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…

LOFmechanismLOEUF 0.15

Clinical Summary— KALRN

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

19 VUS of 147 total submissions

Explore recent and relevant literature in Research Assistant →

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

This gene — mechanism propensity

0.4388th %ile

GOF

0.5562th %ile

LOF

0.64top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.15

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

147 submitted variants in ClinVar

ClinVar

Classification Summary

VUS19

Likely Benign29

Benign32

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	18	0	0	19
Likely Benign	2	8	2	17	29
Benign	0	6	4	22	32
Total	3	32	6	39	80

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

18 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap KALRN — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →