KALRN

Summary

KALRN (kalirin RhoGEF kinase, HGNC:4814) is a protein-coding gene on chromosome 3q21.1-q21.2, encoding Kalirin (O60229). Promotes the exchange of GDP by GTP.

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.

Source: NCBI Gene 8997 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 52
• Clinical variants (ClinVar): 150 total — 1 pathogenic
• MANE Select transcript: NM_001388419

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4814
Approved symbol	KALRN
Name	kalirin RhoGEF kinase
Location	3q21.1-q21.2
Locus type	gene with protein product
Status	Approved
Aliases	duo, Hs.8004, TRAD, DUET, Kalirin, ARHGEF24, KALNC2
Ensembl gene	ENSG00000160145
Ensembl biotype	protein_coding
OMIM	604605
Entrez	8997

Gene structure

Transcript identifiers

Ensembl transcripts: 52 — 23 protein_coding, 14 protein_coding_CDS_not_defined, 8 nonsense_mediated_decay, 7 retained_intron

ENST00000240874, ENST00000291478, ENST00000354186, ENST00000360013, ENST00000393496, ENST00000393501, ENST00000439170, ENST00000448253, ENST00000454902, ENST00000459915, ENST00000460856, ENST00000462213, ENST00000471431, ENST00000473056, ENST00000477496, ENST00000483658, ENST00000484224, ENST00000484542, ENST00000488825, ENST00000494648, ENST00000498499, ENST00000522553, ENST00000682277, ENST00000682290, ENST00000682363, ENST00000682506, ENST00000682540, ENST00000682575, ENST00000682625, ENST00000682636, ENST00000682674, ENST00000682695, ENST00000682861, ENST00000682890, ENST00000683124, ENST00000683146, ENST00000683280, ENST00000683356, ENST00000683428, ENST00000683512, ENST00000683571, ENST00000683592, ENST00000683827, ENST00000683922, ENST00000684186, ENST00000684276, ENST00000684360, ENST00000684374, ENST00000684382, ENST00000684410, ENST00000684441, ENST00000684480

RefSeq mRNA: 25 — MANE Select: NM_001388419 NM_001024660, NM_001322988, NM_001322989, NM_001322990, NM_001322991, NM_001322992, NM_001322993, NM_001322994, NM_001322995, NM_001322996, NM_001322997, NM_001322998, NM_001322999, NM_001323000, NM_001323001, NM_001388412, NM_001388413, NM_001388414, NM_001388415, NM_001388416, NM_001388417, NM_001388418, NM_001388419, NM_003947, NM_007064

CCDS: CCDS3027, CCDS3028, CCDS82829, CCDS93359, CCDS93360, CCDS93361, CCDS93362, CCDS93363

Canonical transcript exons

ENST00000682506 — 60 exons

Exon	Start	End
ENSE00001050118	124712935	124713135
ENSE00001078843	124492740	124492882
ENSE00001078871	124491323	124491424
ENSE00001078892	124661851	124661928
ENSE00001078893	124637208	124637303
ENSE00001078894	124659365	124659457
ENSE00001078896	124666449	124666634
ENSE00001078899	124671660	124671898
ENSE00001078904	124655601	124655667
ENSE00001078908	124667012	124667183
ENSE00001078912	124658431	124658517
ENSE00001078913	124657734	124657803
ENSE00001078916	124657448	124657551
ENSE00001121896	124702038	124702116
ENSE00001121906	124699869	124700033
ENSE00001121918	124697593	124697724
ENSE00001121926	124696134	124696255
ENSE00001121946	124693804	124693831
ENSE00001179563	124717247	124717385
ENSE00001283533	124632420	124632703
ENSE00001286464	124496311	124496413
ENSE00001304756	124678190	124678313
ENSE00001317463	124660923	124660973
ENSE00001326215	124679458	124679517
ENSE00001327535	124694332	124694503
ENSE00001413257	124562843	124563089
ENSE00002211456	124384845	124385036
ENSE00002231617	124268743	124269255
ENSE00002258261	124234829	124234943
ENSE00002271870	124325980	124326171
ENSE00002286359	124329861	124329992
ENSE00002287598	124488204	124488315
ENSE00002299573	124264498	124264690
ENSE00002303965	124227990	124228064
ENSE00002312898	124334265	124334495
ENSE00002315494	124347143	124347265
ENSE00003459375	124395135	124395343
ENSE00003470442	124398697	124398871
ENSE00003477518	124650808	124650938
ENSE00003479705	124298791	124298913
ENSE00003488118	124446161	124446276
ENSE00003494391	124434307	124434525
ENSE00003498004	124430656	124430775
ENSE00003499422	124455177	124455359
ENSE00003500290	124438888	124439037
ENSE00003502993	124474663	124474732
ENSE00003516936	124413470	124413665
ENSE00003516946	124490694	124490884
ENSE00003536815	124441945	124442059
ENSE00003562312	124422812	124422978
ENSE00003603321	124456610	124456728
ENSE00003633206	124446763	124446885
ENSE00003638457	124461890	124461956
ENSE00003639880	124482808	124482900
ENSE00003655272	124462524	124462633
ENSE00003694388	124477245	124477334
ENSE00003707968	124718925	124726325
ENSE00003916324	124674364	124674614
ENSE00003918959	124033369	124033813
ENSE00003922302	124633852	124633953

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 99.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.7713 / max 789.4488, expressed in 1149 samples.

