ALCAM

Summary

ALCAM (activated leukocyte cell adhesion molecule, HGNC:400) is a protein-coding gene on chromosome 3q13.11, encoding CD166 antigen (Q13740). Cell adhesion molecule that mediates both heterotypic cell-cell contacts via its interaction with CD6, as well as homotypic cell-cell contacts. In precision oncology, ALCAM EXPRESSION is associated with resistance to Fluorouracil in Colorectal Cancer (CIViC Level B).

This gene encodes activated leukocyte cell adhesion molecule (ALCAM), also known as CD166 (cluster of differentiation 166), which is a member of a subfamily of immunoglobulin receptors with five immunoglobulin-like domains (VVC2C2C2) in the extracellular domain. This protein binds to T-cell differentiation antigene CD6, and is implicated in the processes of cell adhesion and migration. Multiple alternatively spliced transcript variants encoding different isoforms have been found.

Source: NCBI Gene 214 — RefSeq curated summary.

At a glance

• GWAS associations: 31 (top 4% of genes corpus-wide)
• Clinical variants (ClinVar): 113 total
• GTEx eGene: eQTL in 24 tissues, sQTL in 1 (q < 0.05)
• Drug target: yes — 1 curated mechanism-of-action drug
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.47 (moderately constrained)
• MANE Select transcript: NM_001627

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:400
Approved symbol	ALCAM
Name	activated leukocyte cell adhesion molecule
Location	3q13.11
Locus type	gene with protein product
Status	Approved
Aliases	CD166, MEMD
Ensembl gene	ENSG00000170017
Ensembl biotype	protein_coding
OMIM	601662
Entrez	214

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 8 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

MANE Select: ENST00000306107

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 4, TSL 4: 1, TSL 5: 1

ENST00000306107, ENST00000460954, ENST00000465413, ENST00000470756, ENST00000472644, ENST00000481337, ENST00000486979, ENST00000489178, ENST00000491388, ENST00000880066, ENST00000932235, ENST00001069811, ENST00001110864, ENST00001120121, ENST00001141248

RefSeq mRNA: 4 — MANE Select: NM_001627 NM_001243280, NM_001243281, NM_001243283, NM_001627

CCDS: CCDS33810, CCDS58841

Canonical transcript exons

ENST00000306107 — 16 exons

Exon	Start	End
ENSE00001151818	105545223	105545335
ENSE00001878770	105574477	105576900
ENSE00001938712	105366909	105367481
ENSE00003465269	105552468	105552585
ENSE00003466834	105539975	105540102
ENSE00003491728	105547149	105547284
ENSE00003514640	105571852	105571964
ENSE00003517275	105534663	105534845
ENSE00003543620	105541633	105541765
ENSE00003564076	105532002	105532066
ENSE00003602326	105552144	105552182
ENSE00003633089	105533603	105533690
ENSE00003633421	105520067	105520167
ENSE00003652780	105550127	105550259
ENSE00003659444	105547390	105547523
ENSE00003667569	105524289	105524508

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 61.0058 / max 596.1041, expressed in 1746 samples.

Highest expression (Bgee): bronchial epithelial cell, mucosa of paranasal sinus, epithelium of bronchus, endothelial cell, bronchus.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ALCAM is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 24 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 25 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	1.8e-42	+0.37	3:105140433:G:C
Thyroid	eqtl	2.1e-28	+0.22	3:105484849:C:T
Artery Aorta	eqtl	4.6e-14	+0.22	3:104886681:T:C
Esophagus Muscularis	eqtl	3.9e-11	-0.28	3:105150679:T:C
Nerve Tibial	eqtl	1.6e-10	+0.21	3:104442925:T:G
Heart Atrial Appendage	eqtl	2.5e-05	-0.37	3:105613505:G:T
Skin Sun Exposed Lower leg	eqtl	5.5e-05	+0.19	3:105469945:T:G
Colon Transverse	eqtl	3.8e-04	+0.17	3:104798231:C:G
Cells EBV-transformed lymphocytes	eqtl	4.4e-04	-0.23	3:105431850:G:C
Artery Tibial	eqtl	4.9e-04	+0.11	3:104893053:T:C
Esophagus Gastroesophageal Junction	eqtl	1.7e-03	+0.23	3:105138283:C:T
Cells Cultured fibroblasts	eqtl	2.9e-03	+0.19	3:105357836:C:T
Testis	sqtl	3.0e-03	-0.63	3:105534358:A:G
Adipose Visceral Omentum	eqtl	6.0e-03	-0.21	3:105507667:G:A
Prostate	eqtl	1.3e-02	-0.71	3:106005026:C:T
Adipose Subcutaneous	eqtl	1.3e-02	+0.10	3:104892075:A:G
Brain Cerebellar Hemisphere	eqtl	1.7e-02	-0.20	3:105697772:T:A
Muscle Skeletal	eqtl	1.8e-02	-0.33	3:104519130:A:C
Testis	eqtl	1.9e-02	-0.39	3:105520580:C:T
Stomach	eqtl	2.5e-02	+0.09	3:105072968:G:T

FANTOM5 promoters

7 alternative TSS:

Promoter ID	TPM avg	Samples expressed
37742	45.2687	1730
37740	6.8254	1520
37741	3.9115	1227
37743	2.2757	1026
37739	1.2014	675
37738	0.7759	299
37737	0.7472	278

Top tissues by expression

showing 100 of 302 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	99.66	gold quality
mucosa of paranasal sinus	UBERON:0005030	99.60	gold quality
epithelium of bronchus	UBERON:0002031	99.56	gold quality
endothelial cell	CL:0000115	99.54	gold quality
bronchus	UBERON:0002185	99.52	gold quality
palpebral conjunctiva	UBERON:0001812	99.30	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.07	gold quality
corpus callosum	UBERON:0002336	99.04	gold quality
visceral pleura	UBERON:0002401	98.96	gold quality
lateral globus pallidus	UBERON:0002476	98.94	gold quality
substantia nigra pars compacta	UBERON:0001965	98.91	gold quality
trigeminal ganglion	UBERON:0001675	98.81	gold quality
inferior vagus X ganglion	UBERON:0005363	98.80	gold quality
epithelium of nasopharynx	UBERON:0001951	98.75	gold quality
lower lobe of lung	UBERON:0008949	98.62	gold quality
superior vestibular nucleus	UBERON:0007227	98.53	gold quality
nasal cavity mucosa	UBERON:0001826	98.32	gold quality
subthalamic nucleus	UBERON:0001906	98.32	gold quality
medulla oblongata	UBERON:0001896	98.30	gold quality
cranial nerve II	UBERON:0000941	98.18	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.11	gold quality
dorsal root ganglion	UBERON:0000044	97.99	gold quality
nasal cavity epithelium	UBERON:0005384	97.94	gold quality
ventral tegmental area	UBERON:0002691	97.78	gold quality
pons	UBERON:0000988	97.72	gold quality
descending thoracic aorta	UBERON:0002345	97.70	gold quality
germinal epithelium of ovary	UBERON:0001304	97.62	gold quality
inferior olivary complex	UBERON:0002127	97.56	gold quality
periodontal ligament	UBERON:0008266	97.37	gold quality
islet of Langerhans	UBERON:0000006	97.31	gold quality
globus pallidus	UBERON:0001875	97.29	gold quality
amniotic fluid	UBERON:0000173	97.15	gold quality
dorsal plus ventral thalamus	UBERON:0001897	97.11	gold quality
middle frontal gyrus	UBERON:0002702	97.08	gold quality
corpus epididymis	UBERON:0004359	97.05	gold quality
medial globus pallidus	UBERON:0002477	96.85	gold quality
thoracic aorta	UBERON:0001515	96.80	gold quality
entorhinal cortex	UBERON:0002728	96.79	gold quality
ascending aorta	UBERON:0001496	96.73	gold quality
choroid plexus epithelium	UBERON:0003911	96.72	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.68	gold quality
epithelium of mammary gland	UBERON:0003244	96.63	gold quality
mammary duct	UBERON:0001765	96.61	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.58	gold quality
seminal vesicle	UBERON:0000998	96.41	gold quality
urethra	UBERON:0000057	96.34	gold quality
CA1 field of hippocampus	UBERON:0003881	96.31	gold quality
parietal lobe	UBERON:0001872	96.14	gold quality
stromal cell of endometrium	CL:0002255	96.09	gold quality
right lung	UBERON:0002167	96.08	gold quality
type B pancreatic cell	CL:0000169	96.03	gold quality
lung	UBERON:0002048	96.02	gold quality
parotid gland	UBERON:0001831	95.99	gold quality
postcentral gyrus	UBERON:0002581	95.94	gold quality
tongue squamous epithelium	UBERON:0006919	95.90	gold quality
saphenous vein	UBERON:0007318	95.81	gold quality
right uterine tube	UBERON:0001302	95.80	gold quality
spinal cord	UBERON:0002240	95.79	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.76	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.70	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.62	gold quality
middle temporal gyrus	UBERON:0002771	95.60	gold quality
eye	UBERON:0000970	95.28	gold quality
endometrium	UBERON:0001295	95.28	gold quality
epididymis	UBERON:0001301	95.18	gold quality
caput epididymis	UBERON:0004358	95.13	gold quality
mucosa of urinary bladder	UBERON:0001259	95.09	gold quality
endometrium epithelium	UBERON:0004811	95.01	gold quality
nephron tubule	UBERON:0001231	94.92	gold quality
orbitofrontal cortex	UBERON:0004167	94.83	gold quality
occipital lobe	UBERON:0002021	94.66	gold quality
temporal lobe	UBERON:0001871	94.63	gold quality
renal glomerulus	UBERON:0000074	94.60	gold quality
upper leg skin	UBERON:0004262	94.59	gold quality
metanephric glomerulus	UBERON:0004736	94.53	gold quality
trachea	UBERON:0003126	94.50	gold quality
midbrain	UBERON:0001891	94.42	gold quality
superior frontal gyrus	UBERON:0002661	94.40	gold quality
pleura	UBERON:0000977	94.38	gold quality
pylorus	UBERON:0001166	94.38	gold quality
putamen	UBERON:0001874	94.30	gold quality
hypothalamus	UBERON:0001898	94.24	gold quality
Ammon’s horn	UBERON:0001954	94.15	gold quality
pancreas	UBERON:0001264	94.10	gold quality
oral cavity	UBERON:0000167	94.09	gold quality
upper lobe of lung	UBERON:0008948	94.09	gold quality
substantia nigra	UBERON:0002038	94.02	gold quality
caudate nucleus	UBERON:0001873	93.88	gold quality
nucleus accumbens	UBERON:0001882	93.88	gold quality
primary visual cortex	UBERON:0002436	93.87	gold quality
adrenal tissue	UBERON:0018303	93.86	gold quality
cardia of stomach	UBERON:0001162	93.79	gold quality
upper lobe of left lung	UBERON:0008952	93.74	gold quality
cartilage tissue	UBERON:0002418	93.71	gold quality
right coronary artery	UBERON:0001625	93.61	gold quality
aorta	UBERON:0000947	93.55	gold quality
mammalian vulva	UBERON:0000997	93.49	gold quality
cauda epididymis	UBERON:0004360	93.43	gold quality
body of pancreas	UBERON:0001150	93.37	gold quality
amygdala	UBERON:0001876	93.23	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-MTAB-9154	yes	970.09
E-HCAD-35	yes	78.28
E-CURD-114	yes	50.45
E-HCAD-10	yes	17.97
E-MTAB-5061	yes	16.90
E-GEOD-83139	yes	8.19
E-GEOD-130148	yes	8.05
E-GEOD-93593	yes	4.91
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Parathyroid gland	tissue	412.8	high
Caudate putamen	tissue	121.7
Putamen	tissue	105.6
Ventral forebrain	tissue	103.4
Basal ganglia	tissue	97.1	medium
Septum	tissue	81.5
Nucleus accumbens	tissue	81.3
Breast	tissue	76.0	medium
Superior colliculi	tissue	73.7
Lung	tissue	69.9	high
Hypothalamus	tissue	69.7
Frontal cortex	tissue	68.5
Hippocampal formation	tissue	64.2
Pons	tissue	59.8
Locus coeruleus	tissue	59.4
Thyroid gland	tissue	58.4	medium
Substantia nigra	tissue	56.2
Periaqueductal gray	tissue	55.4
Prefrontal cortex	tissue	55.0
Cerebral cortex	tissue	55.0	medium
Corpus callosum	tissue	54.5
Entorhinal cortex	tissue	53.4
Medulla oblongata	tissue	52.1
Motor cortex	tissue	51.1
Amygdala	tissue	51.1
Thalamus	tissue	50.5
Insular cortex	tissue	49.8
Midbrain	tissue	48.4
Retrosplenial and cingulate cortex	tissue	48.4
Temporal cortex	tissue	48.4
Fallopian tube	tissue	46.2	high
Occipital cortex	tissue	46.0
Liver	tissue	44.8	high
Somatosensory cortex	tissue	44.1
Retrosplenial cortex	tissue	43.6
Spinal cord	tissue	42.3
Hippocampus	tissue	41.9	low
Postcentral gyrus	tissue	37.8
Seminal vesicle	tissue	37.3	high
Epididymis	tissue	33.4	high
Ovary	tissue	33.1	low
Stomach 1	tissue	31.6	high
Adrenal gland	tissue	30.9	low
Pancreas	tissue	30.8	high
Prostate	tissue	30.7	high
Cervix	tissue	26.3	high
Salivary gland	tissue	26.3	medium
Urinary bladder	tissue	23.9	medium
Gallbladder	tissue	21.9	medium
Kidney	tissue	20.8	high
Olfactory bulb	tissue	18.9
Choroid plexus	tissue	18.2
Pituitary gland	tissue	17.9
Small intestine	tissue	16.4	low
Duodenum	tissue	16.0	low
Smooth muscle	tissue	15.2	low
Endometrium 1	tissue	14.4	high
Rectum	tissue	13.6	low
Tonsil	tissue	13.6	medium
Thymus	tissue	13.3

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Parieto-temporal junction (white matter) (160.6), Corpus callosum, genu (white matter) (145.7), Corpus callosum, splenium (white matter) (138.1), Mammillary body (137.1), Cerebellar white matter (130.1).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GDNF, GLI1, NFKB, REL, SP1

miRNA regulators (miRDB)

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

showing 30 of 175 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882

Functional genomics

gnomAD constraint: pLI 0.995, LOEUF 0.474, missense Z 1.75 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000306107 splits into 2 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
3:105,367,409–105,547,168	427 / 450.4	0.95	no
3:105,547,169–105,571,936	164 / 244.7	0.67	no

Literature-anchored findings (GeneRIF, showing 40)

• ALCAM expression up-regulated in low-grade prostate tumors and down-regulated in high-grade tumors; may play role in progression of prostate cancer (PMID:12481253)
• ALCAM is expressed on human endometrial epithelial cells and blastocysts. (PMID:12843199)
• the intact cell adhesion function of ALCAM may both favor primary tumor growth and represent a rate-limiting step for tissue invasion from vertical growth phase melanoma. (PMID:15140234)
• PKCA has a major role in cytoskeleton-dependent avidity modulation of ALCAM. (PMID:15169840)
• a novel soluble isoform of ALCAM may have ALCAM-dependent and ALCAM-independent functions (PMID:15496415)
• Overexpression of activated leukocyte cell adhesion molecule is associated with tumor invasion and nodal metastasis in esophageal squamous cell carcinoma (PMID:16024937)
• Data attribute a novel signaling role to ALCAM in regulation of proteolysis and support its previously postulated sensor function in invasive growth. (PMID:16204050)
• Localization of ALCAM specifically at cell-cell junctions in endothelial cells supported its role in transendothelial migration (PMID:16650408)
• Engagement of CD6 with CD166 on tumor cells plays an important role in gammadelta T cell activation by tumor cells sensitized with nonpeptide antigens endogenously or exogenously. (PMID:16818742)
• the CD6-ALCAM interaction results in activation of the three MAP kinase cascades, likely influencing the dynamic balance that determines whether resting or activated lymphocytes survive or undergo apoptosis. (PMID:16818773)
• The above results indicate that ALCAM-ALCAM interactions are crucial to the survival and primary site maintenance of breast cancer cells. (PMID:16865058)
• HLA-A *0201 restricted ALCAM peptides primed autologous CD8(+) T cells to elicit cytotoxic response against ALCAM(+) human cancer cells. (PMID:17624664)
• These results indicate that homotypic and heterotypic ALCAM-mediated adhesion are governed by significantly distinct kinetic and mechanical properties. (PMID:17971418)
• These findings indicate an important function for ALCAM in the recruitment of leukocytes into the brain. (PMID:18157132)
• disruption of ALCAM-mediated adhesion is a relevant step in ovarian cancer cell motility, and ADAM17/TACE takes part in this process, which may be relevant to invasive potential (PMID:18171982)
• activated leukocyte cell adhesion molecule (ALCAM/CD166) may have a role in breast cancer (PMID:18172759)
• This study has, for the first time, shown that patients who develop skeletal metastasis tend to have the lowest levels of ALCAM transcripts in their breast cancers. (PMID:18202807)
• Over the past decade, alterations in expression of ALCAM have been reported in several human tumors (melanoma, prostate cancer, breast cancer, colorectal carcinoma, bladder cancer, and esophageal squamous cell carcinoma). (PMID:18279810)
• Decreased/lost ALCAM membrane expression is a marker of poorer outcome in epithelial ovarian cancer. (PMID:18347173)
• ALCAM coordinates tissue growth and cell migration in a process involvnig L1CAM (PMID:18483249)
• Higher ALCAM expression showed a positive correlation with estrogen receptor status and is a useful predictive marker for the response to taxane-free chemotherapy. (PMID:18810438)
• Increased ALCAM expression in the cytoplasm is associated with oral cancer (PMID:19142865)
• Elevated levels of ALCAM in serum is associated with breast cancer. (PMID:19322904)
• upregulation of CD166 in a von Hippel-Lindau tumour suppressor gene defective renal cell carcinoma cell line. (PMID:19337990)
• ALCAM overexpression is a relevant independent prognostic marker for poor survival and early tumour relapse in pancreatic cancer. (PMID:19603023)
• Report prognostic significance of the cancer stem cell markers CD133, CD44, and CD166 in colorectal cancer. (PMID:19626493)
• Data show that compounds 17 and 18 were discovered as new potential inhibitors, with a nanomolar activity for ADAM-17 isolated enzyme and soluble ALCAM release in cancer cells. (PMID:20180536)
• ALCAM is expressed in neuroblastoma primary tumors with diverse patterns of subcellular localization. (PMID:20208136)
• examined ALCAM expression levels in primary breast cancer and distant metastases of the same patient within 29 autopsy cases to better understand the underlying mechanisms of metastases and the role of adhesion molecules in this process (PMID:20364042)
• Loss of ALCAM in breast cancer cells facilitates the invasive behaviour of breast cancer and high levels of ALCAM in the cells have a suppressive role in the aggressive nature of breast cancer cells. (PMID:20530423)
• Prognostic impact of this and other cancer stem cell markers expression in colorectal cancer. (PMID:20606680)
• Data show that CD6-ALCAM interaction in vitro induced a synergistic co-stimulation of normal peripheral blood mononuclear cells. (PMID:20726988)
• CD166 is highly expressed within the endogenous intestinal stem cell niche (PMID:20826154)
• Data suggests that loss of ALCAM expression, due in part to DNA methylation of extensive segments of the promoter, significantly impairs the ability of circulating tumor cells to adhere to each other, and may therefore promote metastasis. (PMID:20929568)
• involvement of ALCAM in the pathogenesis of different types of tumors [review] (PMID:20952758)
• ALCAM expression was associated with estrogen receptor-positive phenotype, nodal involvement and breast tumor cells in bone marrow. Strong ALCAM expression in ductal carcinomas correlated with shorter recurrence-free intervals/overall survival. (PMID:20972617)
• Both transfection of mimics of microRNA-192 or -215 and ALCAM knockdown by an ALCAM-specific siRNA significantly increased the migration of HFE145 cells (PMID:21119604)
• There is a lineage-specific silencing of ALCAM in bi-potential erythromegakaryocytic progenitor cell lines. (PMID:21126364)
• polymorphisms in ALCAM gene is associated with breast cancer. (PMID:21293922)
• ALCAM may have an important role in thyroid tumor biology. (PMID:21364949)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	alcama	ENSDARG00000026531
danio_rerio	alcamb	ENSDARG00000058538
mus_musculus	Alcam	ENSMUSG00000022636
rattus_norvegicus	Alcam	ENSRNOG00000001989

Paralogs (3): MCAM (ENSG00000076706), BCAM (ENSG00000187244), AGER (ENSG00000204305)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1313266) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 4 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal motor neuron innervation pattern	1
abnormal retina morphology	1
abnormal photoreceptor outer segment morphology	1
abnormal retina ganglion layer morphology	1

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
Oryctolagus cuniculus	O46651	95.0%	Diamond
Bos taurus	Q9BH13	94.3%	Diamond
Canis lupus familiaris	O46634	93.7%	Diamond
Carassius auratus	Q90304	85.6%	Diamond
Gallus gallus	P42292	75.0%	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
CBLB	protein-coding	868

Protein

Protein identifiers

CD166 antigen — Q13740 (reviewed: Q13740)

Alternative names: Activated leukocyte cell adhesion molecule

All UniProt accessions (3): Q13740, F5GXJ9, H7C543

UniProt curated annotations — full annotation on UniProt →

Function. Cell adhesion molecule that mediates both heterotypic cell-cell contacts via its interaction with CD6, as well as homotypic cell-cell contacts. Promotes T-cell activation and proliferation via its interactions with CD6. Contributes to the formation and maturation of the immunological synapse via its interactions with CD6. Mediates homotypic interactions with cells that express ALCAM. Acts as a ligand for the LILRB4 receptor, enhancing LILRB4-mediated inhibition of T cell proliferation. Required for normal hematopoietic stem cell engraftment in the bone marrow. Mediates attachment of dendritic cells onto endothelial cells via homotypic interaction. Inhibits endothelial cell migration and promotes endothelial tube formation via homotypic interactions. Required for normal organization of the lymph vessel network. Required for normal hematopoietic stem cell engraftment in the bone marrow. Plays a role in hematopoiesis; required for normal numbers of hematopoietic stem cells in bone marrow. Promotes in vitro osteoblast proliferation and differentiation. Promotes neurite extension, axon growth and axon guidance; axons grow preferentially on surfaces that contain ALCAM. Mediates outgrowth and pathfinding for retinal ganglion cell axons. Inhibits activities of membrane-bound isoforms by competing for the same interaction partners. Inhibits cell attachment via homotypic interactions. Promotes endothelial cell migration. Inhibits endothelial cell tube formation.

Subunit / interactions. Homodimer. Interacts (via extracellular domain) with CD6 (via extracellular domain). Homodimerization and interaction with CD6 involve the same region and cannot occur simultaneously. The affinity for CD6 is much higher than the affinity for self-association. Interacts (via glycosylated extracellular domain) with LGALS1 and LGALS3. Interaction with LGALS1 or LGALS3 inhibits interaction with CD6.

Subcellular location. Cell membrane. Cell projection. Axon. Dendrite Secreted.

Tissue specificity. Detected on hematopoietic stem cells derived from umbilical cord blood. Detected on lymph vessel endothelial cells, skin and tonsil. Detected on peripheral blood monocytes. Detected on monocyte-derived dendritic cells (at protein level). Detected at low levels in spleen, placenta, liver. Expressed by activated T-cells, B-cells, monocytes and thymic epithelial cells. Isoform 1 and isoform 3 are detected in vein and artery endothelial cells, astrocytes, keratinocytes and artery smooth muscle cells. Expressed by neurons in the brain. Restricted expression in tumor cell lines. Detected in highly metastasizing melanoma cell lines.

Post-translational modifications. Glycosylated.

Domain organisation. The CD6 binding site is located in the N-terminal Ig-like domain.

Induction. Up-regulated by TNF and IFNG (at protein level).

Miscellaneous. Secreted form, inhibits isoform 1 homophilic interaction.

Isoforms (4)

UniProt ID	Names	Canonical?
Q13740-1	1	yes
Q13740-2	2
Q13740-3	3, sALCAM
Q13740-4	4

RefSeq proteins (4): NP_001230209, NP_001230210, NP_001230212, NP_001618* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013162	CD80_C2-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR051116	Surface_Rcpt/Adhesion_Mol	Family

Pfam: PF08205, PF13927

UniProt features (64 total): strand 18, glycosylation site 9, sequence variant 6, disulfide bond 5, splice variant 5, helix 5, domain 5, turn 4, topological domain 2, signal peptide 1, chain 1, region of interest 1, compositionally biased region 1, transmembrane region 1

Structure

Experimental structures (PDB)

1 structures by resolution:

PDB	Title	Method	Resolution (Å)
5A2F	Two membrane distal IgSF domains of CD166	X-RAY DIFFRACTION	1.86

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13740-F1	86.13	0.72

Human Protein Atlas

Protein class: CD markers, Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins, Predicted secreted proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles

Antibody reliability (HPA): IH enhanced · IF uncertain

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 (5)

Type	Positions
Disulfide bond	43–113, 157–220, 270–313, 354–392, 435–485

Glycosylation sites (9)

Type	Positions
N-linked (glcnac…) asparagine	91, 95, 167, 265, 306, 361, 457, 480, 499

Function

Pathways and Gene Ontology

Reactome pathways

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

4 pathways:

ID	Pathway	Evidence
R-HSA-422475	Axon guidance	—
R-HSA-1266738	Developmental Biology	—
R-HSA-373760	L1CAM interactions	electronic
R-HSA-9675108	Nervous system development	—

MSigDB gene sets: 544 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, WENDT_COHESIN_TARGETS_UP, GCACCTT_MIR18A_MIR18B, MODULE_97, MODULE_52, TAATAAT_MIR126, WANG_CLIM2_TARGETS_UP, GOBP_HETEROPHILIC_CELL_CELL_ADHESION, FARMER_BREAST_CANCER_CLUSTER_7, ZHAN_MULTIPLE_MYELOMA_PR_DN, GOBP_NEURON_PROJECTION_EXTENSION, XU_GH1_AUTOCRINE_TARGETS_UP, GOBP_RETINAL_GANGLION_CELL_AXON_GUIDANCE, GOBP_NEURON_PROJECTION_EXTENSION_INVOLVED_IN_NEURON_PROJECTION_GUIDANCE

GO Biological Process (9): adaptive immune response (GO:0002250), cell adhesion (GO:0007155), heterophilic cell-cell adhesion (GO:0007157), signal transduction (GO:0007165), neuron projection development (GO:0031175), retinal ganglion cell axon guidance (GO:0031290), axon extension involved in axon guidance (GO:0048846), neuron projection extension (GO:1990138), immune system process (GO:0002376)

GO Molecular Function (3): signaling receptor binding (GO:0005102), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (10): immunological synapse (GO:0001772), plasma membrane (GO:0005886), focal adhesion (GO:0005925), external side of plasma membrane (GO:0009897), axon (GO:0030424), dendrite (GO:0030425), neuronal cell body (GO:0043025), extracellular exosome (GO:0070062), extracellular region (GO:0005576), T cell receptor complex (GO:0042101)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Axon guidance	1
Nervous system development	1
Developmental Biology	1

