KLHL3

Chr 5ADAR

kelch like family member 3

Also known as: PHA2D

NCBI Gene: 26249ENSG00000146021UniProt: Q9UH77

This gene is ubiquitously expressed and encodes a full-length protein which has an N-terminal BTB domain followed by a BACK domain and six kelch-like repeats in the C-terminus. These kelch-like repeats promote substrate ubiquitination of bound proteins via interaction of the BTB domain with the CUL3 (cullin 3) component of a cullin-RING E3 ubiquitin ligase (CRL) complex. Muatations in this gene cause pseudohypoaldosteronism type IID (PHA2D); a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Mar 2012]

Primary Disease Associations & Inheritance

Pseudohypoaldosteronism, type IIDMIM #614495
ADAR
0
Active trials
42
Pathogenic / LP
413
ClinVar variants
12
Pubs (1 yr)
3.0
Missense Z
0.34
LOEUF· LoF intolerant
Clinical Summary— KLHL3
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.94). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
42 Pathogenic / Likely Pathogenic· 232 VUS of 413 total submissions
📖
GeneReview available — KLHL3
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.34LOEUF
pLI 0.945
Z-score 4.35
OE 0.16 (0.08–0.34)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
2.99Z-score
OE missense 0.56 (0.50–0.63)
206 obs / 367.5 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.16 (0.08–0.34)
0≤0.351.4
Missense OE0.56 (0.50–0.63)
0≤0.61.4
Synonymous OE0.92
0≤1.21.6
LoF obs/exp: 5 / 31.2Missense obs/exp: 206 / 367.5Syn Z: 0.75
DNLOF
DN
0.6260th %ile
GOF
0.5759th %ile
LOF
0.54top 25%

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-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 · 1 literature citation
LOFLOEUF 0.34

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

DNWe further demonstrated that the dimerization of KLHL3 can explain this dominant negative effect.PMID:28052936

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

413 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32
Likely Pathogenic10
VUS232
Likely Benign46
Benign89
Conflicting4
32
Pathogenic
10
Likely Pathogenic
232
VUS
46
Likely Benign
89
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
13
17
0
32
Likely Pathogenic
0
8
2
0
10
VUS
1
151
76
4
232
Likely Benign
0
0
18
28
46
Benign
0
0
81
8
89
Conflicting
—4
Total317219440413

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

View in ClinVar →

KLHL3 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Familial Hyperkalemic Hypertension.
Cornelius RJ et al.·Compr Physiol
2024Review
WNK1 in the kidney.
Bahena-Lopez JP et al.·Curr Opin Nephrol Hypertens
2022Review
The Molecular Genetics of Gordon Syndrome.
Mabillard H et al.·Genes (Basel)
2019Review
KLHL3 deficiency in mice ameliorates obesity, insulin resistance, and nonalcoholic fatty liver disease by regulating energy expenditure.
Jang JH et al.·Exp Mol Med
2022
Hypertension-causing cullin 3 mutations disrupt COP9 signalosome binding.
Cornelius RJ et al.·Am J Physiol Renal Physiol
2020Review
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients