ALKAL2

Summary

ALKAL2 (ALK and LTK ligand 2, HGNC:27683) is a protein-coding gene on chromosome 2p25.3, encoding ALK and LTK ligand 2 (Q6UX46). Cytokine that acts as a physiological ligand for receptor tyrosine kinases LTK and ALK, leading to their activation.

Enables cytokine activity; receptor signaling protein tyrosine kinase activator activity; and receptor tyrosine kinase binding activity. Involved in cell surface receptor protein tyrosine kinase signaling pathway; positive regulation of MAPK cascade; and positive regulation of neuron projection development. Is active in obsolete extracellular space. Implicated in neuroblastoma.

Source: NCBI Gene 285016 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 26 (top 5% of genes corpus-wide)
• Clinical variants (ClinVar): 43 total
• GTEx eGene: eQTL in 17 tissues, sQTL in 5 (q < 0.05)
• Constraint (gnomAD): pLI 0.03 (LoF-tolerant), LOEUF 1.30 (unconstrained)
• MANE Select transcript: NM_001002919

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27683
Approved symbol	ALKAL2
Name	ALK and LTK ligand 2
Location	2p25.3
Locus type	gene with protein product
Status	Approved
Aliases	AUGA
Ensembl gene	ENSG00000189292
Ensembl biotype	protein_coding
OMIM	619671
Entrez	285016

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 21 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

MANE Select: ENST00000403610

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 2, TSL 3: 3, TSL 4: 1

ENST00000403610, ENST00000344414, ENST00000401489, ENST00000401503, ENST00000405290, ENST00000452023, ENST00000463919, ENST00000896929, ENST00000896930, ENST00000896931, ENST00000896932, ENST00000896933, ENST00000896934, ENST00000896935, ENST00000896936, ENST00000955429, ENST00000955430, ENST00000955431, ENST00001041716, ENST00001112895, ENST00001112896, ENST00001123104, ENST00001142106

RefSeq mRNA: 1 — MANE Select: NM_001002919 NM_001002919

CCDS: CCDS46218

Canonical transcript exons

ENST00000403610 — 6 exons

Exon	Start	End
ENSE00001377245	286123	286203
ENSE00001556616	279558	280152
ENSE00001897894	288013	288091
ENSE00002259337	287583	287892
ENSE00003598600	286290	286343
ENSE00003785964	283111	283175

Expression profiles

Bgee: expression breadth ubiquitous, 204 present calls, max score 98.57.

FANTOM5 (CAGE): breadth broad, TPM avg 0.9726 / max 164.0091, expressed in 307 samples.

Highest expression (Bgee): adrenal gland cortex, adrenal cortex, adrenal gland, body of pancreas, ovary.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ALKAL2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 17 tissues and its splicing (sQTL) in 5 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 22 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	eqtl	8.3e-49	-0.78	2:259774:T:A
Brain Spinal cord cervical c-1	eqtl	2.3e-21	-0.69	2:237346:GGTGACACTACCA:G
Testis	sqtl	2.5e-11	-0.40	2:255580:G:C
Skin Sun Exposed Lower leg	eqtl	1.1e-05	-0.16	2:434511:T:C
Thyroid	eqtl	1.8e-04	-0.26	2:209292:A:G
Lung	eqtl	2.7e-04	-0.23	2:199410:G:A
Artery Tibial	eqtl	6.7e-04	-0.16	2:440589:A:G
Pituitary	eqtl	9.1e-04	-0.44	2:286812:G:A
Adipose Subcutaneous	eqtl	1.4e-03	+0.13	2:487043:A:G
Adipose Visceral Omentum	eqtl	3.6e-03	+0.75	2:351654:C:T
Brain Substantia nigra	eqtl	6.0e-03	-0.40	2:305203:T:C
Nerve Tibial	sqtl	9.5e-03	+0.86	2:188981:T:C
Brain Cortex	eqtl	1.0e-02	-0.36	2:206636:T:C
Artery Tibial	sqtl	2.5e-02	+0.24	2:240785:G:A
Artery Aorta	eqtl	3.1e-02	+0.35	2:1168819:A:G
Spleen	eqtl	3.4e-02	+0.30	2:597557:C:T
Whole Blood	eqtl	3.4e-02	-0.18	2:981516:T:A
Brain Caudate basal ganglia	eqtl	3.5e-02	-0.18	2:318239:A:G
Lung	sqtl	3.7e-02	+0.28	2:281741:T:C
Skin Sun Exposed Lower leg	sqtl	3.9e-02	-0.96	2:1112024:G:A

FANTOM5 promoters

8 alternative TSS:

Promoter ID	TPM avg	Samples expressed
26631	0.3567	90
26628	0.2399	122
26630	0.2064	85
26632	0.0732	26
26629	0.0714	31
26627	0.0162	3
26626	0.0056	3
26625	0.0033	2

Top tissues by expression

showing 100 of 248 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left adrenal gland cortex	UBERON:0035825	98.57	gold quality
adrenal cortex	UBERON:0001235	98.51	gold quality
right adrenal gland cortex	UBERON:0035827	98.49	gold quality
left adrenal gland	UBERON:0001234	98.47	gold quality
right adrenal gland	UBERON:0001233	98.38	gold quality
adrenal gland	UBERON:0002369	97.42	gold quality
body of pancreas	UBERON:0001150	96.97	gold quality
right ovary	UBERON:0002118	96.16	gold quality
left ovary	UBERON:0002119	95.63	gold quality
tibial artery	UBERON:0007610	92.99	gold quality
popliteal artery	UBERON:0002250	92.98	gold quality
left testis	UBERON:0004533	92.33	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.13	gold quality
right testis	UBERON:0004534	92.05	gold quality
ovary	UBERON:0000992	91.80	gold quality
pancreas	UBERON:0001264	91.41	gold quality
left uterine tube	UBERON:0001303	91.14	gold quality
decidua	UBERON:0002450	91.11	gold quality
testis	UBERON:0000473	91.05	gold quality
tibial nerve	UBERON:0001323	90.42	gold quality
upper lobe of left lung	UBERON:0008952	90.29	gold quality
right lung	UBERON:0002167	90.05	gold quality
body of uterus	UBERON:0009853	89.72	gold quality
adrenal tissue	UBERON:0018303	89.45	gold quality
upper lobe of lung	UBERON:0008948	89.39	gold quality
aorta	UBERON:0000947	88.92	gold quality
calcaneal tendon	UBERON:0003701	87.56	gold quality
lower lobe of lung	UBERON:0008949	86.70	gold quality
descending thoracic aorta	UBERON:0002345	86.36	gold quality
lung	UBERON:0002048	86.25	gold quality
omental fat pad	UBERON:0010414	85.77	gold quality
peritoneum	UBERON:0002358	85.73	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.15	gold quality
adult mammalian kidney	UBERON:0000082	84.38	gold quality
body of stomach	UBERON:0001161	83.83	gold quality
thoracic aorta	UBERON:0001515	83.62	gold quality
adipose tissue of abdominal region	UBERON:0007808	83.61	gold quality
superficial temporal artery	UBERON:0001614	83.36	gold quality
left coronary artery	UBERON:0001626	83.23	gold quality
ascending aorta	UBERON:0001496	83.08	gold quality
skin of leg	UBERON:0001511	82.69	gold quality
nucleus accumbens	UBERON:0001882	82.43	gold quality
gall bladder	UBERON:0002110	82.37	gold quality
islet of Langerhans	UBERON:0000006	82.29	gold quality
uterus	UBERON:0000995	82.18	gold quality
endometrium	UBERON:0001295	82.13	gold quality
myometrium	UBERON:0001296	81.83	gold quality
upper arm skin	UBERON:0004263	81.69	silver quality
adult organism	UBERON:0007023	81.56	gold quality
caput epididymis	UBERON:0004358	81.10	gold quality
coronary artery	UBERON:0001621	81.07	gold quality
mucosa of transverse colon	UBERON:0004991	81.06	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	80.66	gold quality
colonic epithelium	UBERON:0000397	80.56	gold quality
stomach	UBERON:0000945	80.29	gold quality
female reproductive system	UBERON:0000474	79.90	gold quality
metanephros cortex	UBERON:0010533	79.90	gold quality
skin of abdomen	UBERON:0001416	79.85	gold quality
zone of skin	UBERON:0000014	79.82	gold quality
kidney epithelium	UBERON:0004819	79.75	silver quality
spleen	UBERON:0002106	79.73	gold quality
right lobe of thyroid gland	UBERON:0001119	79.56	gold quality
spinal cord	UBERON:0002240	79.52	gold quality
germinal epithelium of ovary	UBERON:0001304	79.43	gold quality
kidney	UBERON:0002113	79.35	gold quality
sperm	CL:0000019	79.30	gold quality
metanephros	UBERON:0000081	79.19	gold quality
subcutaneous adipose tissue	UBERON:0002190	78.75	gold quality
urethra	UBERON:0000057	78.65	gold quality
adenohypophysis	UBERON:0002196	78.65	gold quality
cauda epididymis	UBERON:0004360	78.46	gold quality
left lobe of thyroid gland	UBERON:0001120	78.42	gold quality
epithelial cell of pancreas	CL:0000083	78.10	silver quality
fundus of stomach	UBERON:0001160	77.27	gold quality
fallopian tube	UBERON:0003889	77.22	gold quality
rectum	UBERON:0001052	76.99	gold quality
thyroid gland	UBERON:0002046	76.81	gold quality
pituitary gland	UBERON:0000007	76.75	gold quality
transverse colon	UBERON:0001157	76.73	gold quality
sural nerve	UBERON:0015488	76.73	gold quality
adipose tissue	UBERON:0001013	75.70	gold quality
nipple	UBERON:0002030	75.27	gold quality
right coronary artery	UBERON:0001625	74.71	gold quality
cortex of kidney	UBERON:0001225	74.54	gold quality
mammary duct	UBERON:0001765	74.20	gold quality
epithelium of mammary gland	UBERON:0003244	74.18	gold quality
small intestine Peyer’s patch	UBERON:0003454	74.17	gold quality
buccal mucosa cell	CL:0002336	74.04	gold quality
colon	UBERON:0001155	73.80	gold quality
large intestine	UBERON:0000059	73.73	gold quality
intestine	UBERON:0000160	73.61	gold quality
minor salivary gland	UBERON:0001830	73.46	gold quality
caudate nucleus	UBERON:0001873	73.44	gold quality
thoracic mammary gland	UBERON:0005200	73.44	gold quality
mammary gland	UBERON:0001911	73.41	gold quality
mucosa of sigmoid colon	UBERON:0004993	73.38	gold quality
amygdala	UBERON:0001876	73.33	gold quality
penis	UBERON:0000989	73.21	gold quality
small intestine	UBERON:0002108	73.08	gold quality
right lobe of liver	UBERON:0001114	73.06	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	58.74
E-ANND-3	yes	9.21

