KLHL1

Chr 13

kelch like family member 1

Also known as: MRP2

NCBI Gene: 57626 ENSG00000150361 UniProt: Q9NR64

The KLHL1 protein organizes the actin cytoskeleton of brain cells. Mutations cause autosomal dominant neuroaxonal dystrophy with brain iron accumulation, characterized by progressive neurodegeneration affecting movement and cognition. The gene shows moderate constraint against loss-of-function variants, suggesting some tolerance to protein disruption.

ResearchSummary from RefSeq, UniProt

The KLHL1 protein belongs to a family of actin-organizing proteins related to Drosophila Kelch (Nemes et al., 2000 [PubMed 10888605]).[supplied by OMIM, Feb 2010]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.71

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.71LOEUF

pLI 0.000

Z-score 2.89

OE 0.47 (0.32–0.71)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.08Z-score

OE missense 0.99 (0.91–1.07)

392 obs / 396.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.47 (0.32–0.71)

0≤0.351.4

Missense OE?0.99 (0.91–1.07)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 16 / 34.3Missense obs/exp: 392 / 396.5Syn Z: -1.26

Background carrier burden — how many people carry a rare variant somewhere in KLHL1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 74

992 rare PASS variants

Rare truncating (LoF)

1 in 1,800

112 rare PASS variants

Rare synonymous (reference)

1 in 120

383 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KLHL1. 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 89	1 in 1,700
South Asian	~43k	1 in 86	1 in 1,000
Remaining (unassigned)	~30k	1 in 67	1 in 2,700
European (Finnish)	~27k	1 in 170	≈ 1 in 6,100
Admixed American	~22k	1 in 62	1 in 800
African / African American	~21k	1 in 67	1 in 1,400
East Asian	~20k	1 in 99	1 in 1,500
Ashkenazi Jewish	~13k	1 in 350	none seen
Middle Eastern	~2,884	1 in 59	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): All 11 coding exons well covered in gnomAD exomes and genomes.? see exons ↓