GO top-level categories

30 GO namespaces:

Category	Terms
cellular process	2
axon guidance	2
protein binding	2
plasma membrane	2
cellular anatomical structure	2
neuron projection	2
immune response	1
cell-cell adhesion	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
neuron development	1
plasma membrane bounded cell projection organization	1
axon extension	1
developmental cell growth	1
neuron projection morphogenesis	1
developmental growth involved in morphogenesis	1
biological_process	1
binding	1
membrane	1
cell periphery	1
cell-substrate junction	1
cell surface	1
side of membrane	1
dendritic tree	1
somatodendritic compartment	1
cell body	1
extracellular vesicle	1
plasma membrane signaling receptor complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 22 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
heterophilic cell-cell adhesion	BP	mutant phenotype
extracellular exosome	CC	high-throughput assay
focal adhesion	CC	high-throughput assay
immunological synapse	CC	direct assay
plasma membrane	CC	direct assay
identical protein binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,638 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALCAM	CD6	P30203	948
ALCAM	ENG	P17813	880
ALCAM	NT5E	P21589	807
ALCAM	THY1	P04216	807
ALCAM	CD44	P16070	807
ALCAM	ITGB1	P05556	801
ALCAM	CNTN6	Q9UQ52	784
ALCAM	CD34	P28906	767
ALCAM	PTPRC	P08575	751
ALCAM	PROM1	O43490	750
ALCAM	TAMALIN	Q7Z6J2	736
ALCAM	PECAM1	P16284	675
ALCAM	ANPEP	P15144	665
ALCAM	CD24	P25063	654
ALCAM	EPCAM	P16422	623

IntAct

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

9 partners by confidence:

Partner	Interaction type	MIscore	Records
CD6	direct interaction	0.850	5
LGALS1	physical association	0.770	4
LGALS3	direct interaction	0.740	3
AAMDC	physical association	0.400	1
HEPHL1	physical association	0.400	1
PINX1	physical association	0.400	1
ART3	physical association	0.370	1
LAMB1	association	0.350	1
UBE2D4	association	0.350	1

BioGRID (131 interactions; top human partners by supporting records): CHD2 (Cross-Linking-MS (XL-MS); 4 records), LGALS9 (Affinity Capture-MS; 4 records), UBR4 (Cross-Linking-MS (XL-MS); 4 records), LGALS1 (Affinity Capture-MS; 3 records), LGALS3 (Affinity Capture-MS; 3 records), LGALS8 (Affinity Capture-MS; 3 records), SOSTDC1 (Affinity Capture-MS; 3 records), APOD (Affinity Capture-MS; 2 records), CD6 (Reconstituted Complex; 2 records), FBXO2 (Affinity Capture-MS; 2 records), PCDH12 (Affinity Capture-MS; 2 records), RAB35 (Proximity Label-MS; 2 records), ABCB6 (Co-fractionation), ABCC1 (Affinity Capture-MS), ACE2 (Proximity Label-MS)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
GDNF	“up-regulates quantity by expression”	ALCAM	“transcriptional regulation”

Ligand–receptor pairs (CellPhoneDB) (1)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

1 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
CD6	ligand

Disease & clinical

Genetic variants

Variant evidence for ALCAM: 113 ClinVar records (0 pathogenic / likely pathogenic); 1 CIViC cancer variant; 31 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	71
Likely benign	7
Benign	8

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 34 predictions of 1,872):

Position(s)	Effect	Δscore	Sites
3:105534846–105534847	donor_loss	1.0000	5
3:105540759	donor_gain	1.0000
3:105547285–105547286	donor_loss	1.0000	4
3:105549332	donor_gain	1.0000
3:105549346	donor_gain	1.0000
3:105552460	acceptor_gain	1.0000
3:105552466–105552467	acceptor_loss	1.0000	5
3:105571850–105571851	acceptor_loss	1.0000	6
3:105571965–105571966	donor_loss	1.0000	5
3:105367482–105367483	donor_loss	0.9900	5

AlphaMissense

1,085 missense substitutions predicted likely pathogenic (of 3,839 scored), across 305 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
D107	8	0.990	0.997
N489	8	0.983	0.999
F53	8	0.955	0.998
N480	8	0.936	0.989
F111	8	0.929	0.998
D213	8	0.913	0.972
F379	8	0.884	0.990
S359	8	0.877	0.996
D333	8	0.826	0.904
C485	7	0.998	0.999
C113	7	0.997	0.999
C392	7	0.997	0.999
C435	7	0.997	1.000
C220	7	0.996	0.999
C157	7	0.995	0.998
C270	7	0.995	0.999
C313	7	0.995	0.999
C354	7	0.994	0.998
C43	7	0.993	0.997
W447	7	0.993	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	7.99e-07
Glioblastoma Multiforme (validation)	favorable	0.00061
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000977

Disease associations

OMIM: gene MIM:601662 | disease phenotypes:

GWAS associations

showing 30 of 31 associations:

Study	Trait	p-value
GCST010225_11	Cortical surface area (visual PC2)	3e-17
GCST005580_29	Intraocular pressure	2e-15
GCST010225_14	Cortical surface area (visual PC2)	2e-15
GCST011617_36	Cortical surface area	4e-15
GCST90011770_18	Glaucoma (primary open-angle)	8e-13
GCST010988_412	Adult body size	4e-12
GCST005580_223	Intraocular pressure	7e-11
GCST010225_15	Cortical surface area (visual PC2)	1e-10
GCST011616_33	Cortical volume	2e-10
GCST010225_6	Cortical surface area (visual PC2)	1e-9
GCST011616_44	Cortical volume	1e-9
GCST007576_121	Chronotype	1e-8
GCST009665_13	Breast cancer	1e-8
GCST010225_12	Cortical surface area (visual PC2)	1e-8
GCST006941_63	Irritable mood	2e-8
GCST002337_52	Amyotrophic lateral sclerosis (sporadic)	4e-8
GCST009368_77	HDL cholesterol levels x long total sleep time interaction (2df test)	4e-8
GCST010241_271	Apolipoprotein A1 levels	4e-8
GCST010225_22	Cortical surface area (visual PC2)	5e-8
GCST001572_1	Erectile dysfunction in type 1 diabetes	7e-7
GCST006585_336	Blood protein levels	7e-7
GCST004369_4	Ovarian disease with few adhesions	8e-7
GCST011696_2	Alzheimer’s disease	9e-7
GCST002444_2	Plasma omega-6 polyunsaturated fatty acid levels (dihomo-gamma-linolenic acid)	2e-6
GCST002783_545	Body mass index	4e-6
GCST005023_54	Initial pursuit acceleration	5e-6
GCST003139_4	Glomerular filtration rate in chronic kidney disease	6e-6
GCST008473_10	Visceral fat	6e-6
GCST009391_1665	Metabolite levels	6e-6
GCST009441_16	Age-related cognitive decline (memory) (slope of z-scores)	7e-6

EFO canonical traits (from GWAS)

11 canonical traits:

EFO ID	Trait name
EFO:0005680	omega-6 polyunsaturated fatty acid measurement
EFO:0004340	body mass index
EFO:0008434	initial pursuit acceleration
EFO:0004695	intraocular pressure measurement
EFO:0009594	irritability measurement
EFO:0008328	chronotype measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0010422	triacylglycerol 54:4 measurement
EFO:0007710	cognitive decline measurement
EFO:0004771	visual cortical surface area measurement
EFO:0004614	apolipoprotein A 1 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4665584 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the ALCAM protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

1 curated-mechanism drugs:

Drug	Modality	Max phase
PRALUZATAMAB RAVTANSINE	Antibody drug conjugate	2

Clinical evidence (CIViC)

Drug × variant × indication, from 1 curated evidence items. CIViC evidence level: A (validated) → B (clinical) → C (case study) → D (preclinical) → E (inferential).

1 predictive associations by evidence level:

Variant	Therapy	Indication	Effect	Level	CIViC
ALCAM EXPRESSION	Fluorouracil	Colorectal Cancer	Resistance	CIViC B	EID853

CIViC curated variants (1)

Named clinical variants curated in CIViC for this gene (the catalogue beneath the predictive evidence above):

EXPRESSION.

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
sodium arsenite	decreases expression, increases abundance, affects cotreatment, increases expression	4
trichostatin A	affects cotreatment, increases expression	3
Estradiol	affects expression, affects cotreatment, increases expression, decreases expression, decreases reaction	3
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, affects expression, decreases expression	3
methylmercuric chloride	decreases expression, increases expression	2
mercuric bromide	affects cotreatment, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Progesterone	increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Tretinoin	affects cotreatment, increases expression	2
Cyclosporine	decreases expression	2
Medroxyprogesterone Acetate	increases expression	2
Cadmium Chloride	increases palmitoylation, increases expression, decreases reaction, increases abundance	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
napabucasin	decreases expression	1
dicrotophos	decreases expression	1
bisphenol A	affects expression	1
terbufos	increases methylation	1
sulforaphane	decreases expression	1
2-bromopalmitate	increases palmitoylation, decreases reaction, increases abundance	1
N-acetyl-4-benzoquinoneimine	affects response to substance	1
nickel sulfate	increases expression	1
1-nitropyrene	increases expression	1
di-n-butylphosphoric acid	affects expression	1

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B7VX	Abcam Raji ALCAM KO	Cancer cell line	Male
CVCL_B9WF	Abcam THP-1 ALCAM KO	Cancer cell line	Male
CVCL_C6YG	Abcam PC-3 ALCAM KO	Cancer cell line	Male
CVCL_E6P1	Genomeditech CHO-K1 H_ALCAM(CD166)	Spontaneously immortalized cell line	Female
CVCL_SC21	HAP1 ALCAM (-) 1	Cancer cell line	Male
CVCL_XL23	HAP1 ALCAM (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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