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 74 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Adrenal gland	tissue	189.3
Pancreas	tissue	60.2
Ovary	tissue	46.6
Testis	tissue	33.1
Endometrium 1	tissue	22.6
Kidney	tissue	19.6
Breast	tissue	17.4
Nucleus accumbens	tissue	16.0
Choroid plexus	tissue	13.0
Epididymis	tissue	12.6
Adipose tissue	tissue	12.0
Gallbladder	tissue	10.1
Smooth muscle	tissue	9.3
Placenta	tissue	9.0
Spleen	tissue	8.8
Pituitary gland	tissue	8.3
Colon	tissue	7.6
Lung	tissue	7.4
Small intestine	tissue	7.3
Stomach 1	tissue	7.1
Hippocampus	tissue	6.8
Locus coeruleus	tissue	6.2
Rectum	tissue	6.1
Postcentral gyrus	tissue	5.6
Fallopian tube	tissue	5.5
Salivary gland	tissue	5.0
Vagina	tissue	4.8
Duodenum	tissue	3.5
Urinary bladder	tissue	3.3
Amygdala	tissue	3.3
Seminal vesicle	tissue	2.5
Hippocampal formation	tissue	2.3
Parathyroid gland	tissue	2.1
Basal ganglia	tissue	2.1
Liver	tissue	1.9
Prostate	tissue	1.9
Appendix	tissue	1.9
Skin 1	tissue	1.7
Cerebral cortex	tissue	1.7
Putamen	tissue	1.7
Temporal cortex	tissue	1.7
Thymus	tissue	1.5
Tonsil	tissue	1.5
Ventral forebrain	tissue	1.5
Cervix	tissue	1.3
Heart muscle	tissue	1.3
Thyroid gland	tissue	1.1
Insular cortex	tissue	1.1
Esophagus	tissue	1.0
Spinal cord	tissue	1.0
Retrosplenial cortex	tissue	1.0
Lymph node	tissue	0.9
Prefrontal cortex	tissue	0.9
Motor cortex	tissue	0.9
Entorhinal cortex	tissue	0.9
Frontal cortex	tissue	0.8
Retrosplenial and cingulate cortex	tissue	0.7
Septum	tissue	0.7
Bone marrow	tissue	0.6
Somatosensory cortex	tissue	0.6