FANTOM5 promoters (23 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38298	4.5123	840
38309	2.9150	81
38317	1.1845	483
38297	0.9818	489
38318	0.7086	295
38302	0.6778	81
38321	0.2971	39
38307	0.2260	58
38299	0.1953	92
38303	0.1709	49

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.46	gold quality
oocyte	CL:0000023	98.41	gold quality
frontal pole	UBERON:0002795	97.52	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.13	gold quality
ascending aorta	UBERON:0001496	96.67	gold quality
thoracic aorta	UBERON:0001515	96.60	gold quality
descending thoracic aorta	UBERON:0002345	96.02	gold quality
prefrontal cortex	UBERON:0000451	95.99	gold quality
right coronary artery	UBERON:0001625	95.67	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.90	gold quality
primary visual cortex	UBERON:0002436	94.73	gold quality
frontal cortex	UBERON:0001870	94.72	gold quality
right frontal lobe	UBERON:0002810	94.72	gold quality
sural nerve	UBERON:0015488	94.67	gold quality
neocortex	UBERON:0001950	94.29	gold quality
aorta	UBERON:0000947	94.18	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.17	gold quality
superior frontal gyrus	UBERON:0002661	94.16	gold quality
orbitofrontal cortex	UBERON:0004167	93.86	gold quality
cingulate cortex	UBERON:0003027	93.75	gold quality
anterior cingulate cortex	UBERON:0009835	93.71	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.70	gold quality
left coronary artery	UBERON:0001626	93.61	gold quality
cortical plate	UBERON:0005343	93.48	gold quality
middle temporal gyrus	UBERON:0002771	93.36	gold quality
occipital lobe	UBERON:0002021	93.22	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.15	gold quality
cerebral cortex	UBERON:0000956	93.13	gold quality
jejunal mucosa	UBERON:0000399	92.95	gold quality
coronary artery	UBERON:0001621	92.85	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	4889.17
E-HCAD-25	yes	1492.63
E-HCAD-35	yes	100.12
E-CURD-119	yes	33.90
E-ANND-3	yes	7.79
E-GEOD-124858	no	144.24

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

75 targeting KALRN, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-4658	99.77	64.94	514
HSA-MIR-6790-5P	99.77	65.24	505
HSA-MIR-6885-3P	99.75	70.36	3187

Literature-anchored findings (GeneRIF, showing 30)

• we have identified multiple transcriptional start sites in rats and humans. These multiple transcriptional start sites result in full-length Kalirin transcripts possessing different 5’ ends encoding proteins with differing amino termini (PMID:14742910)
• Kalirin GEF1 domain induces lamellipodia through activation of Pak, where Guanine nucleotide exchange factor (GEF) activity is not required. (PMID:15950621)
• Three SNPs from the kalirin (KALRN) gene are associated with early-onset coronary artery disease. (PMID:17357071)
• ARF6 recruits KALRN to the cell membrane facilitating Rac activation. (PMID:17640372)
• Our observation is the first to relate kalirin to Alzheimer’s disease. Kalirin was consistently under-expressed in Alzheimer’s disease hippocampus. (PMID:17851188)
• Kalirin-7 is an essential component of both shaft and spine excitatory synapses in hippocampal interneurons. (PMID:18199770)
• Two SNPs in the KALRN gene region (rs17286604 and rs11712619)constitute risk factors for ischemic stroke. (PMID:20107840)
• SNX1 and SNX2 interact with Kalirin-7. Overexpression of SNX1 or SNX2 and Kalirin-7 partially redistributes both SNXs to the plasma membrane, and results in RhoG-dependent lamellipodia formation. (PMID:20604901)
• Studies indicate that Kalirin-7 plays a key role in excitatory synapse formation and function. (PMID:20730383)
• Missense mutations in KALRN may be genetic risk factors for schizophrenia. (PMID:21041834)
• KALRN gene variation is not associated with overall ischemic stroke (PMID:21664346)
• We found Kalirin-9 expression to be paradoxically increased in schizophrenia (PMID:22120753)
• Neuronal guanine nucleotide exchange factor (GEF) kalirin is emerging as a key regulator of structural and functional plasticity at dendritic spines. (PMID:22194219)
• The kalirin expression were reduced in Alzheimer disease with psychosis. (PMID:22429885)
• In both anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC), study found a reduction of Duo expression and PAK1 phosphorylation in schizophrenia. Cdc42 protein expression was decreased in ACC but not in DLPFC (PMID:22458949)
• The age-at-onset of Huntington disease (HD) is not associated with eleven SNPs, including SNP rs10934657 in the kalirin gene in 680 European HD patients. (PMID:22720673)
• A sequence variant in human KALRN impairs protein ability to activate Rac1 and coincides with reduced cortical thickness. (PMID:25224588)
• consider the GG genotype and the G allele of rs9289231 polymorphism of KALRN to be genetic risk factors for CAD in an Iranian population, especially in early-stage atherosclerotic vascular disease (PMID:25316661)
• 4 KALRN gene SNPs were studied in Han ischemic stroke patients. rs11712619 seemed associated with lacunar stroke until risk factors were considered. re6438833 was significantly associated with ischemic and lacunar stroke. (PMID:25917671)
• GG genotype and the G allele of the rs9289231 polymorphism of KALRN and the rs224766 polymorphism of ADIPOQ genes may be considered genetic risk factors for Iranian type 2 diabetic patients with coronary artery disease. (PMID:27218147)
• DNA sequencing provided evidence linking KALRN to monogenic intellectual disability in two patients. (PMID:27421267)
• Data suggest protein levels of kalirin and CHD7 in circulating extracellular vesicles (EVs) as endothelial dysfunction markers to monitor vascular condition in hypertensive patients with albuminuria. (PMID:28152519)
• The GG genotype and G allele of SNP rs7620580 were associated with a risk for ischemic stroke with an adjusted OR of 3.195 and an OR of 1.446, respectively. Haplotype analysis revealed that A-T-G,G-T-A, and A-T-A haplotypes were associated with ischemic stroke. Our results provide evidence that kalirin gene variations were associated with ischemic stroke in the Chinese Han population. (PMID:28706949)
• The data of this study reveal a novel mechanism for disease-associated single nucleotide variants of KALARN and provide a platform for modeling morphological changes in mental disorders. (PMID:29241584)
• Combination of polymorphisms in the NOD2, IL17RA, EPHA2 and KALRN genes could play a significant role in the development of sarcoidosis by maintaining a chronic pro-inflammatory status in macrophages (PMID:29554915)
• The interaction of kalirin with the C-terminal region of Htt influences the function of kalirin and modulates the cytotoxicity induced by C-terminal Htt. (PMID:29789657)
• SNPs of the KALRN gene are associated with intracranial atherosclerotic stenosis in the northern Chinese population. (PMID:30232674)
• Synaptic Kalirin-7 and Trio Interactomes Reveal a GEF Protein-Dependent Neuroligin-1 Mechanism of Action. (PMID:31801062)
• KALRN mutations promote antitumor immunity and immunotherapy response in cancer. (PMID:33037113)
• Kalirin-RAC controls nucleokinetic migration in ADRN-type neuroblastoma. (PMID:33658318)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	kalrnb	ENSDARG00000063538
danio_rerio	kalrna	ENSDARG00000104119
mus_musculus	Kalrn	ENSMUSG00000061751
rattus_norvegicus	Kalrn	ENSRNOG00000001706
rattus_norvegicus		ENSRNOG00000072161

Paralogs (22): TRIO (ENSG00000038382), MCF2L2 (ENSG00000053524), PLEKHG2 (ENSG00000090924), MCF2 (ENSG00000101977), ARHGEF7 (ENSG00000102606), PLEKHG1 (ENSG00000120278), MCF2L (ENSG00000126217), ARHGEF6 (ENSG00000129675), ARHGEF9 (ENSG00000131089), VAV3 (ENSG00000134215), VAV1 (ENSG00000141968), TIAM2 (ENSG00000146426), KIAA1755 (ENSG00000149633), PLEKHG4B (ENSG00000153404), TIAM1 (ENSG00000156299), VAV2 (ENSG00000160293), ARHGEF40 (ENSG00000165801), SPATA13 (ENSG00000182957), SESTD1 (ENSG00000187231), PLEKHN1 (ENSG00000187583), PLEKHG4 (ENSG00000196155), ARHGEF25 (ENSG00000240771)

Protein

Protein identifiers

Kalirin — O60229 (reviewed: O60229)

Alternative names: Huntingtin-associated protein-interacting protein, Protein Duo, Serine/threonine-protein kinase with Dbl- and pleckstrin homology domain

All UniProt accessions (25): O60229, A0A0D9SGH1, A0A804HHT5, A0A804HI42, A0A804HI83, A0A804HI91, A0A804HII1, A0A804HIK8, A0A804HIN3, A0A804HIP9, A0A804HIY9, A0A804HJ49, A0A804HJ74, A0A804HJC5, A0A804HJX0, A0A804HJZ3, A0A804HKJ7, A0A804HKT9, A0A804HKU9, A0A804HLC8, A0A804HLF3, C9IZQ6, C9J1B4, H7BXZ5, H7C1X7

UniProt curated annotations — full annotation on UniProt →

Function. Promotes the exchange of GDP by GTP. Activates specific Rho GTPase family members, thereby inducing various signaling mechanisms that regulate neuronal shape, growth, and plasticity, through their effects on the actin cytoskeleton. Induces lamellipodia independent of its GEF activity.

Subunit / interactions. Interacts with the C-terminal of peptidylglycine alpha-amidating monooxygenase (PAM) and with the huntingtin-associated protein 1 (HAP1). Interacts with FASLG.

Subcellular location. Cytoplasm. Cytoskeleton.

Tissue specificity. Isoform 2 is brain specific. Highly expressed in cerebral cortex, putamen, amygdala, hippocampus and caudate nucleus. Weakly expressed in brain stem and cerebellum. Isoform 4 is expressed in skeletal muscle.

Post-translational modifications. Autophosphorylated.

Domain organisation. The two GEF domains catalyze nucleotide exchange for RAC1 and RhoA which are bound by DH1 and DH2 respectively. The two GEF domains appear to play differing roles in neuronal development and axonal outgrowth. SH3 1 binds to the first GEF domain inhibiting GEF activity only when in the presence of a PXXP peptide, suggesting that the SH3 domain/peptide interaction mediates binding to GEF1. CRK1 SH3 domain binds to and inhibits GEF1 activity.

Miscellaneous. Called DUO because the encoded protein is closely related to but shorter than TRIO.

Similarity. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family.

Isoforms (6)

UniProt ID	Names	Canonical?
O60229-1	1	yes
O60229-2	2
O60229-4	4, DUET, TRAD
O60229-5	5
O60229-6	6
O60229-7	7

RefSeq proteins (25): NP_001019831, NP_001309917, NP_001309918, NP_001309919, NP_001309920, NP_001309921, NP_001309922, NP_001309923, NP_001309924, NP_001309925, NP_001309926, NP_001309927, NP_001309928, NP_001309929, NP_001309930, NP_001375341, NP_001375342, NP_001375343, NP_001375344, NP_001375345, NP_001375346, NP_001375347, NP_001375348, NP_003938, NP_008995 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR000719	Prot_kinase_dom	Domain
IPR001251	CRAL-TRIO_dom	Domain
IPR001452	SH3_domain	Domain
IPR001849	PH_domain	Domain
IPR002017	Spectrin_repeat	Repeat
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR003961	FN3_dom	Domain
IPR007110	Ig-like_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR018159	Spectrin/alpha-actinin	Repeat
IPR028570	Kalirin_TRIO_SH3_1	Domain
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR036865	CRAL-TRIO_dom_sf	Homologous_superfamily
IPR047053	Kalirin_TRIO_SH3_2	Domain
IPR047054	Kalirin_TRIO_PH_1	Domain
IPR051336	RhoGEF_Guanine_NuclExch_SF	Family
IPR055251	SOS1_NGEF_PH	Domain
IPR058918	KALRN/TRIO-like_spectrin	Domain

Pfam: PF00041, PF00069, PF00435, PF00621, PF07679, PF13716, PF16609, PF22697, PF23323, PF23587

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (89 total): helix 26, splice variant 11, domain 10, repeat 9, modified residue 7, region of interest 5, compositionally biased region 5, sequence variant 5, turn 3, binding site 2, chain 1, active site 1, disulfide bond 1, mutagenesis site 1, sequence conflict 1, strand 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
8C7D	X-RAY DIFFRACTION	1.86
5QQJ	X-RAY DIFFRACTION	1.9
5QQD	X-RAY DIFFRACTION	1.91
5QQE	X-RAY DIFFRACTION	1.95
5QU9	X-RAY DIFFRACTION	2
5QQM	X-RAY DIFFRACTION	2.02
5QQI	X-RAY DIFFRACTION	2.08
5QQH	X-RAY DIFFRACTION	2.09
5QQG	X-RAY DIFFRACTION	2.23
5QQK	X-RAY DIFFRACTION	2.24
5QQL	X-RAY DIFFRACTION	2.25
5QQF	X-RAY DIFFRACTION	2.26
5QQN	X-RAY DIFFRACTION	2.26

Predicted structure (AlphaFold)

No AlphaFold model available for O60229 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 2803 (proton acceptor)

Ligand- & substrate-binding residues (2): 2690–2698; 2713

Post-translational modifications (7): 1750, 1753, 1799, 1812, 1817, 1913, 2262

Disulfide bonds (1): 2492–2548

Mutagenesis-validated functional residues (1):

Position	Phenotype
2713	loss of autophosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

