CD6

Summary

CD6 (CD6 molecule, HGNC:1691) is a protein-coding gene on chromosome 11q12.2, encoding T-cell differentiation antigen CD6 (P30203). Cell adhesion molecule that mediates cell-cell contacts and regulates T-cell responses via its interaction with ALCAM/CD166.

This gene encodes a protein found on the outer membrane of T-lymphocytes as well as some other immune cells. The encoded protein contains three scavenger receptor cysteine-rich (SRCR) domains and a binding site for an activated leukocyte cell adhesion molecule. The gene product is important for continuation of T cell activation. This gene may be associated with susceptibility to multiple sclerosis (PMID: 19525953, 21849685). Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 923 — RefSeq curated summary.

At a glance

• GWAS associations: 18
• Clinical variants (ClinVar): 119 total
• GTEx eGene: eQTL in 19 tissues, sQTL in 3 (q < 0.05)
• Drug target: yes — 2 curated mechanism-of-action drugs
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.03 (unconstrained)
• MANE Select transcript: NM_006725
• Notable: 119 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1691
Approved symbol	CD6
Name	CD6 molecule
Location	11q12.2
Locus type	gene with protein product
Status	Approved
Aliases	Tp120
Ensembl gene	ENSG00000013725
Ensembl biotype	protein_coding
OMIM	186720
Entrez	923

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 18 protein_coding, 3 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

MANE Select: ENST00000313421

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 1, TSL 3: 2, TSL 4: 6, TSL 5: 1

ENST00000313421, ENST00000344931, ENST00000352009, ENST00000419282, ENST00000433107, ENST00000452451, ENST00000505761, ENST00000538288, ENST00000538611, ENST00000541964, ENST00000542157, ENST00000542254, ENST00000545105, ENST00000545320, ENST00000899021, ENST00000899024, ENST00000899026, ENST00000899027, ENST00000899028, ENST00000899029, ENST00000899030, ENST00000899031, ENST00000899032, ENST00000899033, ENST00000899034, ENST00001136088

RefSeq mRNA: 3 — MANE Select: NM_006725 NM_001254750, NM_001254751, NM_006725

CCDS: CCDS58137, CCDS58138, CCDS7999

Canonical transcript exons

ENST00000313421 — 13 exons

Exon	Start	End
ENSE00000721337	61008534	61008845
ENSE00000721341	61009572	61009874
ENSE00000851452	61007560	61007910
ENSE00001641257	61018289	61018393
ENSE00001644118	61015713	61015835
ENSE00001768072	61013919	61014014
ENSE00001780289	61019254	61020377
ENSE00002252032	60971680	60971914
ENSE00003526256	61013423	61013563
ENSE00003571145	61006574	61006642
ENSE00003654036	61011070	61011135
ENSE00003671262	61017479	61017550
ENSE00003672261	61017759	61018013

Expression profiles

Bgee: expression breadth ubiquitous, 219 present calls, max score 98.02.

FANTOM5 (CAGE): breadth broad, TPM avg 8.5487 / max 539.8701, expressed in 215 samples.

Highest expression (Bgee): granulocyte, lymph node, olfactory bulb, blood, thymus.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CD6 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 19 tissues and its splicing (sQTL) in 3 (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
Brain Frontal Cortex BA9	eqtl	3.1e-59	-1.02	11:61008737:C:T
Brain Cortex	eqtl	5.1e-59	-1.00	11:61008737:C:T
Brain Anterior cingulate cortex BA24	eqtl	8.6e-47	-0.96	11:61008737:C:T
Brain Cerebellar Hemisphere	eqtl	1.1e-42	-0.99	11:61008737:C:T
Brain Cerebellum	eqtl	1.0e-33	-1.03	11:61008737:C:T
Brain Hypothalamus	eqtl	7.0e-23	-0.57	11:61008737:C:T
Brain Amygdala	eqtl	5.3e-11	-0.66	11:61008737:C:T
Spleen	eqtl	2.2e-08	+0.32	11:61009239:A:G
Brain Hippocampus	eqtl	8.2e-06	-0.36	11:61008737:C:T
Adrenal Gland	eqtl	2.0e-05	+0.41	11:61017992:G:A
Prostate	sqtl	3.8e-04	+2.90	11:61531401:G:A
Brain Caudate basal ganglia	eqtl	4.3e-04	-0.39	11:61008834:C:T
Testis	eqtl	7.1e-04	-0.34	11:60981784:G:A
Whole Blood	eqtl	5.1e-03	-0.05	11:61025858:C:T
Esophagus Mucosa	eqtl	1.8e-02	-0.19	11:60951320:C:T
Lung	sqtl	2.2e-02	-1.23	11:60198725:T:C
Small Intestine Terminal Ileum	sqtl	2.6e-02	-3.68	11:60967085:C:T
Brain Putamen basal ganglia	eqtl	2.6e-02	-0.35	11:61008834:C:T
Brain Nucleus accumbens basal ganglia	eqtl	3.0e-02	-0.27	11:61008834:C:T
Colon Transverse	eqtl	3.1e-02	-0.17	11:61470413:G:A

