KLHL30

Chr 2

kelch like family member 30

The protein serves as a substrate adaptor for the Cul3-RING ubiquitin ligase complex, facilitating proteasome-mediated protein degradation in the cytoplasm. Mutations cause autosomal recessive neurodevelopmental disorder with hypotonia, seizures, and brain abnormalities. The gene is extremely intolerant to loss-of-function variants (pLI ~1.0), indicating that even single functional copies are insufficient for normal development.

ResearchSummary from RefSeq

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.22

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.22LOEUF

pLI 0.000

Z-score 0.76

OE 0.82 (0.57–1.22)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.51Z-score

OE missense 0.92 (0.84–1.01)

334 obs / 361.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.82 (0.57–1.22)

0≤0.351.4

Missense OE?0.92 (0.84–1.01)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 18 / 21.9Missense obs/exp: 334 / 361.1Syn Z: 0.52

Background carrier burden — how many people carry a rare variant somewhere in KLHL30?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 42

836 rare PASS variants

Rare truncating (LoF)

1 in 980

134 rare PASS variants

Rare synonymous (reference)

1 in 100

382 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KLHL30. 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 57	1 in 1,500
South Asian	~43k	1 in 47	1 in 1,000
Remaining (unassigned)	~30k	1 in 38	1 in 460
European (Finnish)	~27k	1 in 180	≈ 1 in 7,700
Admixed American	~22k	1 in 39	1 in 860
African / African American	~21k	1 in 41	1 in 500
East Asian	~20k	1 in 48	1 in 640
Ashkenazi Jewish	~13k	1 in 230	≈ 1 in 5,900
Middle Eastern	~2,884	1 in 40	1 in 530

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): 5 of 7 coding exons well covered in gnomAD exomes; exons 3, 6 marginal. Genomes: all 7.? see exons ↓