22 pathways

ID	Pathway
R-HSA-193648	NRAGE signals death through JNK
R-HSA-3928662	EPHB-mediated forward signaling
R-HSA-416476	G alpha (q) signalling events
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-5687128	MAPK6/MAPK4 signaling
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013408	RHOG GTPase cycle
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-194315	Signaling by Rho GTPases
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE
R-HSA-2682334	EPH-Ephrin signaling
R-HSA-372790	Signaling by GPCR
R-HSA-388396	GPCR downstream signalling
R-HSA-422475	Axon guidance
R-HSA-5683057	MAPK family signaling cascades
R-HSA-73887	Death Receptor Signaling
R-HSA-9012999	RHO GTPase cycle
R-HSA-9675108	Nervous system development
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 279 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, AAGCCAT_MIR135A_MIR135B, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, REACTOME_NRAGE_SIGNALS_DEATH_THROUGH_JNK, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, LHX3_01, AATGGAG_MIR136, PID_ARF6_DOWNSTREAM_PATHWAY, GGGCATT_MIR365, SRF_C, WANG_LMO4_TARGETS_DN

GO Biological Process (8): protein phosphorylation (GO:0006468), signal transduction (GO:0007165), nervous system development (GO:0007399), axon guidance (GO:0007411), vesicle-mediated transport (GO:0016192), intracellular signal transduction (GO:0035556), ephrin receptor signaling pathway (GO:0048013), regulation of small GTPase mediated signal transduction (GO:0051056)

GO Molecular Function (10): protein serine/threonine kinase activity (GO:0004674), guanyl-nucleotide exchange factor activity (GO:0005085), ATP binding (GO:0005524), metal ion binding (GO:0046872), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (8): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), postsynaptic density (GO:0014069), actin cytoskeleton (GO:0015629), extrinsic component of membrane (GO:0019898), extracellular exosome (GO:0070062), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
RHO GTPase cycle	3
Signal Transduction	3
GPCR downstream signalling	2
Cell death signalling via NRAGE, NRIF and NADE	1
EPH-Ephrin signaling	1
MAPK family signaling cascades	1
Death Receptor Signaling	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
p75 NTR receptor-mediated signalling	1
Axon guidance	1
Signaling by GPCR	1
Nervous system development	1
Signaling by Rho GTPases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cellular process	2
intracellular anatomical structure	2
protein kinase activity	2
phosphorylation	1
protein modification process	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
system development	1
axonogenesis	1
neuron projection guidance	1
transport	1
signal transduction	1
cell surface receptor protein tyrosine kinase signaling pathway	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
nuclear lumen	1
cytoplasm	1
asymmetric synapse	1
postsynaptic specialization	1
cytoskeleton	1
membrane	1
extracellular vesicle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1512 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KALRN	PAM	P19021	967
KALRN	DLG4	P78352	942
KALRN	ARHGAP31	Q2M1Z3	877
KALRN	RABIF	P47224	848
KALRN	RHOG	P35238	828
KALRN	MYLK	Q15746	814
KALRN	DISC1	Q9NRI5	762
KALRN	GRIA1	P42261	756
KALRN	SLC17A7	Q9P2U7	697
KALRN	GRIN2B	Q13224	659
KALRN	TIAM1	Q13009	645
KALRN	GRIA2	P42262	628
KALRN	SYNGAP1	Q96PV0	624
KALRN	NLGN1	Q8N2Q7	618
KALRN	SLC32A1	Q9H598	608

IntAct

42 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
rep	KALRN	psi-mi:“MI:0915”(physical association)	0.560
KALRN	rep	psi-mi:“MI:0915”(physical association)	0.560
KALRN	FASLG	psi-mi:“MI:0407”(direct interaction)	0.440
Nlgn1	KALRN	psi-mi:“MI:0915”(physical association)	0.400
KALRN	HAP1	psi-mi:“MI:0915”(physical association)	0.400
KALRN	ATXN7	psi-mi:“MI:0915”(physical association)	0.370
CACNA1A	KALRN	psi-mi:“MI:0915”(physical association)	0.370
SPG11	KALRN	psi-mi:“MI:0915”(physical association)	0.370
SNCAIP	KALRN	psi-mi:“MI:0915”(physical association)	0.370
APBB1	SSPOP	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
HCN1	USP27X	psi-mi:“MI:0914”(association)	0.350
CACNA1C	IGLL5	psi-mi:“MI:0914”(association)	0.350
RIMS1	PSMD12	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	POM121C	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	POTEF	psi-mi:“MI:0914”(association)	0.350
KALRN	AKT1	psi-mi:“MI:2364”(proximity)	0.270
KALRN	DISC1	psi-mi:“MI:0915”(physical association)	0.000
KALRN	NDEL1	psi-mi:“MI:0915”(physical association)	0.000
FMR1	KALRN	psi-mi:“MI:0915”(physical association)	0.000
DISC1	KALRN	psi-mi:“MI:0915”(physical association)	0.000
STXBP1	KALRN	psi-mi:“MI:0915”(physical association)	0.000
NDEL1	KALRN	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (49): PAM (Two-hybrid), SNCAIP (Affinity Capture-Western), KALRN (Two-hybrid), KALRN (Affinity Capture-Western), DICER1 (Co-fractionation), KALRN (Two-hybrid), ERBB4 (Affinity Capture-Western), RAC1 (Affinity Capture-Western), FYN (Affinity Capture-Western), KALRN (Affinity Capture-RNA), KALRN (Affinity Capture-MS), KALRN (Two-hybrid), KALRN (Affinity Capture-MS), KALRN (Proximity Label-MS), KALRN (Two-hybrid)