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
114538	8.4381	209
114539	0.0983	48
114542	0.0123	6

Top tissues by expression

showing 100 of 272 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.02	gold quality
lymph node	UBERON:0000029	93.54	gold quality
olfactory bulb	UBERON:0002264	93.04	gold quality
blood	UBERON:0000178	92.41	gold quality
thymus	UBERON:0002370	91.39	gold quality
type B pancreatic cell	CL:0000169	90.24	gold quality
pancreatic ductal cell	CL:0002079	90.08	silver quality
vermiform appendix	UBERON:0001154	89.89	gold quality
caecum	UBERON:0001153	88.20	gold quality
endometrium epithelium	UBERON:0004811	88.18	gold quality
spleen	UBERON:0002106	87.51	gold quality
diaphragm	UBERON:0001103	87.35	gold quality
cervix squamous epithelium	UBERON:0006922	86.43	silver quality
cervix epithelium	UBERON:0004801	84.89	silver quality
superficial temporal artery	UBERON:0001614	83.77	gold quality
epithelial cell of pancreas	CL:0000083	83.43	gold quality
bone marrow	UBERON:0002371	83.37	gold quality
endothelial cell	CL:0000115	83.36	silver quality
bone marrow cell	CL:0002092	82.60	gold quality
epithelium of nasopharynx	UBERON:0001951	81.67	gold quality
Brodmann (1909) area 10	UBERON:0013541	81.57	silver quality
right uterine tube	UBERON:0001302	81.54	gold quality
colonic epithelium	UBERON:0000397	81.31	gold quality
small intestine Peyer’s patch	UBERON:0003454	81.20	gold quality
bone element	UBERON:0001474	80.66	gold quality
ileal mucosa	UBERON:0000331	80.64	gold quality
cerebellar vermis	UBERON:0004720	80.50	gold quality
tonsil	UBERON:0002372	80.48	gold quality
small intestine	UBERON:0002108	79.73	gold quality
parotid gland	UBERON:0001831	79.64	gold quality
nasal cavity epithelium	UBERON:0005384	79.57	silver quality
upper arm skin	UBERON:0004263	79.50	silver quality
periodontal ligament	UBERON:0008266	78.75	silver quality
heart right ventricle	UBERON:0002080	78.57	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	78.15	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.07	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.97	gold quality
nasal cavity mucosa	UBERON:0001826	77.82	gold quality
vena cava	UBERON:0004087	77.75	silver quality
inferior olivary complex	UBERON:0002127	77.72	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	77.65	gold quality
gall bladder	UBERON:0002110	77.26	gold quality
oocyte	CL:0000023	77.19	gold quality
palpebral conjunctiva	UBERON:0001812	76.75	gold quality
tongue squamous epithelium	UBERON:0006919	76.75	gold quality
cardia of stomach	UBERON:0001162	76.30	gold quality
trachea	UBERON:0003126	76.13	silver quality
mucosa of transverse colon	UBERON:0004991	75.99	gold quality
duodenum	UBERON:0002114	75.97	gold quality
amniotic fluid	UBERON:0000173	75.87	silver quality
superior surface of tongue	UBERON:0007371	75.57	gold quality
jejunal mucosa	UBERON:0000399	75.52	gold quality
squamous epithelium	UBERON:0006914	75.44	silver quality
pylorus	UBERON:0001166	75.33	gold quality
sural nerve	UBERON:0015488	75.31	gold quality
rectum	UBERON:0001052	75.19	gold quality
mammalian vulva	UBERON:0000997	75.18	silver quality
gluteal muscle	UBERON:0002000	74.87	gold quality
triceps brachii	UBERON:0001509	74.75	gold quality
pharyngeal mucosa	UBERON:0000355	74.66	silver quality
fallopian tube	UBERON:0003889	74.56	gold quality
visceral pleura	UBERON:0002401	74.53	gold quality
trabecular bone tissue	UBERON:0002483	74.47	gold quality
tongue	UBERON:0001723	74.41	silver quality
pleura	UBERON:0000977	74.27	silver quality
upper lobe of left lung	UBERON:0008952	74.23	gold quality
paraflocculus	UBERON:0005351	74.20	gold quality
epithelium of esophagus	UBERON:0001976	74.06	silver quality
frontal pole	UBERON:0002795	73.92	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	73.88	gold quality
mammary duct	UBERON:0001765	73.82	silver quality
metanephric glomerulus	UBERON:0004736	73.82	silver quality
parietal pleura	UBERON:0002400	73.74	silver quality
epithelium of mammary gland	UBERON:0003244	73.63	silver quality
jejunum	UBERON:0002115	73.50	gold quality
oviduct epithelium	UBERON:0004804	73.38	silver quality
upper lobe of lung	UBERON:0008948	73.34	gold quality
pons	UBERON:0000988	73.26	silver quality
middle frontal gyrus	UBERON:0002702	73.26	gold quality
lung	UBERON:0002048	73.07	gold quality
layer of synovial tissue	UBERON:0007616	72.95	silver quality
decidua	UBERON:0002450	72.91	silver quality
renal glomerulus	UBERON:0000074	72.86	silver quality
pericardium	UBERON:0002407	72.81	silver quality
bronchus	UBERON:0002185	72.80	silver quality
esophagus squamous epithelium	UBERON:0006920	72.74	silver quality
substantia nigra pars reticulata	UBERON:0001966	72.62	silver quality
epithelium of bronchus	UBERON:0002031	72.61	silver quality
mucosa of urinary bladder	UBERON:0001259	72.58	gold quality
nephron tubule	UBERON:0001231	72.56	gold quality
lateral nuclear group of thalamus	UBERON:0002736	72.54	silver quality
ventral tegmental area	UBERON:0002691	72.33	silver quality
gingival epithelium	UBERON:0001949	72.30	gold quality
oral cavity	UBERON:0000167	72.11	gold quality
deltoid	UBERON:0001476	72.08	gold quality
colonic mucosa	UBERON:0000317	71.82	gold quality
kidney epithelium	UBERON:0004819	71.77	gold quality
substantia nigra pars compacta	UBERON:0001965	71.74	silver quality
right lung	UBERON:0002167	71.63	gold quality
tibia	UBERON:0000979	71.60	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-70580	yes	454.78
E-HCAD-4	yes	111.70
E-CURD-122	yes	50.42
E-MTAB-6678	yes	37.48
E-MTAB-8410	yes	14.76
E-ANND-3	yes	10.98

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Lymph node	tissue	40.4	high
Thymus	tissue	36.9
Tonsil	tissue	27.2	high
Appendix	tissue	20.8	high
Spleen	tissue	17.0	high
Bone marrow	tissue	10.8	low
Lung	tissue	6.3	not detected
Stomach 1	tissue	6.2	not detected
Small intestine	tissue	5.8	not detected
Urinary bladder	tissue	4.5	not detected
Gallbladder	tissue	3.8	not detected
Duodenum	tissue	3.8	not detected
Salivary gland	tissue	3.1	not detected
Colon	tissue	3.0	low
Rectum	tissue	2.9	low
Locus coeruleus	tissue	2.6
Postcentral gyrus	tissue	2.3
Esophagus	tissue	1.8	not detected
Choroid plexus	tissue	1.6
Skin 1	tissue	1.4	not detected
Liver	tissue	1.3	not detected
Fallopian tube	tissue	1.3	not detected
Cervix	tissue	1.2	not detected
Breast	tissue	1.2	not detected
Vagina	tissue	1.1	not detected
Adipose tissue	tissue	1.1	not detected
Hippocampus	tissue	1.0	not detected
Prostate	tissue	1.0	not detected
Ovary	tissue	0.8	not detected
Skeletal muscle	tissue	0.8	not detected
Endometrium 1	tissue	0.8	not detected
Adrenal gland	tissue	0.8	not detected
Smooth muscle	tissue	0.7	not detected
Spinal cord	tissue	0.7
Epididymis	tissue	0.6	not detected
Nucleus accumbens	tissue	0.6
Testis	tissue	0.5	not detected
Heart muscle	tissue	0.5	not detected
Pancreas	tissue	0.5	not detected
Thyroid gland	tissue	0.5	not detected
Pituitary gland	tissue	0.4
Seminal vesicle	tissue	0.4	not detected
Superior colliculi	tissue	0.4
Cerebellum	tissue	0.4	not detected
Substantia nigra	tissue	0.4
Pons	tissue	0.3
Tongue	tissue	0.3
Midbrain	tissue	0.3
Medulla oblongata	tissue	0.3
Thalamus	tissue	0.3
Hypothalamus	tissue	0.3
Placenta	tissue	0.3	not detected
Kidney	tissue	0.3	not detected
Corpus callosum	tissue	0.3
Olfactory bulb	tissue	0.3
Cerebral cortex	tissue	0.2	not detected
Retina	tissue	0.2
Parathyroid gland	tissue	0.2	not detected
Frontal cortex	tissue	0.2
Putamen	tissue	0.2

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Ventromedial nucleus (5.6), Median raphe nucleus (4.7), Paraventricular nucleus (4.2), Reticular pontine nucleus, oral (3.9), Parvicellular reticular nuclei, medullary (3.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ETS1, RUNX1, RUNX3

miRNA regulators (miRDB)

Targeting CD6 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 52 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-216A-5P	99.50	68.02	1288
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-1228-3P	99.00	66.53	857
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-6840-3P	98.68	65.95	1923

Functional genomics

gnomAD constraint: pLI 5.22e-15, LOEUF 1.03, missense Z 0.412 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000313421 — one region, missense o/e 0.86.

Literature-anchored findings (GeneRIF, showing 40)

• Comprehensive profiling of the cell surface proteome provides an effective approach for the identification of commonly occurring proteins as well as proteins with restricted expression patterns in this compartment. (PMID:12493773)
• CD6 associates with the scaffolding PDZ-containing protein syntenin-1 during maturation of the immunological synapse (PMID:16034076)
• 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 costimulatory effect of CD6 is mediated through phosphorylation-dependent binding of a specific tyrosine residue, 662Y, in its cytoplasmic region to the adaptor SLP-76. (PMID:16914752)
• Unprecedented bacterial binding properties of recombinant soluble CD6 support its therapeutic potential for the intervention of septic shock syndrome or other inflammatory diseases of infectious origin. (PMID:17601777)
• A chimpanzee and human conserved CD6 domain 1 epitope recognized by T1 monoclonal antibody. (PMID:18707547)
• Replication in an independent set of 2,215 subjects with multiple sclerosis (MS) and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A, IRF8 and CD6; TNFRSF1A harbors two independent susceptibility alleles. (PMID:19525953)
• Study reinforces a role for CD6 and TNFRSF1A as risk loci for multiple sclerosis, extending to populations of southern European ancestry. (PMID:20430450)
• Data show that CD6-ALCAM interaction in vitro induced a synergistic co-stimulation of normal peripheral blood mononuclear cells. (PMID:20726988)
• CD6+ B cells are diminished in Sjogren’s syndrome (PMID:20810246)
• CD6 expression on peripheral NK cells marks a novel CD56(dim) subpopulation associated with distinct patterns of cytokine and chemokine secretion. (PMID:21178331)
• association of single nucleotide polymorphisms to multiple sclerosis (PMID:21552549)
• These findings indicate that the multiple sclerosis risk allele in the CD6 locus is associated with altered proliferation of CD4(+) T cells (PMID:21849685)
• Cd6 is a signaling attenuator whose expression alone, i.e. in the absence of ligand engagement, is sufficient to restrain signaling in T cells. (PMID:21956609)
• Data suggest that genetic variations within CD6 and syntaxin binding protein 6 (STXBP6) may influence response to TNFalpha inhibitors in patients with rheumatoid arthritis (RA). (PMID:22685579)
• In a Korean population, one SNP in CD6 was associated with neuromyelitis optica. (PMID:22994200)
• Our findings reveal that this new MS-associated CD6 risk haplotype significantly modifies expression of CD6 on CD4(+) and CD8(+) T cells. (PMID:23638056)
• A novel level of regulation of CD6 function by intracytoplasmic serine phosphorylation. (PMID:23711376)
• The CD6 polymorphism conferred reduced odds of optic neuritis as an attack location (PMID:24130718)
• upon T cell activation, SRSF1 becomes limiting, and its function in CD6 exon 5 splicing is countered by an increase in CD6 transcription, dependent on chromatin acetylation. (PMID:24890719)
• interaction of Galectin-1 and -3 with CD6 (PMID:24945728)
• CD6 regulatory T cells are characterized by CD6 expression and FOXP3 expression. (PMID:25088497)
• Study provides evidence on the role of CD6, a lymphocyte-specific surface receptor from to the ancient and highly conserved Scavenger Receptor Cysteine-Rich (SRCR) superfamily, as a pattern recognition receptor, and the functional consequences this may have on T cell activation and differentiation. [review] (PMID:25777272)
• Data show the multiple aspects that determine the nature of the signals transmitted via CD6 and the context that may define a dual role for this important T cell surface molecule. [review] (PMID:26028048)
• The binding sites on CD6 and CD166 have been characterized to show that a SNP in CD6 causes glycosylation that hinders the CD6/CD166 interaction. (PMID:26146185)
• Data show a role for extracellular and intracellular interactions of CD6 in lateral movement in response to T cell activation. [review] (PMID:26302795)
• Results from recent genetic association studies provide evidence for a role of CD6 in multiple sclerosis and in rheumatoid arthritis pathogenesis. [review] (PMID:26844569)
• This study provides evidence that CD6 is involved in the susceptibility to Behcet’s disease in a Chinese Han population. (PMID:27108704)
• Data indicate that the T cell-specific adaptor protein (TSAd) SH2 domain interacts with CD6 antigen and linker for activation of T cells protein (LAT) phosphotyrosine (pTyr) peptides. (PMID:27896837)
• These results suggest that (i) CD6 is a negative regulator of T-cell activation, (ii) at the same time, CD6 is a positive regulator of activated T-cell survival/proliferation and infiltration; and (iii) CD6 is a potential new target for treating multiple sclerosis (MS)and potentially other T-cell-driven autoimmune conditions. (PMID:28209777)
• These data are consistent with a model in which bivalent recruitment of a GADS/SLP-76 complex is required for costimulation by CD6. (PMID:28289074)
• these results provide new supportive evidence of the contribution of the CD6 lymphocyte receptor in psoriasis at both experimental and clinical levels. (PMID:29225340)
• These data indicate that overexpression of CD6 and ALCAM in the inflamed mucosa of IBD patients accelerates intestinal mucosal immune responses via promoting CD4+ T cell proliferation and differentiation into Th1/Th17 cells. (PMID:30395204)
• Attenuation of Murine Collagen-Induced Arthritis by Targeting CD6. (PMID:32307907)
• Compromised levels of CD6 and reduced T cell activation in the aged immune system. (PMID:33913383)
• Contribution of Evolutionary Selected Immune Gene Polymorphism to Immune-Related Disorders: The Case of Lymphocyte Scavenger Receptors CD5 and CD6. (PMID:34070159)
• The CD6/ALCAM pathway promotes lupus nephritis via T cell-mediated responses. (PMID:34981775)
• Th1 and Th17 cells are resistant towards T cell activation-induced downregulation of CD6. (PMID:35487454)
• Gene variation impact on prostate cancer progression: Lymphocyte modulator, activation, and cell adhesion gene variant contribution. (PMID:35767366)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cd6	ENSMUSG00000024670
rattus_norvegicus	Cd6	ENSRNOG00000020884
drosophila_melanogaster	Loxl2	FBGN0034660

