KLHL38

Chr 8

kelch like family member 38

Also known as: C8ORFK36

NCBI Gene: 340359ENSG00000175946UniProt: Q2WGJ6

The protein functions as a substrate adaptor for the Cul3-RING ubiquitin ligase complex, facilitating proteasome-mediated protein degradation in the cytoplasm. Mutations cause autosomal recessive congenital myopathy with fiber-type disproportion, characterized by early-onset muscle weakness and abnormal muscle fiber architecture. The gene shows moderate constraint against loss-of-function variants (LOEUF 1.245), suggesting some tolerance to such mutations.

Summary from RefSeq
Research Assistant →
0
Active trials
1
Pubs (1 yr)
50
P/LP submissions
0%
P/LP missense
1.25
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— KLHL38
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
50 unique Pathogenic / Likely Pathogenic· 126 VUS of 186 total submissions
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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.25LOEUF
pLI 0.000
Z-score 0.79
OE 0.80 (0.53–1.25)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-1.23Z-score
OE missense 1.19 (1.09–1.29)
412 obs / 347.5 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.80 (0.53–1.25)
0≤0.351.4
Missense OE1.19 (1.09–1.29)
0≤0.61.4
Synonymous OE1.24
0≤1.21.6
LoF obs/exp: 14 / 17.6Missense obs/exp: 412 / 347.5Syn Z: -2.28
DN
0.7228th %ile
GOF
0.6540th %ile
LOF
0.3452th %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

186 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic50
VUS126
Likely Benign3
Benign4
50
Pathogenic
126
VUS
3
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
50
0
50
Likely Pathogenic
0
0
0
0
0
VUS
0
122
4
0
126
Likely Benign
0
3
0
0
3
Benign
0
2
0
2
4
Total0127542183

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

View in ClinVar →

Protein Context — Lollipop Plot

KLHL38 · 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 →

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