KLHL2

Chr 4

kelch like family member 2

Also known as: ABP-KELCH, MAV, MAYVEN

NCBI Gene: 11275 ENSG00000109466 UniProt: O95198 OMIM: 605774

KLHL2 encodes a substrate-specific adapter protein for E3 ubiquitin ligase complexes that targets specific proteins including WNK kinases for proteasomal degradation and promotes actin cytoskeleton reorganization and oligodendrocyte precursor cell projection growth. Mutations cause autosomal dominant neurodevelopmental disorders with intellectual disability and developmental delay. This gene is highly constrained against loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, UniProt

Enables actin binding activity; identical protein binding activity; and ubiquitin-like ligase-substrate adaptor activity. Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process and protein ubiquitination. Located in actin cytoskeleton. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.18

LOEUF· LoF intol.

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.18LOEUF

pLI 1.000

Z-score 5.09

OE 0.06 (0.02–0.18)

Highly constrained

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

Missense Constraint?

3.89Z-score

OE missense 0.40 (0.35–0.46)

134 obs / 333.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.18)

0≤0.351.4

Missense OE?0.40 (0.35–0.46)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 2 / 34.0Missense obs/exp: 134 / 333.8Syn Z: 0.77

Background carrier burden — how many people carry a rare variant somewhere in KLHL2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

454 rare PASS variants

Rare truncating (LoF)

1 in 3,300

54 rare PASS variants

Rare synonymous (reference)

1 in 350

244 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KLHL2. 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 220	1 in 4,400
South Asian	~43k	1 in 180	1 in 1,000
Remaining (unassigned)	~30k	1 in 120	1 in 5,800
European (Finnish)	~27k	1 in 380	≈ 1 in 13,000
Admixed American	~22k	1 in 160	≈ 1 in 7,400
African / African American	~21k	1 in 140	1 in 2,200
East Asian	~20k	1 in 260	1 in 1,100
Ashkenazi Jewish	~13k	1 in 460	none seen
Middle Eastern	~2,884	1 in 240	none seen

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): 13 of 15 coding exons well covered in gnomAD exomes; exons 1, 6 marginal. Genomes: all 15.? see exons ↓