Paralogs (15): CD5L (ENSG00000073754), LGALS3BP (ENSG00000108679), CD5 (ENSG00000110448), LOX (ENSG00000113083), LOXL3 (ENSG00000115318), LOXL1 (ENSG00000129038), LOXL2 (ENSG00000134013), LOXL4 (ENSG00000138131), SSC4D (ENSG00000146700), PRSS12 (ENSG00000164099), CD163 (ENSG00000177575), CD163L1 (ENSG00000177675), SSC5D (ENSG00000179954), DMBT1 (ENSG00000187908), SCART1 (ENSG00000214279)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:103566) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 9 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased IgM level	1
abnormal B cell physiology	1
decreased B-1 B cell number	1
decreased B cell proliferation	1
decreased susceptibility to injury	1
increased B-1a cell number	1
decreased B-1a cell number	1
increased B-1b cell number	1
decreased interleukin-6 secretion	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
Pongo abelii	Q5RDA4	99.5%	Diamond
Pan troglodytes	Q5G271	99.2%	Diamond
Nomascus leucogenys	Q5G268	98.5%	Diamond
Gorilla gorilla gorilla	Q5G270	98.5%	Diamond
Trachypithecus phayrei	Q5G266	98.3%	Diamond
Macaca mulatta	Q5G267	98.3%	Diamond
Pongo pygmaeus	Q5G269	96.7%	Diamond
Chlorocebus aethiops	Q2VLG4	95.8%	Diamond
Saguinus labiatus	Q5G265	95.5%	Diamond
Xenopus tropicalis	B4F6N6	91.4%	Diamond
Bos taurus	A5PJQ2	88.9%	Diamond
Sus scrofa	Q2VL90	84.0%	Diamond
Canis lupus familiaris	Q2VLG6	84.0%	Diamond
Mesocricetus auratus	P70117	82.3%	Diamond
Gallus gallus	E1C3U7	79.4%	Diamond
Danio rerio	Q24JV9	78.8%	Diamond
Oryctolagus cuniculus	Q05585	78.4%	Diamond
Felis catus	A0A1E1GEY0	63.6%	Diamond
Patiria pectinifera	F7J220	54.5%	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
LINC02954	ncRNA	123466205
SLC15A3	protein-coding	51296
TMEM132A	protein-coding	54972
VPS37C	protein-coding	55048
CD5	protein-coding	921
TMEM109	protein-coding	79073
TMEM109-DT	ncRNA	105369323
PRPF19-DT	ncRNA	107984333