ESM2 similar proteins: A0A8M2BID5, A0A8M9PQ61, A1Z7A6, D3ZHV2, E9Q557, F1LMV6, F1M0Z1, G3V7L1, O43150, O60229, O60437, O75962, O97592, O97902, P0CE94, P0CE95, P10911, P11530, P11531, P11532, P11533, P15924, P30427, P33175, P46939, Q03001, Q0KL02, Q15149, Q1AAU6, Q1LUA6, Q5GN48, Q6ZWR6, Q7SIG6, Q8CIS0, Q8NF91, Q8WXH0, Q91ZU6, Q92817, Q95RG8, Q9BXL7

Diamond homologs: A1IGU3, A1IGU4, A1IGU5, A1ZAY1, E7F1U2, O15068, O15085, O60229, P10569, P15498, P40995, Q08DN7, Q1LUA6, Q3LAC4, Q5BKC9, Q5DU57, Q5RDX5, Q60992, Q63406, Q64096, Q69ZK0, Q6RFZ7, Q70Z35, Q80VK6, Q8CHT1, Q8N5V2, Q8TCU6, Q96N96, Q9ES67, Q9NHV9, Q9NXL2, A2ASS6, A2CG49, A4IFM7, A8C984, A8X6H4, E9PT87, F1M0Z1, O02827, O14936

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CDK5	“up-regulates activity”	KALRN	phosphorylation
MAPKAPK5	“up-regulates activity”	KALRN	phosphorylation
MAPK6	“up-regulates activity”	KALRN	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

150 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	21
Likely benign	29
Benign	32

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1452099	NC_000003.11:g.(?120365818)(133465047_?)del	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

19813 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:124228053:C:A	A44D	1.000
3:124234859:T:C	L58P	1.000
3:124234865:T:C	F60S	1.000
3:124264527:T:A	V96D	1.000
3:124264553:T:A	W105R	1.000
3:124264553:T:C	W105R	1.000
3:124264555:G:C	W105C	1.000
3:124264555:G:T	W105C	1.000
3:124264565:A:G	K109E	1.000
3:124264567:G:C	K109N	1.000
3:124264567:G:T	K109N	1.000
3:124264575:T:C	L112P	1.000
3:124264584:T:C	L115P	1.000
3:124264617:C:A	A126D	1.000
3:124264620:T:C	L127P	1.000
3:124264626:T:A	I129N	1.000
3:124264628:A:G	K130E	1.000
3:124264630:A:C	K130N	1.000
3:124264630:A:T	K130N	1.000
3:124264640:T:C	F134L	1.000
3:124264641:T:C	F134S	1.000
3:124264641:T:G	F134C	1.000
3:124264642:C:A	F134L	1.000
3:124264642:C:G	F134L	1.000
3:124264643:T:A	W135R	1.000
3:124264643:T:C	W135R	1.000
3:124264645:G:C	W135C	1.000
3:124264645:G:T	W135C	1.000
3:124264649:A:G	K137E	1.000
3:124264650:A:T	K137I	1.000

dbSNP variants (sampled 300 via entrez): RS1000000415 (3:124246770 A>T), RS1000004191 (3:124699253 C>A), RS1000006997 (3:124391564 G>A), RS1000009887 (3:124222466 G>T), RS1000029519 (3:124134449 C>G), RS1000035851 (3:124292177 G>A), RS1000040843 (3:124116725 A>G), RS1000042710 (3:124489560 G>A,T), RS1000048992 (3:124600677 A>G), RS1000050128 (3:124510581 C>T), RS1000050752 (3:124207067 A>T), RS1000051401 (3:124056966 G>A,C), RS1000051594 (3:124652647 G>T), RS1000061144 (3:124549586 T>C), RS1000062963 (3:124686210 A>C)

Disease associations

OMIM: gene MIM:604605 | disease phenotypes: MIM:203500, MIM:608901

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability	Limited	Autosomal recessive
coronary artery disorder	Limited	Autosomal dominant

