550th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

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.

ClinVar Variant Classifications

87 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic3

VUS62

Likely Benign3

Benign2

Conflicting1

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	0	4	0	0	4
Likely Pathogenic	0	3	0	0	3
VUS	2	60	0	0	62
Likely Benign	0	1	1	1	3
Benign	0	1	1	0	2
Conflicting	—				1
Total	2	69	2	1	75

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

View in ClinVar →

34 pathogenic / likely-pathogenic (of 43) ClinVar copy-number / structural variants overlap KLHL20 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →