BTNL8

Summary

BTNL8 (butyrophilin like 8, HGNC:26131) is a protein-coding gene on chromosome 5q35.3, encoding Butyrophilin-like protein 8 (Q6UX41). May stimulate primary immune response.

Predicted to enable signaling receptor binding activity. Predicted to be involved in T cell receptor signaling pathway and regulation of cytokine production. Predicted to be located in plasma membrane. Predicted to be active in external side of plasma membrane.

Source: NCBI Gene 79908 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 85 total — 1 likely-pathogenic
• MANE Select transcript: NM_001040462

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26131
Approved symbol	BTNL8
Name	butyrophilin like 8
Location	5q35.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ21458, BTN9.2
Ensembl gene	ENSG00000113303
Ensembl biotype	protein_coding
OMIM	615606
Entrez	79908

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 14 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000231229, ENST00000340184, ENST00000400707, ENST00000503543, ENST00000505126, ENST00000508408, ENST00000511704, ENST00000513442, ENST00000514448, ENST00000533815, ENST00000610640, ENST00000897988, ENST00000897989, ENST00000897990, ENST00000946752, ENST00000946753, ENST00000946754

RefSeq mRNA: 6 — MANE Select: NM_001040462 NM_001040462, NM_001159707, NM_001159708, NM_001159709, NM_001159710, NM_024850

CCDS: CCDS43413, CCDS4459, CCDS54956, CCDS54957, CCDS54958, CCDS54959

Canonical transcript exons

ENST00000340184 — 8 exons

Exon	Start	End
ENSE00001671084	180908586	180908933
ENSE00002045039	180899159	180899359
ENSE00003477752	180948920	180948946
ENSE00003484484	180949904	180950906
ENSE00003514662	180948355	180948375
ENSE00003528187	180949239	180949265
ENSE00003561666	180947512	180947625
ENSE00003610583	180911339	180911614

Expression profiles

Bgee: expression breadth ubiquitous, 161 present calls, max score 95.18.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.2311 / max 356.0594, expressed in 110 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60666	0.6917	90
60665	0.3303	16
60663	0.1890	15
60664	0.0125	9
203824	0.0075	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	95.18	gold quality
rectum	UBERON:0001052	91.97	gold quality
duodenum	UBERON:0002114	91.96	gold quality
ileal mucosa	UBERON:0000331	91.52	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.42	gold quality
blood	UBERON:0000178	86.70	gold quality
jejunal mucosa	UBERON:0000399	86.66	gold quality
small intestine	UBERON:0002108	86.62	gold quality
transverse colon	UBERON:0001157	83.19	gold quality
colonic mucosa	UBERON:0000317	81.81	gold quality
mucosa of paranasal sinus	UBERON:0005030	80.38	gold quality
type B pancreatic cell	CL:0000169	79.21	gold quality
germinal epithelium of ovary	UBERON:0001304	79.15	silver quality
olfactory bulb	UBERON:0002264	79.05	gold quality
mucosa of sigmoid colon	UBERON:0004993	78.83	gold quality
gall bladder	UBERON:0002110	78.45	gold quality
superficial temporal artery	UBERON:0001614	76.84	gold quality
lower lobe of lung	UBERON:0008949	76.76	silver quality
jejunum	UBERON:0002115	76.58	gold quality
right lung	UBERON:0002167	76.39	gold quality
intestine	UBERON:0000160	75.95	gold quality
epithelium of nasopharynx	UBERON:0001951	75.50	gold quality
tongue squamous epithelium	UBERON:0006919	74.54	gold quality
bone marrow	UBERON:0002371	74.43	gold quality
granulocyte	CL:0000094	73.79	gold quality
right testis	UBERON:0004534	73.70	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	72.84	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.82	gold quality
left testis	UBERON:0004533	72.75	gold quality
large intestine	UBERON:0000059	72.39	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.25

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

49 targeting BTNL8, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-2054	99.20	68.89	1699
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-8066	99.05	68.66	1532
HSA-MIR-412-3P	98.86	66.89	712
HSA-MIR-6754-3P	98.84	66.60	889
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-6761-5P	98.71	68.03	1504
HSA-MIR-6811-3P	98.62	66.54	944
HSA-MIR-934	98.49	70.44	581
HSA-MIR-326	98.25	66.44	1565
HSA-MIR-660-3P	98.14	66.04	1434
HSA-MIR-3130-5P	98.14	66.00	711
HSA-MIR-1245B-3P	98.01	68.91	1387
HSA-MIR-299-3P	97.73	66.67	773
HSA-MIR-4482-5P	97.53	65.68	598
HSA-MIR-4712-5P	97.24	67.79	775
HSA-MIR-770-5P	97.24	68.10	758
HSA-MIR-6748-3P	97.20	65.66	836