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Blood vessel (43.6), Arcuate nucleus (14.0), Centromedial thalamic nucleus (13.4), Dorsal funiculus (white matter) (12.3), Ventral posterolateral thalamic nucleus (12.3).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting ALKAL2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 83 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488

Functional genomics

gnomAD constraint: pLI 0.0255, LOEUF 1.3, missense Z -2.25 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000403610 — one region, missense o/e 1.14.

Literature-anchored findings (GeneRIF, showing 6)

• Only two related secreted factors, FAM150A and FAM150B (family with sequence similarity 150 member A and member B), stimulated LTK phosphorylation. (PMID:25331893)
• In conclusion, these data show that ALK is robustly activated by the FAM150A/B ligands. (PMID:26418745)
• Data show FAM150B, which was named as augmentor-alpha (AUG-alpha), binds and activtes both anaplastic lymphoma kinase (ALK) and tyrosine kinase (LTK). (PMID:26630010)
• activation of ALK/LTK family receptors by small ALKAL proteins (FAM150, AUG) conserved in vertebrates (PMID:29317532)
• ALK ligand ALKAL2 potentiates MYCN-driven neuroblastoma in the absence of ALK mutation. (PMID:33411331)
• The autocrine loop of ALK receptor and ALKAL2 ligand is an actionable target in consensus molecular subtype 1 colon cancer. (PMID:35351152)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	alkal2b	ENSDARG00000042815
danio_rerio	alkal2a	ENSDARG00000091073
mus_musculus	Alkal2	ENSMUSG00000054204
rattus_norvegicus	Alkal2	ENSRNOG00000005154

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:3697448) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 28 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased body weight	1
cornea opacity	1
hyperactivity	1
decreased white adipose tissue amount	1
abnormal skin morphology	1
exophthalmos	1
increased insulin sensitivity	1
increased lean body mass	1
increased energy expenditure	1
narrow eye opening	1
increased oxygen consumption	1
improved glucose tolerance	1
decreased percent body fat/body weight	1
decreased susceptibility to diet-induced obesity	1
slow postnatal weight gain	1
decreased subcutaneous adipose tissue amount	1
increased carbon dioxide production	1
decreased white fat cell size	1
decreased gonadal fat pad weight	1
decreased retroperitoneal fat pad weight	1
increased respiratory quotient	1
increased fluid intake	1
decreased fluid intake	1
decreased compensatory feeding amount	1
hyperactivity elicited by feed restriction	1

+3 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Tetraodon nigroviridis	Q4RU86	77.5%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
LINC01865	ncRNA	105373350
SH3YL1	protein-coding	26751
ACP1	protein-coding	52
FAM110C	protein-coding	642273

Protein

Protein identifiers

ALK and LTK ligand 2 — Q6UX46 (reviewed: Q6UX46)

Alternative names: Augmentor alpha

All UniProt accessions (5): A0A0B4J1W8, B5MC33, B5MCG6, H0Y3U4, Q6UX46

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine that acts as a physiological ligand for receptor tyrosine kinases LTK and ALK, leading to their activation. Cytokine-binding is sufficient to activate LTK. In contrast, ALKAL2-driven activation of ALK is coupled with heparin-binding to ALK. Stimulation of ALK signaling is involved in neural development and regulation of energy expenditure.

Subunit / interactions. Homodimer; interchain disulfide bond is not required for homodimerization.

Subcellular location. Secreted. Cell membrane.

Tissue specificity. Widely expressed with highest levels in adrenal gland and modest levels in pancreas, testis and uterus.

