KALRN

Chr 3

kalirin RhoGEF kinase

Also known as: ARHGEF24, CHDS5, DUET, DUO, HAPIP, KALNC2, TRAD

NCBI Gene: 8997 ENSG00000160145 UniProt: O60229 OMIM: 604605

This protein functions as a guanine nucleotide exchange factor that activates Rho GTPases to regulate neuronal shape, growth, and plasticity through effects on the actin cytoskeleton. Mutations cause neurodevelopmental disorders with intellectual disability, autism spectrum disorder, and seizures, following autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants, indicating that haploinsufficiency is likely not tolerated in the general population.

OMIM ResearchSummary from RefSeq, UniProt

Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein that interacts with the huntingtin-associated protein 1, which is a huntingtin binding protein that may function in vesicle trafficking. [provided by RefSeq, Apr 2016]

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

0.15

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.15LOEUF

pLI 1.000

Z-score 8.26

OE 0.08 (0.05–0.15)

Highly constrained

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

Missense Constraint?

4.36Z-score

OE missense 0.61 (0.57–0.65)

590 obs / 972.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.08 (0.05–0.15)

0≤0.351.4

Missense OE?0.61 (0.57–0.65)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 8 / 94.7Missense obs/exp: 590 / 972.7Syn Z: -0.03

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 22

3,186 rare PASS variants

Rare truncating (LoF)

1 in 1,200

174 rare PASS variants

Rare synonymous (reference)

1 in 26

1,545 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KALRN. 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 27	1 in 1,200
South Asian	~43k	1 in 21	1 in 620
Remaining (unassigned)	~30k	1 in 20	1 in 600
European (Finnish)	~27k	1 in 58	1 in 600
Admixed American	~22k	1 in 21	1 in 590
African / African American	~21k	1 in 21	1 in 840
East Asian	~20k	1 in 23	1 in 2,000
Ashkenazi Jewish	~13k	1 in 48	1 in 1,200
Middle Eastern	~2,884	1 in 23	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): 40 of 60 coding exons well covered in gnomAD exomes; exons 2, 3, 19, 20, 24 and 14 more marginal. Genomes: 59 of 60 (exon 10 below).? see exons ↓