Literature-anchored findings (GeneRIF, showing 2)

• Data suggest that butyrophilin-like molecule BTNL8 may play an essential role in priming of naive T lymphocytes. (PMID:24036152)
• analysis of genomic information from multiple non-cancer cohorts showed that both the NEGR1 promoter deletion and the BTNL3-8 deletion were CNVs occurring at high frequencies in the general population. Intriguingly, the upstream NEGR1 CNV deletion was homozygous in ~ 40% of individuals in the non-cancer population. (PMID:32375678)

Cross-species orthologs

0 orthologs

Paralogs (15): BTN3A1 (ENSG00000026950), CD276 (ENSG00000103855), BTN3A3 (ENSG00000111801), BTN2A1 (ENSG00000112763), HHLA2 (ENSG00000114455), BTN2A2 (ENSG00000124508), BTN1A1 (ENSG00000124557), VTCN1 (ENSG00000134258), ICOSLG (ENSG00000160223), ERMAP (ENSG00000164010), BTNL9 (ENSG00000165810), BTNL3 (ENSG00000168903), BTN3A2 (ENSG00000186470), BTNL2 (ENSG00000204290), MOG (ENSG00000204655)

Protein

Protein identifiers

Butyrophilin-like protein 8 — Q6UX41 (reviewed: Q6UX41)

All UniProt accessions (3): D6R9I8, D6RIR7, Q6UX41

UniProt curated annotations — full annotation on UniProt →

Function. May stimulate primary immune response. Acts on T-cell stimulated sub-optimally through the TCR/CD3 complex stimulating their proliferation and cytokine production.

Subcellular location. Membrane.

Tissue specificity. Expressed in neutrophils. Isoforms 1 and 5 are expressed at high levels in the colon, lung,testis, lymph nodes and thyroid tissue. Isoform 5, but not isoform 1, is detected in spleen.

Induction. Down-regulated in neutrophils after treatment with LPS and TNF.

Similarity. Belongs to the immunoglobulin superfamily. BTN/MOG family.

Isoforms (7)

UniProt ID	Names	Canonical?
Q6UX41-1	1, BTN-like	yes
Q6UX41-2	2
Q6UX41-3	3
Q6UX41-4	4
Q6UX41-5	5, B7-like
Q6UX41-6	6
Q6UX41-7	7

RefSeq proteins (6): NP_001035552, NP_001153179, NP_001153180, NP_001153181, NP_001153182, NP_079126 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001870	B30.2/SPRY	Domain
IPR003599	Ig_sub	Domain
IPR003877	SPRY_dom	Domain
IPR003879	Butyrophylin_SPRY	Domain
IPR006574	PRY	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR043136	B30.2/SPRY_sf	Homologous_superfamily
IPR050504	IgSF_BTN/MOG-like	Family
IPR053896	BTN3A2-like_Ig-C	Domain

Pfam: PF00622, PF07686, PF13765, PF22705

UniProt features (27 total): splice variant 8, sequence variant 5, domain 3, disulfide bond 2, topological domain 2, signal peptide 1, chain 1, glycosylation site 1, sequence conflict 1, transmembrane region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UX41-F1	86.68	0.66

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 (2): 40–114, 154–206

Glycosylation sites (1): 103

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-8851680	Butyrophilin (BTN) family interactions
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 64 (showing top): REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOCC_CELL_SURFACE, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_CYTOKINE_PRODUCTION, GOBP_ADAPTIVE_IMMUNE_RESPONSE, GOBP_T_CELL_RECEPTOR_SIGNALING_PATHWAY, SABATES_COLORECTAL_ADENOMA_DN, GOMF_SIGNALING_RECEPTOR_BINDING, GOBP_T_CELL_SELECTION, GOCC_SIDE_OF_MEMBRANE, CAMPS_COLON_CANCER_COPY_NUMBER_DN, GOBP_T_CELL_DIFFERENTIATION, GOBP_LYMPHOCYTE_DIFFERENTIATION, GOBP_ACTIVATION_OF_IMMUNE_RESPONSE

GO Biological Process (5): regulation of cytokine production (GO:0001817), adaptive immune response (GO:0002250), extrathymic T cell selection (GO:0045062), T cell receptor signaling pathway (GO:0050852), immune system process (GO:0002376)