Similarity. Belongs to the ALKAL family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6UX46-1	1	yes
Q6UX46-2	2

RefSeq proteins (1): NP_001002919* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029364	ALKL1/2	Family

Pfam: PF15129

UniProt features (21 total): helix 7, mutagenesis site 6, disulfide bond 3, splice variant 2, signal peptide 1, chain 1, strand 1

Structure

Experimental structures (PDB)

5 structures by resolution:

PDB	Title	Method	Resolution (Å)
7N00	Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 648-1025 …	ELECTRON MICROSCOPY	2.27
7LS0	Structure of the Human ALK GRD bound to AUG	X-RAY DIFFRACTION	3.05
9G5I	Cryo-EM structure of a 2:1 ALK:ALKAL2 complex obtained after re-processing of …	ELECTRON MICROSCOPY	3.2
7NWZ	ALK:ALKAL2 complex	X-RAY DIFFRACTION	4.17
7MZX	AUGalpha - FAM150B - ALKL2 77-152	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UX46-F1	71.41	0.26

Human Protein Atlas

Protein class: Predicted secreted proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Functional residue map

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

Disulfide bonds (3)

Type	Positions
Interchain	66
Disulfide bond	111–147, 125–134

Mutagenesis-validated functional residues (6)

Position	Phenotype
100	slightly reduced affinity for receptor tyrosine kinase ltk.
123	reduced affinity for receptor tyrosine kinases alk and ltk.
136	reduced affinity for receptor tyrosine kinases alk and ltk.
66	abolished interchain disulfide bond without affecting homodimerization.
94–100	abolished association with the cell membrane, leading to impaired activation of receptor tyrosine kinase alk.
97	slightly reduced affinity for receptor tyrosine kinase ltk.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-9842663	Signaling by LTK	curated
R-HSA-162582	Signal Transduction	—
R-HSA-201556	Signaling by ALK	electronic
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases	—

MSigDB gene sets: 84 (showing top): chr2p25, GOBP_GROWTH, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_RESPONSE_TO_FOOD, GOBP_NEUROGENESIS, GOMF_KINASE_ACTIVATOR_ACTIVITY, GTGCCTT_MIR506, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_MULTICELLULAR_ORGANISM_GROWTH, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_NEURON_PROJECTION_DEVELOPMENT, GOMF_CYTOKINE_ACTIVITY, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, GOBP_ENERGY_HOMEOSTASIS, GOBP_CONNECTIVE_TISSUE_DEVELOPMENT

GO Biological Process (5): cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), positive regulation of neuron projection development (GO:0010976), positive regulation of ERK1 and ERK2 cascade (GO:0070374), positive regulation of ERK5 cascade (GO:0070378), signal transduction (GO:0007165)

GO Molecular Function (4): cytokine activity (GO:0005125), receptor signaling protein tyrosine kinase activator activity (GO:0030298), receptor tyrosine kinase binding (GO:0030971), protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), plasma membrane (GO:0005886)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Signaling by Receptor Tyrosine Kinases	2
Signal Transduction	1

GO top-level categories

22 GO namespaces:

Category	Terms
positive regulation of MAPK cascade	2
enzyme-linked receptor protein signaling pathway	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
ERK5 cascade	1
regulation of ERK5 cascade	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
receptor ligand activity	1
protein tyrosine kinase activator activity	1
signaling receptor binding	1
protein tyrosine kinase binding	1
binding	1
cellular anatomical structure	1
membrane	1
cell periphery	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 12 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
cell surface receptor protein tyrosine kinase signaling pathway	BP	direct assay
positive regulation of ERK1 and ERK2 cascade	BP	direct assay
positive regulation of ERK5 cascade	BP	direct assay
positive regulation of neuron projection development	BP	direct assay
extracellular region	CC	direct assay
cytokine activity	MF	direct assay
receptor signaling protein tyrosine kinase activator activity	MF	direct assay
receptor tyrosine kinase binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 302 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALKAL2	SH3YL1	Q96HL8	716
ALKAL2	LTK	P29376	701
ALKAL2	ALK	Q9UM73	547
ALKAL2	FAM110C	Q1W6H9	539
ALKAL2	DIS3L	Q8TF46	489
ALKAL2	TMEM18	Q96B42	400
ALKAL2	MRGPRG	Q86SM5	388
ALKAL2	ROS1	P08922	371
ALKAL2	POLN	Q7Z5Q5	370
ALKAL2	MYCN	P04198	369
ALKAL2	PKIA	P04541	367
ALKAL2	ERGIC1	Q969X5	362
ALKAL2	HSD11B1	P28845	358
ALKAL2	PTN	P21246	344
ALKAL2	SLC14A2	Q15849	328