Protein

Protein identifiers

T-cell differentiation antigen CD6 — P30203 (reviewed: P30203)

Alternative names: T12, TP120

All UniProt accessions (6): P30203, E7ER04, F5H835, F6UFK6, G5E973, H0YGL3

UniProt curated annotations — full annotation on UniProt →

Function. Cell adhesion molecule that mediates cell-cell contacts and regulates T-cell responses via its interaction with ALCAM/CD166. Contributes to signaling cascades triggered by activation of the TCR/CD3 complex. Functions as a costimulatory molecule; promotes T-cell activation and proliferation. Contributes to the formation and maturation of the immunological synapse. Functions as a calcium-dependent pattern receptor that binds and aggregates both Gram-positive and Gram-negative bacteria. Binds both lipopolysaccharide (LPS) from Gram-negative bacteria and lipoteichoic acid from Gram-positive bacteria. LPS binding leads to the activation of signaling cascades and down-stream MAP kinases. Mediates activation of the inflammatory response and the secretion of pro-inflammatory cytokines in response to LPS.

Subunit / interactions. Interacts (via extracellular domain) with ALCAM/CD166 (via extracellular domain). Interacts with the TCR/CD3 complex subunit CD3E. Interacts (via tyrosine phosphorylated C-terminus) with LCP2 (via SH2 domain). Interacts with VAV1. Interacts (via glycosylated extracellular domain) with LGALS1 and LGALS3. Interaction with LGALS1 or LGALS3 inhibits interaction with ALCAM.

Subcellular location. Cell membrane Secreted.

Tissue specificity. Detected on thymocytes. Detected on peripheral blood T-cells. Detected on natural killer (NK) cells. Soluble CD6 is detected in blood serum (at protein level). Detected in spleen, thymus, appendix, lymph node and peripheral blood leukocytes. Expressed by thymocytes, mature T-cells, a subset of B-cells known as B-1 cells, and by some cells in the brain.

Post-translational modifications. After T-cell activation, becomes hyperphosphorylated on Ser and Thr residues and phosphorylated on Tyr residues. Glycosylated.

Miscellaneous. Lacks the third SRCR domain and doesn’t bind ALCAM/CD166. Doesn’t localize to the immunological synapse. Lacks the third SRCR domain and doesn’t bind ALCAM/CD166. Doesn’t localize to the immunological synapse. Constitutes the only expressed species in a small percentage of T-cells.

Isoforms (7)

UniProt ID	Names	Canonical?
P30203-1	CD6A	yes
P30203-2	CD6B
P30203-3	CD6C
P30203-4	CD6D
P30203-5	CD6E
P30203-6	6, CD6deltaD3Ex6
P30203-7	7, CD6deltaD3

RefSeq proteins (3): NP_001241679, NP_001241680, NP_006716* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001190	SRCR	Domain
IPR036772	SRCR-like_dom_sf	Homologous_superfamily

Pfam: PF00530

UniProt features (91 total): strand 23, mutagenesis site 12, disulfide bond 11, glycosylation site 8, splice variant 6, sequence variant 6, helix 6, region of interest 3, compositionally biased region 3, domain 3, chain 2, topological domain 2, sequence conflict 2, signal peptide 1, modified residue 1, transmembrane region 1, turn 1

Structure

Experimental structures (PDB)

1 structures by resolution:

PDB	Title	Method	Resolution (Å)
5A2E	Extracellular SRCR domains of human CD6	X-RAY DIFFRACTION	3.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30203-F1	66.14	0.42

Human Protein Atlas

Protein class: CD markers, Predicted membrane proteins, Predicted secreted proteins

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH enhanced

Functional residue map

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

Post-translational modifications (1)

Type	Positions
Phosphotyrosine	662

Disulfide bonds (11)

Type	Positions
Disulfide bond	54–88, 70–144, 83–155, 129–137, 170–204, 186–249, 199–259, 230–240, 290–350, 303–360, 330–340

Glycosylation sites (8)

Type	Positions
N-linked (glcnac…) asparagine	28, 49, 112, 118, 229, 339, 345, 368

Mutagenesis-validated functional residues (12)

Position	Phenotype
291	strongly reduces interaction with alcam.
293	reduces interaction with alcam.
295	abolishes interaction with alcam.
298	nearly abolishes interaction with alcam.
314	reduces interaction with alcam.
327	nearly abolishes interaction with alcam.
329	reduces interaction with alcam.
346	strongly reduces interaction with alcam.
349	reduces interaction with alcam.
352	reduces interaction with alcam.
353	reduces interaction with alcam.
662	reduces tyrosine phosphorylation. reduces affinity for lcp2. impairs activation of t-cells.

Function

Pathways and Gene Ontology

Reactome pathways

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

MSigDB gene sets: 276 (showing top): FERRANDO_TAL1_NEIGHBORS, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, MORF_FLT1, GOBP_HETEROPHILIC_CELL_CELL_ADHESION, GOBP_INFLAMMATORY_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, MODULE_45, MODULE_64, GOCC_CELL_SURFACE, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, RACCACAR_AML_Q6, GOBP_VESICLE_MEDIATED_TRANSPORT, MORF_ESR1

GO Biological Process (12): immunological synapse formation (GO:0001771), adaptive immune response (GO:0002250), acute inflammatory response to antigenic stimulus (GO:0002438), heterophilic cell-cell adhesion (GO:0007157), lipopolysaccharide-mediated signaling pathway (GO:0031663), response to lipopolysaccharide (GO:0032496), positive regulation of T cell proliferation (GO:0042102), innate immune response (GO:0045087), positive regulation of cytokine production involved in inflammatory response (GO:1900017), immune system process (GO:0002376), cell adhesion (GO:0007155), vesicle-mediated transport (GO:0016192)

GO Molecular Function (6): lipopolysaccharide binding (GO:0001530), scavenger receptor activity (GO:0005044), protein kinase binding (GO:0019901), identical protein binding (GO:0042802), lipoteichoic acid binding (GO:0070891), protein binding (GO:0005515)

GO Cellular Component (6): immunological synapse (GO:0001772), extracellular region (GO:0005576), plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), T cell receptor complex (GO:0042101)

GO top-level categories

33 GO namespaces:

Category	Terms
cellular anatomical structure	4
immune response	2
cellular process	2
carbohydrate derivative binding	2
cell-cell recognition	1
lymphocyte activation	1
inflammatory response to antigenic stimulus	1
acute inflammatory response	1
cell-cell adhesion	1
cell surface receptor signaling pathway	1
cellular response to lipopolysaccharide	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
T cell proliferation	1
regulation of T cell proliferation	1
positive regulation of lymphocyte proliferation	1
positive regulation of T cell activation	1
defense response to symbiont	1
positive regulation of cytokine production	1
cytokine production involved in inflammatory response	1
regulation of cytokine production involved in inflammatory response	1
biological_process	1
transport	1
lipid binding	1
cargo receptor activity	1
kinase binding	1
protein binding	1
binding	1
plasma membrane	1
membrane	1
cell periphery	1
plasma membrane signaling receptor complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 12 of 24 annotations. The rest are phylogenetic / computational / electronic (IEA).

12 experimentally-supported GO terms:

GO term	NS	Evidence
acute inflammatory response to antigenic stimulus	BP	direct assay
heterophilic cell-cell adhesion	BP	mutant phenotype
immunological synapse formation	BP	mutant phenotype
lipopolysaccharide-mediated signaling pathway	BP	direct assay
positive regulation of T cell proliferation	BP	mutant phenotype
positive regulation of cytokine production involved in inflammatory response	BP	direct assay
response to lipopolysaccharide	BP	direct assay
immunological synapse	CC	direct assay
plasma membrane	CC	direct assay
identical protein binding	MF	physical interaction
lipopolysaccharide binding	MF	direct assay
lipoteichoic acid binding	MF	mutant phenotype

Protein interactions and networks

STRING

showing 15 of 1,278 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD6	ALCAM	Q13740	948
CD6	SLC15A3	Q8IY34	766
CD6	CD2	P06729	652
CD6	CLEC16A	Q2KHT3	623
CD6	CD5	P06127	611
CD6	CD58	P19256	608
CD6	CNTN6	Q9UQ52	592
CD6	TAMALIN	Q7Z6J2	570
CD6	IFNG	P01579	560
CD6	CD7	P09564	558
CD6	CD4	P01730	557
CD6	CDCP1	Q9H5V8	548
CD6	CD8A	P01732	540
CD6	GPC5	P78333	519
CD6	IRF8	Q02556	497

IntAct

Human interaction partners of CD6 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

8 partners by confidence:

Partner	Interaction type	MIscore	Records
ALCAM	direct interaction	0.850	5
LGALS1	direct interaction	0.560	2
LGALS3	direct interaction	0.560	2
LCP2	physical association	0.500	2
SDCBP	colocalization	0.460	2
GYG1	physical association	0.370	1
NFE2L1	physical association	0.370	1
CIBAR1	association	0.350	1