Mondo (5): alkaptonuria (MONDO:0008753), neurodevelopmental disorder (MONDO:0700092), coronary heart disease, susceptibility to, 5 (MONDO:0012147), intellectual disability (MONDO:0001071), coronary artery disorder (MONDO:0005010)

Orphanet (1): Alkaptonuria (Orphanet:56)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

52 associations (top):

Study	Trait	p-value
GCST001335_11	Mean platelet volume	5.000000e-10
GCST002373_5	Thyroid peroxidase antibody levels	3.000000e-08
GCST002579_9	Heschl’s gyrus morphology	2.000000e-06
GCST003175_2	Amyotrophic lateral sclerosis	2.000000e-06
GCST003264_408	Post bronchodilator FEV1/FVC ratio	4.000000e-07
GCST003264_410	Post bronchodilator FEV1/FVC ratio	5.000000e-07
GCST003264_866	Post bronchodilator FEV1/FVC ratio	1.000000e-06
GCST003942_2	Acute graft versus host disease in bone marrow transplantation (donor effect)	4.000000e-08
GCST004599_80	Mean platelet volume	4.000000e-26
GCST004599_81	Mean platelet volume	6.000000e-53
GCST004599_82	Mean platelet volume	2.000000e-54
GCST004603_253	Platelet count	2.000000e-10
GCST004607_258	Plateletcrit	1.000000e-11
GCST004616_144	Platelet distribution width	3.000000e-32
GCST004616_145	Platelet distribution width	3.000000e-12
GCST004616_146	Platelet distribution width	4.000000e-36
GCST005580_289	Intraocular pressure	2.000000e-09
GCST005580_302	Intraocular pressure	3.000000e-09
GCST006269_1203	General cognitive ability	4.000000e-08
GCST006412_35	Intraocular pressure	5.000000e-09
GCST007201_145	Schizophrenia	4.000000e-07
GCST008179_6	Moderate-to-late spontaneous preterm birth	4.000000e-06
GCST008601_6	Longevity (age >99th survival percentile)	8.000000e-07
GCST008615_4	Low urine pH	7.000000e-06
GCST008616_1	Urine pH measurement	4.000000e-10
GCST008728_1	Diffuse large B-cell lymphoma or systemic lupus erythematosus	1.000000e-08
GCST008729_2	Marginal zone lymphoma or systemic lupus erythematosus	2.000000e-08
GCST009391_1564	Metabolite levels	8.000000e-10
GCST009391_1565	Metabolite levels	8.000000e-10
GCST009391_1566	Metabolite levels	8.000000e-10

EFO canonical traits (19, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0004599	acute graft vs. host disease
EFO:0007892	donor genotype effect measurement
EFO:0004309	platelet count
EFO:0007985	platelet crit
EFO:0007984	platelet component distribution width
EFO:0004695	intraocular pressure measurement
EFO:0004337	intelligence
EFO:0006917	spontaneous preterm birth
EFO:0010136	urinary pH measurement
EFO:0010516	orotic acid measurement
EFO:0006335	systolic blood pressure
EFO:0010724	lifestyle measurement
EFO:0004348	hematocrit
EFO:0004587	lymphocyte count
EFO:0005091	monocyte count
EFO:0007990	neutrophil percentage of leukocytes
EFO:0009188	Red cell distribution width
EFO:0004532	serum gamma-glutamyl transferase measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D000474	Alkaptonuria	C16.320.565.100.187; C18.452.648.100.187
D003324	Coronary Artery Disease	C14.280.647.250.260; C14.907.137.126.339; C14.907.585.250.260
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Trio family

CTD chemical–gene interactions

43 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases expression, increases mutagenesis	5
Valproic Acid	decreases methylation, increases expression, affects expression	3
trichostatin A	decreases expression, increases expression	2
Arsenic Trioxide	increases expression	2
Arsenic	affects methylation, decreases methylation, increases abundance	2
Aflatoxin B1	decreases expression, increases methylation	2
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	affects methylation	1
butyraldehyde	increases expression	1
sulindac sulfide	decreases expression	1
benzo(e)pyrene	increases methylation	1
cadmium acetate	decreases expression	1
aflatoxin B2	increases methylation	1
triadimefon	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Vorinostat	decreases expression	1
Leflunomide	increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Endosulfan	decreases expression, increases expression	1
Estradiol	decreases expression	1
Hydrogen Peroxide	affects expression	1

Clinical trials (associated diseases)

