KLHL38

Chr 8

kelch like family member 38

Also known as: C8ORFK36

NCBI Gene: 340359 ENSG00000175946 UniProt: 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.

ResearchSummary from RefSeq

Predicted to enable ubiquitin-like ligase-substrate adaptor activity. Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Predicted to be part of Cul3-RING ubiquitin ligase complex. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.25

LOEUF

Multiple*

Mechanism· predicted

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 OE?0.80 (0.53–1.25)

0≤0.351.4

Missense OE?1.19 (1.09–1.29)

0≤0.61.4

Synonymous OE?1.24

0≤1.21.6

LoF obs/exp: 14 / 17.6Missense obs/exp: 412 / 347.5Syn Z: -2.28

Background carrier burden — how many people carry a rare variant somewhere in KLHL38?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 43

859 rare PASS variants

Rare truncating (LoF)

1 in 950

110 rare PASS variants

Rare synonymous (reference)

1 in 110

339 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KLHL38. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 84	1 in 910
South Asian	~43k	1 in 42	1 in 810
Remaining (unassigned)	~30k	1 in 34	1 in 1,200
European (Finnish)	~27k	1 in 190	≈ 1 in 13,000
Admixed American	~22k	1 in 40	1 in 1,100
African / African American	~21k	1 in 42	1 in 1,000
East Asian	~20k	1 in 72	1 in 640
Ashkenazi Jewish	~13k	1 in 170	≈ 1 in 3,300
Middle Eastern	~2,884	1 in 43	1 in 410

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