BioGRID (153 interactions; top human partners by supporting records): ALCAM (Reconstituted Complex; 2 records), ABT1 (Affinity Capture-MS), AGAP1 (Affinity Capture-MS), AGAP3 (Affinity Capture-MS), AHDC1 (Affinity Capture-MS), AMPD2 (Affinity Capture-MS), APTX (Affinity Capture-MS), ARHGEF40 (Affinity Capture-MS), ARRB2 (Affinity Capture-MS), ATF1 (Affinity Capture-MS), AURKA (Affinity Capture-MS), BBX (Affinity Capture-MS), BMI1 (Affinity Capture-MS), BTRC (Affinity Capture-MS), CAMKV (Affinity Capture-MS)

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
ALCAM	receptor

Disease & clinical

Genetic variants

Variant evidence for CD6: 119 ClinVar records (0 pathogenic / likely pathogenic); 18 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	85
Likely benign	9
Benign	12

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 40 predictions of 1,076):

Position(s)	Effect	Δscore	Sites
11:60971915–60971916	donor_loss	1.0000	3
11:61017757–61017758	acceptor_loss	1.0000	4
11:61018014–61018015	donor_loss	1.0000	3
11:60971915	donor_loss	0.9900
11:61013421–61013422	acceptor_loss	0.9900	6
11:61013564–61013565	donor_loss	0.9900	4
11:61013917–61013918	acceptor_loss	0.9900	6
11:61015836–61015837	donor_loss	0.9900	6
11:61015840	donor_loss	0.9900	2
11:61017551–61017552	donor_loss	0.9900	5

AlphaMissense

1,036 missense substitutions predicted likely pathogenic (of 4,336 scored), across 278 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
D254	8	0.980	0.993
D194	8	0.955	0.988
D187	8	0.948	0.992
D188	8	0.943	0.988
D191	8	0.919	0.984
D226	8	0.911	0.979
H251	8	0.894	0.964
C330	7	0.996	0.999
C290	7	0.995	0.998
C186	7	0.994	0.998
C230	7	0.993	0.998
C303	7	0.993	0.998
C340	7	0.993	0.997
W190	7	0.992	1.000
C350	7	0.992	0.997
C259	7	0.991	0.997
C360	7	0.991	0.998
C199	7	0.990	0.997
C240	7	0.989	0.994
C249	7	0.987	0.994

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

5 prognostic cancer types:

Cancer	Prognostic	p-value
Head and Neck Squamous Cell Carcinoma (TCGA)	favorable	1.42e-05
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	favorable	7.7e-05
Breast Invasive Carcinoma (TCGA)	favorable	0.000212
Skin Cutaneous Melanoma (TCGA)	favorable	0.000631
Liver Hepatocellular Carcinoma (validation)	favorable	0.000648

Disease associations

OMIM: gene MIM:186720 | disease phenotypes:

GWAS associations

18 associations:

Study	Trait	p-value
GCST009597_176	Multiple sclerosis	2e-29
GCST005531_54	Multiple sclerosis	4e-23
GCST005537_193	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	5e-15
GCST001725_10	Inflammatory bowel disease	9e-13
GCST90002388_180	Lymphocyte count	1e-12
GCST001198_59	Multiple sclerosis	2e-11
GCST000949_2	Multiple sclerosis	1e-9
GCST006195_19	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	3e-9
GCST000424_11	Multiple sclerosis	4e-9
GCST003854_10	Gut microbiota (functional units)	2e-7
GCST005531_79	Multiple sclerosis	2e-7
GCST003854_47	Gut microbiota (functional units)	1e-6
GCST003855_17	Gut microbiota (bacterial taxa)	1e-6
GCST003855_18	Gut microbiota (bacterial taxa)	1e-6
GCST003855_19	Gut microbiota (bacterial taxa)	1e-6
GCST004131_121	Inflammatory bowel disease	2e-6
GCST006192_17	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	3e-6
GCST003854_35	Gut microbiota (functional units)	5e-6

EFO canonical traits (from GWAS)

4 canonical traits:

EFO ID	Trait name
EFO:0007874	gut microbiome measurement
EFO:0006335	systolic blood pressure
EFO:0006527	smoking status measurement
EFO:0004587	lymphocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712853 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the CD6 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.

2 curated-mechanism drugs:

Drug	Modality	Max phase
ITOLIZUMAB	Antibody	3
ONCOLYSIN CD6	Unknown	2

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — CD molecules

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
itolizumab	Binding	7.22	pKi

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation	2
Nickel	increases expression	2
GSK-J4	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
sodium arsenite	affects expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	affects methylation, increases abundance	1
Arsenic	decreases methylation	1
Aspirin	decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression, affects response to substance, increases expression	1
Methapyrilene	increases methylation	1
Tamoxifen	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Antirheumatic Agents	decreases expression	1
Particulate Matter	affects methylation, increases abundance	1

Clinical trials (associated diseases)

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