503 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00025766	PHASE4	COMPLETED	Angioplasty and Heart Stents to Treat Individuals With an Occluded Artery Following a Heart Attack
NCT00079638	PHASE4	COMPLETED	Comparative Efficacy Evaluation of Lipids When Treated With Niaspan & Statin or Other Lipid-Modifying Therapies-COMPELL
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00111566	PHASE4	COMPLETED	BRIEF-PCI: Brief Infusion of Eptifibatide Following Percutaneous Coronary Intervention
NCT00129038	PHASE4	COMPLETED	Modified-release Dipyridamole/Aspirin (200mg/25mg bd) Versus Aspirin (75mg) in Aspirin-resistant Patients
NCT00133003	PHASE4	COMPLETED	Abciximab, Clopidogrel and Percutaneous Coronary Intervention in Acute Coronary Syndrome (ISAR-REACT-2)
NCT00133237	PHASE4	COMPLETED	Drug-eluting-stents for Unprotected Left Main Stem Disease (ISAR-LEFT-MAIN)
NCT00133692	PHASE4	COMPLETED	INVEST: INternational VErapamil SR Trandolapril STudy
NCT00139386	PHASE4	COMPLETED	Candesartan for Prevention of Cardiovascular Events After Cypher or Taxus Coronary Stenting (4C) Trial
NCT00140465	PHASE4	COMPLETED	75 or 150 mg Clopidogrel Maintenance Doses Following PCI (ISAR-CHOICE-2)
NCT00140530	PHASE4	COMPLETED	Nonpolymer- and Polymer-Based Drug-Eluting Stents for Restenosis (ISAR-TEST-1)
NCT00146575	PHASE4	COMPLETED	Sirolimus- and Paclitaxel-Eluting Stents for Small Vessels (ISAR-SMART-3)
NCT00152308	PHASE4	TERMINATED	Non-Polymer-Based, Rapamycin-Eluting Stents to Prevent Restenosis
NCT00155350	PHASE4	UNKNOWN	Treatment of Coronary Atherosclerosis by Insulin Sensitizers in Insulin-Resistant Patients
NCT00162370	PHASE4	COMPLETED	A Study of Stress Echocardiography in Post-Menopausal Women at Risk for Coronary Disease
NCT00163202	PHASE4	COMPLETED	Comparative Atorvastatin Pleiotropic Effects
NCT00169819	PHASE4	COMPLETED	EArly Discharge After Transradial Stenting of CoronarY Arteries: The EASY Study
NCT00171275	PHASE4	COMPLETED	Fluvastatin in the Therapy of Acute Coronary Syndrome
NCT00175240	PHASE4	COMPLETED	Enhancing the Secondary Prevention of Coronary Artery Disease
NCT00180388	PHASE4	TERMINATED	VENEK: Healing in Different Vein Harvesting Methods During Aortocoronary Coronary Artery Bypass Graft Surgery (CABG)
NCT00180583	PHASE4	COMPLETED	Vision II: Evaluation of GALILEO Intravascular Radiotherapy System
NCT00189215	PHASE4	COMPLETED	Long-Term Cognitive Decline After Coronary Artery Bypass Grafting: is Off-Pump Surgery Beneficial?
NCT00200629	PHASE4	TERMINATED	Both Exercise and Adenosine Stress Testing
NCT00202904	PHASE4	COMPLETED	Effectiveness and Safety of Ezetimibe Added to Atorvastatin in Patients With High Cholesterol and Coronary Heart Disease (Study P03740)
NCT00209404	PHASE4	COMPLETED	Iodixanol in Multidetector-Row Computed Tomography-Coronary Angiography (MDCT-CA)
NCT00209430	PHASE4	COMPLETED	Renal Effects of Two Iodinated Contrast Media in Patients at Risk Undergoing Coronary Angiography
NCT00220558	PHASE4	UNKNOWN	GISSOC II: Sirolimus Eluting Stent Versus Bare Metal Stent in Chronic Total Coronary Occlusions
NCT00222261	PHASE4	COMPLETED	Aspirin Non-responsiveness and Clopidogrel Endpoint Trial.
NCT00229528	PHASE4	COMPLETED	Effect of Paroxetine on COAT-Platelet Production in Normal Volunteers and Patients With Cardiovascular Disease
NCT00232804	PHASE4	COMPLETED	The BRIDGE Registry: Safety and Efficacy Registry of Bx Cypher Stent
NCT00232856	PHASE4	COMPLETED	A Study of the Cypher SES to Treat Restenotic Native Coronary Artery Lesions.
NCT00235066	PHASE4	COMPLETED	The CYPHER™ Stent Study in Patients With Small de Novo Coronary Artery Lesions.
NCT00235092	PHASE4	COMPLETED	The REALITY Study - Head-to-Head Comparison Between Cypher and Taxus
NCT00235950	PHASE4	COMPLETED	Assessment of the Lipid Lowering Effect of Rosuvastatin Compared to Atorvastatin in Subjects With Coronary Heart Disease
NCT00238004	PHASE4	UNKNOWN	The Low HDL On Six Weeks Statin Therapy (LOW) Study
NCT00241904	PHASE4	COMPLETED	Reducing Total Cardiovascular Risk in an Urban Community