IntAct

Human interaction partners of ALKAL2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
ALK	physical association	0.560	5
LTK	association	0.350	1

Disease & clinical

Genetic variants

Variant evidence for ALKAL2: 43 ClinVar records (0 pathogenic / likely pathogenic); 26 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	3
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 25 predictions of 595):

Position(s)	Effect	Δscore	Sites
2:286288–286289	donor_loss	1.0000	3
2:286344–286345	acceptor_loss	1.0000	5
2:286351	acceptor_gain	1.0000
2:286288	donor_loss	0.9900
2:286344	acceptor_loss	0.9900
2:287581–287582	donor_loss	0.9900	5
2:286118	donor_loss	0.9700
2:286121–286122	donor_loss	0.9700	6
2:287216	donor_gain	0.9700
2:287277	donor_gain	0.9700

AlphaMissense

368 missense substitutions predicted likely pathogenic (of 957 scored), across 73 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D90	8	0.971	0.990
H100	8	0.971	0.996
D124	8	0.965	0.996
F97	8	0.964	0.999
F107	8	0.964	0.998
F115	8	0.963	0.998
S144	8	0.881	0.992
C125	7	0.998	0.999
C134	7	0.996	0.999
C111	7	0.995	0.999
C147	7	0.992	0.997
K94	7	0.983	1.000
R136	7	0.963	0.992
H120	7	0.957	0.995
H116	7	0.851	0.984
I86	7	0.841	0.977
G103	6	0.992	0.998
R133	6	0.992	0.997
L138	6	0.988	0.999
K132	6	0.987	0.999

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Kidney Renal Clear Cell Carcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	7.94e-05
Breast Invasive Carcinoma (TCGA)	favorable	0.000506

Disease associations

OMIM: gene MIM:619671 | disease phenotypes:

GWAS associations

26 associations:

Study	Trait	p-value
GCST010989_176	Body size at age 10	4e-134
GCST005950_2	Body mass index x sex x age interaction (4df test)	5e-75
GCST005951_3	Body mass index	1e-72
GCST004904_43	Body mass index	4e-65
GCST010988_295	Adult body size	7e-60
GCST009121_4	Body mass index	4e-51
GCST009123_3	Hip circumference	6e-45
GCST009122_2	Waist circumference	4e-44
GCST005952_2	Body mass index (age>50)	2e-30
GCST010002_39	Refractive error	6e-25
GCST004904_205	Body mass index	6e-23
GCST005830_33	Hand grip strength	8e-21
GCST007240_7	Obese vs. thin	1e-15
GCST003993_21	Menarche (age at onset)	3e-15
GCST009108_2	Waist circumference variance	4e-14
GCST011703_42	Smoking initiation	6e-13
GCST008295_46	Number of decayed, missing and filled tooth surfaces or use of dentures	9e-12
GCST009107_8	Body mass index variance	1e-11
GCST008306_10	Dentures	1e-10
GCST006291_36	Spherical equivalent or myopia (age of diagnosis)	2e-10
GCST009109_1	Hip circumference variance	2e-9
GCST008526_28	Coffee consumption	5e-9
GCST003985_20	Breast size	3e-8
GCST90002409_12	Childhood body mass index	3e-7
GCST005954_1	Body mass index x age interaction	4e-7
GCST003542_116	Night sleep phenotypes	5e-6

EFO canonical traits (from GWAS)

11 canonical traits:

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0004340	body mass index
EFO:0006941	grip strength measurement
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004847	age at onset
EFO:0007041	obese body mass index status
EFO:0010078	dentures
EFO:0006781	coffee consumption measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0005670	smoking initiation

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation, affects cotreatment, increases expression, affects expression	6
trichostatin A	affects cotreatment, increases expression	3
Benzo(a)pyrene	increases expression	3
methylmercuric chloride	increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cyclosporine	decreases expression, increases expression	2
bisphenol A	increases expression	1
pentanal	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, increases expression	1
licochalcone B	increases expression	1
Malathion	increases expression	1
Quercetin	increases expression	1
Rotenone	increases expression	1
Silicon Dioxide	increases expression	1
Tretinoin	increases expression	1
Aflatoxin B1	increases expression	1
Permethrin	increases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.