GO Molecular Function (2): signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Adaptive Immune System	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytokine production	1
regulation of gene expression	1
regulation of multicellular organismal process	1
immune response	1
extrathymic T cell differentiation	1
T cell selection	1
antigen receptor-mediated signaling pathway	1
biological_process	1
protein binding	1
binding	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

522 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BTNL8	XDH	P47989	969
BTNL8	PLIN2	Q99541	917
BTNL8	MFGE8	Q08431	778
BTNL8	MUC1	P13931	595
BTNL8	LTF	P02788	584
BTNL8	GOT2	P00505	546
BTNL8	CIDEA	O60543	508
BTNL8	MUC15	Q8N387	506
BTNL8	OMG	P23515	492
BTNL8	AASDH	Q4L235	466
BTNL8	LALBA	P00709	445
BTNL8	HLA-A	P01891	440
BTNL8	PLIN1	O60240	438
BTNL8	HLA-DRB1	P01911	432
BTNL8	CD1D	P15813	432

IntAct

17 interactions, top by confidence:

A	B	Type	Score
BTNL8	TFF1	psi-mi:“MI:0915”(physical association)	0.540
BTNL8	TFF1	psi-mi:“MI:0407”(direct interaction)	0.540
TFF1	BTNL8	psi-mi:“MI:0407”(direct interaction)	0.540
BTNL8	BTNL3	psi-mi:“MI:0915”(physical association)	0.400
LILRB2	BTNL8	psi-mi:“MI:0915”(physical association)	0.400
GP6	BTNL8	psi-mi:“MI:0915”(physical association)	0.400
LILRA1	BTNL8	psi-mi:“MI:0915”(physical association)	0.400
LILRA3	BTNL8	psi-mi:“MI:0915”(physical association)	0.400
BTNL8	LILRB1	psi-mi:“MI:0915”(physical association)	0.400
BTNL8	LILRB3	psi-mi:“MI:0915”(physical association)	0.400
BTNL8	SIGLEC6	psi-mi:“MI:0915”(physical association)	0.400
FCGR2A	BTNL8	psi-mi:“MI:0915”(physical association)	0.400
BTNL8	TMEM131L	psi-mi:“MI:0914”(association)	0.350

BioGRID (108): ATRN (Affinity Capture-MS), KIAA0922 (Affinity Capture-MS), CACNA2D2 (Affinity Capture-MS), TCTN2 (Affinity Capture-MS), TMEM87A (Affinity Capture-MS), ITGA2 (Affinity Capture-MS), MFAP3 (Affinity Capture-MS), CNTNAP3 (Affinity Capture-MS), PTK7 (Affinity Capture-MS), DNAJC16 (Affinity Capture-MS), ITGA6 (Affinity Capture-MS), SCARB1 (Affinity Capture-MS), SCAP (Affinity Capture-MS), MR1 (Affinity Capture-MS), TMEM106B (Affinity Capture-MS)

ESM2 similar proteins: A0A0B4J1G0, A0A0B4J1L0, A0A0G2KBC9, A1YIY0, A8MTB9, B6A8R8, C0HJX2, C0HJX3, E2RP87, H0VDZ8, P08637, P09326, P12314, P23505, P26151, P43626, P43627, P43628, P43631, P43632, P83555, P83556, Q01965, Q13291, Q14952, Q14953, Q14954, Q28942, Q2YHT5, Q61400, Q61450, Q640U3, Q68EV1, Q68SN8, Q6UX41, Q6UXE8, Q6UY09, Q6XJV4, Q6XPU4, Q7TST0

Diamond homologs: A0A0E4BZH1, A4QPC6, A7TZE6, A7TZF0, A7TZF3, A7TZG1, A7TZG3, A7XUX6, A7XUY5, A7XUZ6, A7XV04, A7XV07, A7XV14, A8MVZ5, O00478, O00481, O70355, P18892, P55803, P78410, Q13410, Q16653, Q29ZQ1, Q5R7W8, Q5R960, Q5R996, Q61885, Q62556, Q63345, Q6MG97, Q6UX41, Q6UXE8, Q6UXG8, Q7KYR7, Q7TST0, Q8BJE2, Q8WVV5, Q96KV6, Q96PL5, Q9BGS7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 11 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
immune response-regulating signaling pathway	6	248.4×	3e-12
adaptive immune response	5	38.3×	3e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	66
Likely benign	11
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4682632	GRCh37/hg19 5q35.3(chr5:179042971-180407217)x1	Likely pathogenic

SpliceAI

1400 predictions. Top by Δscore:

Variant	Effect	Δscore
5:180947624:GT:G	donor_gain	1.0000
5:180948910:T:TA	acceptor_gain	1.0000
5:180948918:A:AG	acceptor_gain	1.0000
5:180948919:G:GG	acceptor_gain	1.0000
5:180948919:GA:G	acceptor_gain	1.0000
5:180949415:GGT:G	donor_gain	1.0000
5:180949892:ACC:A	acceptor_gain	1.0000
5:180949894:C:A	acceptor_gain	1.0000
5:180908929:GTCAG:G	donor_loss	0.9900
5:180908934:GTCA:G	donor_loss	0.9900
5:180908935:T:A	donor_loss	0.9900
5:180911337:A:AG	acceptor_gain	0.9900
5:180911337:A:G	acceptor_loss	0.9900
5:180911338:G:GA	acceptor_gain	0.9900
5:180911338:GCA:G	acceptor_gain	0.9900
5:180911338:GCACT:G	acceptor_gain	0.9900
5:180911340:ACTG:A	acceptor_gain	0.9900
5:180911611:GGAG:G	donor_gain	0.9900
5:180911612:GAGG:G	donor_gain	0.9900
5:180911613:AGG:A	donor_loss	0.9900
5:180911615:G:A	donor_loss	0.9900
5:180947626:G:GG	donor_gain	0.9900
5:180947756:G:GG	donor_gain	0.9900
5:180948918:AGACT:A	acceptor_gain	0.9900
5:180948919:GAC:G	acceptor_gain	0.9900
5:180948919:GACT:G	acceptor_gain	0.9900
5:180948919:GACTG:G	acceptor_gain	0.9900
5:180948944:CAG:C	donor_loss	0.9900
5:180948945:AG:A	donor_loss	0.9900
5:180948946:GG:G	donor_loss	0.9900

AlphaMissense

3278 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:180908699:T:C	F55L	0.971
5:180908701:C:A	F55L	0.971
5:180908701:C:G	F55L	0.971
5:180950014:T:C	F325L	0.965
5:180950016:T:A	F325L	0.965
5:180950016:T:G	F325L	0.965
5:180911442:G:C	W167C	0.960
5:180911442:G:T	W167C	0.960
5:180950047:T:C	F336L	0.960
5:180950049:C:A	F336L	0.960
5:180950049:C:G	F336L	0.960
5:180950299:T:C	F420L	0.957
5:180950301:C:A	F420L	0.957
5:180950301:C:G	F420L	0.957
5:180950070:G:C	W343C	0.953
5:180950070:G:T	W343C	0.953
5:180911440:T:A	W167R	0.951
5:180911440:T:C	W167R	0.951
5:180950068:T:A	W343R	0.945
5:180950068:T:C	W343R	0.945
5:180911401:T:A	C154S	0.940
5:180911402:G:C	C154S	0.940
5:180908702:T:C	F56L	0.935
5:180908704:C:A	F56L	0.935
5:180908704:C:G	F56L	0.935
5:180908788:G:C	R84S	0.934
5:180908788:G:T	R84S	0.934
5:180908876:T:A	C114S	0.933
5:180908877:G:C	C114S	0.933
5:180911418:G:C	W159C	0.933

dbSNP variants (sampled 300 via entrez): RS1000087075 (5:180908570 G>A,C,T), RS1000164800 (5:180907313 A>C,G), RS1000203615 (5:180928264 C>T), RS1000255270 (5:180900929 C>G), RS1000295706 (5:180940842 A>G), RS1000324464 (5:180934001 C>T), RS1000447527 (5:180941045 T>C), RS1000461621 (5:180897568 G>A), RS1000472582 (5:180941539 A>G), RS1000587643 (5:180949344 G>A), RS1000628466 (5:180913825 A>C), RS1000720839 (5:180927954 C>G,T), RS1000765442 (5:180908157 A>C), RS1000779567 (5:180921114 G>T), RS1000831037 (5:180909265 C>G,T)

Disease associations

OMIM: gene MIM:615606 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_501	Blood protein levels	1.000000e-28

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — Butyrophilin and butyrophilin-like proteins

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	3
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
potassium chromate(VI)	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
bisphenol S	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	decreases expression	1
Estradiol	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1
Phenobarbital	affects expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tretinoin	increases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases methylation	1
Gold Compounds	increases expression	1
Okadaic Acid	decreases expression	1
Magnetite Nanoparticles	increases expression	1

Clinical trials (associated diseases)

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