CD40LG

Summary

CD40LG (CD40 ligand, HGNC:11935) is a protein-coding gene on chromosome Xq26.3, encoding CD40 ligand (P29965). Cytokine that acts as a ligand to CD40/TNFRSF5. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is expressed on the surface of T cells. It regulates B cell function by engaging CD40 on the B cell surface. A defect in this gene results in an inability to undergo immunoglobulin class switch and is associated with hyper-IgM syndrome.

Source: NCBI Gene 959 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyper-IgM syndrome type 1 (Definitive, ClinGen)
• GWAS associations: 4
• Clinical variants (ClinVar): 355 total — 79 pathogenic, 31 likely-pathogenic (top 9% of genes corpus-wide)
• GTEx eGene: eQTL in 4 tissues, sQTL in 0 (q < 0.05)
• Phenotypes (HPO): 56
• Drug target: yes — 6 curated mechanism-of-action drugs
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000074
• Interaction hub: 2,818 STRING partners (top 3% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11935
Approved symbol	CD40LG
Name	CD40 ligand
Location	Xq26.3
Locus type	gene with protein product
Status	Approved
Aliases	CD40L, TRAP, gp39, hCD40L, CD154, CD40-L, HIGM1, T-BAM
Ensembl gene	ENSG00000102245
Ensembl biotype	protein_coding
OMIM	300386
Entrez	959

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000370629

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

ENST00000370629, ENST00000370628, ENST00000695724, ENST00000695725, ENST00000695726, ENST00000695727, ENST00000695728, ENST00000695729, ENST00001132969

RefSeq mRNA: 1 — MANE Select: NM_000074 NM_000074

CCDS: CCDS14659

Canonical transcript exons

ENST00000370629 — 5 exons

Exon	Start	End
ENSE00000677016	136650266	136650397
ENSE00000677017	136654373	136654430
ENSE00000677018	136656356	136656418
ENSE00001125156	136659039	136660390
ENSE00001453187	136648158	136648404

Expression profiles

Bgee: expression breadth ubiquitous, 124 present calls, max score 87.82.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 5.0913 / max 815.4538, expressed in 150 samples.

Highest expression (Bgee): granulocyte, lymph node, blood, vermiform appendix, rectum.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CD40LG is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 4 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

4 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Ovary	eqtl	1.0e-02	-1.52	X:137352605:A:C
Spleen	eqtl	2.8e-02	+0.44	X:136672942:A:G
Skin Sun Exposed Lower leg	eqtl	3.4e-02	+0.33	X:136678241:A:G
Small Intestine Terminal Ileum	eqtl	4.2e-02	-0.35	X:137379700:G:A

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
197721	4.1941	142
197722	0.8972	81

Top tissues by expression

showing 100 of 278 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	87.82	gold quality
lymph node	UBERON:0000029	78.93	gold quality
blood	UBERON:0000178	76.57	gold quality
vermiform appendix	UBERON:0001154	74.90	gold quality
rectum	UBERON:0001052	70.28	gold quality
caecum	UBERON:0001153	69.10	gold quality
spleen	UBERON:0002106	68.19	gold quality
ileal mucosa	UBERON:0000331	68.09	silver quality
gall bladder	UBERON:0002110	68.03	gold quality
cervix squamous epithelium	UBERON:0006922	67.79	gold quality
mucosa of transverse colon	UBERON:0004991	67.52	gold quality
small intestine Peyer’s patch	UBERON:0003454	65.66	gold quality
small intestine	UBERON:0002108	63.88	gold quality
leukocyte	CL:0000738	62.72	gold quality
bone marrow	UBERON:0002371	62.53	gold quality
colonic epithelium	UBERON:0000397	62.12	silver quality
duodenum	UBERON:0002114	61.46	gold quality
endothelial cell	CL:0000115	60.88	gold quality
bone marrow cell	CL:0002092	60.86	silver quality
mononuclear cell	CL:0000842	60.08	gold quality
tonsil	UBERON:0002372	59.92	gold quality
monocyte	CL:0000576	59.83	gold quality
upper lobe of left lung	UBERON:0008952	58.90	gold quality
right coronary artery	UBERON:0001625	58.36	gold quality
smooth muscle tissue	UBERON:0001135	57.83	gold quality
omental fat pad	UBERON:0010414	57.55	gold quality
peritoneum	UBERON:0002358	57.51	gold quality
upper lobe of lung	UBERON:0008948	57.48	gold quality
adipose tissue of abdominal region	UBERON:0007808	56.69	gold quality
right lung	UBERON:0002167	56.59	gold quality
decidua	UBERON:0002450	56.55	gold quality
calcaneal tendon	UBERON:0003701	56.55	gold quality
endometrium epithelium	UBERON:0004811	56.54	gold quality
mucosa of sigmoid colon	UBERON:0004993	55.81	gold quality
colonic mucosa	UBERON:0000317	55.74	gold quality
transverse colon	UBERON:0001157	55.62	gold quality
intestine	UBERON:0000160	55.40	gold quality
amniotic fluid	UBERON:0000173	54.88	gold quality
mammalian vulva	UBERON:0000997	54.67	gold quality
palpebral conjunctiva	UBERON:0001812	54.63	gold quality
trabecular bone tissue	UBERON:0002483	54.26	gold quality
cervix epithelium	UBERON:0004801	53.85	gold quality
left uterine tube	UBERON:0001303	53.84	gold quality
lung	UBERON:0002048	53.84	gold quality
skin of hip	UBERON:0001554	53.28	silver quality
seminal vesicle	UBERON:0000998	53.09	gold quality
large intestine	UBERON:0000059	52.90	gold quality
hair follicle	UBERON:0002073	52.71	gold quality
colon	UBERON:0001155	52.65	gold quality
urinary bladder	UBERON:0001255	51.98	gold quality
thymus	UBERON:0002370	51.90	gold quality
oviduct epithelium	UBERON:0004804	51.49	gold quality
tendon	UBERON:0000043	51.24	gold quality
uterine cervix	UBERON:0000002	50.88	gold quality
liver	UBERON:0002107	50.86	gold quality
fallopian tube	UBERON:0003889	50.47	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
adipose tissue	UBERON:0001013	50.40	gold quality
connective tissue	UBERON:0002384	50.37	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
subcutaneous adipose tissue	UBERON:0002190	50.10	gold quality
quadriceps femoris	UBERON:0001377	49.95	gold quality
fundus of stomach	UBERON:0001160	49.84	gold quality
coronary artery	UBERON:0001621	49.81	gold quality
left coronary artery	UBERON:0001626	49.65	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
tibialis anterior	UBERON:0001385	49.29	silver quality
blood vessel layer	UBERON:0004797	49.29	gold quality
right lobe of liver	UBERON:0001114	49.27	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
muscle tissue	UBERON:0002385	49.21	gold quality
deltoid	UBERON:0001476	49.20	gold quality
vastus lateralis	UBERON:0001379	49.11	gold quality
esophagus mucosa	UBERON:0002469	48.93	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
vagina	UBERON:0000996	48.70	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
metanephros	UBERON:0000081	48.53	silver quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
body of stomach	UBERON:0001161	48.47	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
right lobe of thyroid gland	UBERON:0001119	48.19	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
epithelial cell of pancreas	CL:0000083	47.93	gold quality
tongue squamous epithelium	UBERON:0006919	47.92	gold quality
stomach	UBERON:0000945	47.90	gold quality
mucosa of urinary bladder	UBERON:0001259	47.80	gold quality
ectocervix	UBERON:0012249	47.79	gold quality
metanephric glomerulus	UBERON:0004736	47.74	gold quality
nasal cavity epithelium	UBERON:0005384	47.70	gold quality
renal glomerulus	UBERON:0000074	47.60	gold quality
skin of abdomen	UBERON:0001416	47.49	gold quality
sigmoid colon	UBERON:0001159	47.44	gold quality
skeletal muscle tissue	UBERON:0001134	47.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-122	yes	58.04
E-CURD-46	yes	36.56
E-HCAD-1	yes	35.74
E-MTAB-8410	yes	15.88
E-ANND-3	yes	5.59

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 70 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Thymus	tissue	14.1
Lymph node	tissue	13.0	medium
Tonsil	tissue	13.0	medium
Appendix	tissue	6.6	not detected
Spleen	tissue	4.2	medium
Small intestine	tissue	2.7	not detected
Rectum	tissue	2.5	low
Urinary bladder	tissue	2.2	not detected
Lung	tissue	2.1	not detected
Gallbladder	tissue	1.8	not detected
Stomach 1	tissue	1.7	not detected
Bone marrow	tissue	1.7	medium
Colon	tissue	1.5	low
Duodenum	tissue	1.5	not detected
Breast	tissue	0.9	not detected
Cerebellum	tissue	0.9	not detected
Liver	tissue	0.9	not detected
Esophagus	tissue	0.8	not detected
Choroid plexus	tissue	0.8
Cervix	tissue	0.7	not detected
Prostate	tissue	0.7	not detected
Olfactory bulb	tissue	0.7
Smooth muscle	tissue	0.6	not detected
Postcentral gyrus	tissue	0.6
Skin 1	tissue	0.5	low
Adipose tissue	tissue	0.5	not detected
Salivary gland	tissue	0.5	not detected
Locus coeruleus	tissue	0.5
Spinal cord	tissue	0.5
Vagina	tissue	0.4	not detected
Basal ganglia	tissue	0.4	not detected
Nucleus accumbens	tissue	0.4
Substantia nigra	tissue	0.4
Thyroid gland	tissue	0.4	not detected
Hippocampus	tissue	0.4	not detected
Prefrontal cortex	tissue	0.3
Cerebral cortex	tissue	0.3	not detected
Ovary	tissue	0.3	not detected
Seminal vesicle	tissue	0.3	not detected
Endometrium 1	tissue	0.3	not detected
Epididymis	tissue	0.3	not detected
Putamen	tissue	0.3
Amygdala	tissue	0.3
Medulla oblongata	tissue	0.3
Kidney	tissue	0.3	not detected
Corpus callosum	tissue	0.3
Hippocampal formation	tissue	0.3
Fallopian tube	tissue	0.3	not detected
Septum	tissue	0.3
Testis	tissue	0.2	not detected
Pons	tissue	0.2
Midbrain	tissue	0.2
Thalamus	tissue	0.2
Hypothalamus	tissue	0.2
Superior colliculi	tissue	0.2
Adrenal gland	tissue	0.2	not detected
Entorhinal cortex	tissue	0.2
Ventral forebrain	tissue	0.2
Retrosplenial and cingulate cortex	tissue	0.2
Periaqueductal gray	tissue	0.2

Brain sub-regions (HPA Brain Atlas): detected in 188; highest nTPM — Flocculonodular lobe (1.1), Median raphe nucleus (0.9), Temporal white matter (0.9), Vermis (0.9), Area postrema (0.8).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets:

Target	Regulation
IGSF6	Repression

Upstream regulators (CollecTRI, top): AKNA, AP1, EGR1, EGR3, FOS, GATA3, JUN, JUND, MITF, NFAM1, NFATC2, NFATC3, NFIL3, NFKB1, NFKB, NR3C1, REL, RELA, STAT1, TFE3, TFEB, USF1, USF2

miRNA regulators (miRDB)

Targeting CD40LG by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 73 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-2682-5P	99.73	67.38	1055
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-377-5P	99.70	65.28	712

Functional genomics

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000370629 — one region, missense o/e 0.69. ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Review. In some cases of CLL the malignant cells express both CD40 and CD154. Implications for autoimmunity and therapy are discussed. (PMID:11042507)
• The capacity of natural killer cells to induce B cell activation is regulated by the interaction of CD40 with its ligand CD154. (PMID:11714772)
• the CD40L gene 3’-flanking region acts as a T cell-specific classical transcriptional enhancer by a NF-kappaB p50-dependent mechanism. (PMID:11751888)
• CD40/CD40L interactions are important for the activation of macrophages as effector cells that mediate inflammation and tissue damage in T cell-mediated inflammatory processes. (PMID:11792121)
• CD40 ligand contacts between fibroblasts and cells secreting IL-4 may promote the profibrotic effects of IL-4 by affecting signal transduction and reducing the anti-fibrotic effects of IFN-gamma. (PMID:11801648)
• CD40L-deficient T cells in carriers of X-linked hyper-IgM syndrome are minimally impaired in comparison with CD40L-expressing T cells in several parameters of T cell priming. (PMID:11801691)
• sCD40L levels in blood, quantities released from platelets ex vivo, and quantities released from SFFLRN stimulated platelets ex vivo were compared for preeclamptic and normal pregnancies. (PMID:11816717)
• CD40:CD40L interactions in X-linked and non-X-linked hyper-IgM syndromes. (PMID:11817328)
• CD40 and CD40L are important in autoimmunity and other immune processes. At least 5 signal transduction pathways are involved. (PMID:11826760)
• review of the role of CD154 and the type-1 cytokine response (PMID:11865444)
• CD40L appears to be an alphaIIbbeta3 integrin ligand, a platelet agonist, and necessary for stability of arterial thrombi. (PMID:11875495)
• Latent sensitivity to Fas-mediated apoptosis after CD40 ligation may explain activity of CD154 gene therapy in chronic lymphocytic leukemia (PMID:11891278)
• Role of surface IgM and IgD on survival/apoptosis of B-cell chronic lymphocytic leukemia cells. (PMID:11902141)
• Association of CD40 ligand expression on HTLV-I-infected T cells and maturation of dendritic cells. (PMID:11902332)
• dinucleotide microsatellite in multiple sclerosis (PMID:11918631)
• Elevated soluble CD40 ligand is related to the endothelial adhesion molecules in patients with acute coronary syndrome. (PMID:11922919)
• Burkitt lymphoma cell population depletion activates autonomous CD154-dependent survival. (PMID:11964311)
• role in inducing tissue factor expression in endothelial cells (PMID:11978801)
• Levels of soluble CD40 ligand (CD154) in serum are increased in human immunodeficiency virus type 1-infected patients and correlate with CD4(+) T-cell counts (PMID:11986259)
• Clustering of CD40 ligand is required to form a functional contact with CD40 (PMID:12011072)
• cd154 (cd40 ligand)is expressed during treatment with calcineurin inhibitors after organ transplantation. (PMID:12042657)
• Leishmania priming of human dendritic cells for CD40 ligand-induced interleukin-12p70 secretion is strain and species dependent (PMID:12117904)
• CD40 ligand (CD154) does not contribute to lymphocyte-mediated inhibition of virulent Mycobacterium tuberculosis within human monocytes (PMID:12117990)
• association of a common variant in CD40L with a malaria resistance phenotype (PMID:12140747)
• effect of platelet-derived CD40L on the tissue factor activity of human CD40-positive melanoma cells and monocytes (PMID:12192302)
• In human lung myofibroblasts,CD40 ligand is induced by lipopolysaccharide, thrombin and TNF-alpha. (PMID:12207328)
• CD154 expression in renal cell carcinoma (PMID:12209602)
• Treatment of human gingival fibroblasts with human leukocyte elastase down-regulated CD40 binding to CD40 ligand. HLE treatment of HGF decreases IL-8 and macrophage chemoattractant protein-1 production by HGF when stimulated by CD40L. (PMID:12223522)
• Impact of both donor and recipient strains on cardiac allograft survival after blockade of the cd40 costimulatory pathway (PMID:12352896)
• upregulation of CD40L on platelets triggers CD40L-dependent matrix degradation by vascular endothelial cells (PMID:12379582)
• CD40L induces proliferation, self-renewal, rescue from apoptosis, and production of cytokines by CD40-expressing AML blasts. (PMID:12423681)
• CD40L has a role in activating antigen-presenting cells (APCs) and thereby initiating the human immune response in HIV infection (PMID:12427285)
• findings suggests that there are two groups of immune thrombocytopenic purpura (ITP) patients, one with elevated and one with normal of sCD40L; pathogenesis of ITP may in some patients include alterations of the CD40/CD40L pathway (PMID:12460235)
• CD154 function is determined by binding to PTB and PTB-T and is involved in autoimmune disease (PMID:12509450)
• CD40L expression on CD4+ T-cells is significantly higher in patients with Kawasaki disease (KD) than in the febrile control group, which implies that CD40L over-expression might play a role in the immunopathogenesis of KD. (PMID:12563087)
• CD40L can induce maturation of monocyte-derived dendritic cells and elicit sustained antiviral cytotoxic T lymphocyte responses, either alone or cooperatively with TNF-alpha or RANKL. (PMID:12574344)
• Proapoptotic genes BAX and CD40L are predictors of survival in transitional cell carcinoma of the bladder. (PMID:12592374)
• Serum levels of sCD40L significantly higher in MCTD than in healthy individuals. May play role in pathogenesis of MCTD. (PMID:12605316)
• A key mechanism in the pathogenesis of MS is the increased expression of CD86 and CD40L and the increased production of IL12 during disease progression. (PMID:12672403)
• high shear stress induces CD40L translocation to the platelet surface, which is mediated by the von Willebrand factor (VWF)-GP Ibalpha interaction and enhanced in the presence of a low concentration of epinephrine (PMID:12676191)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cd40lg	ENSMUSG00000031132
rattus_norvegicus	Cd40lg	ENSRNOG00000000871

Paralogs (8): FASLG (ENSG00000117560), TNFSF11 (ENSG00000120659), TNFSF10 (ENSG00000121858), TNFSF14 (ENSG00000125735), TNFSF15 (ENSG00000181634), LTA (ENSG00000226979), LTB (ENSG00000227507), TNF (ENSG00000232810)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88337) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 69 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased IgA level	3
abnormal class switch recombination	3
decreased IgG1 level	3
abnormal immune system physiology	2
decreased IgG level	2
decreased immunoglobulin level	2
decreased IgE level	2
glomerulonephritis	2
absent spleen germinal center	2
decreased IgG3 level	2
decreased platelet aggregation	2
decreased bone mineral density	1
abnormal colon morphology	1
abnormal intestinal mucosa morphology	1
abnormal immune system morphology	1
enlarged spleen	1
enlarged lymph nodes	1
abnormal thalamus morphology	1
weight loss	1
decreased IgM level	1
abnormal antigen presentation	1
abnormal T cell differentiation	1
neurodegeneration	1
abnormal lymph node morphology	1
abnormal bronchus-associated lymphoid tissue morphology	1

+44 more (showing top 25).

Additional cross-species homologs

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

Organism	UniProt	Identity	Method
Macaca mulatta	P63304	100.0%	Diamond
Cercocebus atys	P63305	100.0%	Diamond
Lama glama	P59694	99.6%	Diamond
Camelus bactrianus	Q75N23	99.6%	Diamond
Aotus trivirgatus	Q9BDM3	98.5%	Diamond
Callithrix jacchus	Q9BDN3	98.5%	Diamond
Felis catus	O97605	92.7%	Diamond
Canis lupus familiaris	O97626	92.7%	Diamond
Bos taurus	P51749	92.0%	Diamond
Sus scrofa	Q95MQ5	92.0%	Diamond
Macaca nemestrina	Q9BDM7	91.2%	Diamond
Gallus gallus	Q9I8D8	40.1%	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
MIR934	ncRNA	100126324
VGLL1	protein-coding	51442
ARHGEF6	protein-coding	9459
LINC00892	ncRNA	100128420
HTATSF1	protein-coding	27336

Protein

Protein identifiers

CD40 ligand — P29965 (reviewed: P29965)

Alternative names: T-cell antigen Gp39, TNF-related activation protein, Tumor necrosis factor ligand superfamily member 5

All UniProt accessions (4): P29965, A0A8Q3WKP2, A0A8Q3WL88, Q3L8U2

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine that acts as a ligand to CD40/TNFRSF5. Costimulates T-cell proliferation and cytokine production. Its cross-linking on T-cells generates a costimulatory signal which enhances the production of IL4 and IL10 in conjunction with the TCR/CD3 ligation and CD28 costimulation. Induces the activation of NF-kappa-B. Induces the activation of kinases MAPK8 and PAK2 in T-cells. Induces tyrosine phosphorylation of isoform 3 of CD28. Mediates B-cell proliferation in the absence of co-stimulus as well as IgE production in the presence of IL4. Involved in immunoglobulin class switching. Acts as a ligand for integrins, specifically ITGA5:ITGB1 and ITGAV:ITGB3; both integrins and the CD40 receptor are required for activation of CD40-CD40LG signaling, which have cell-type dependent effects, such as B-cell activation, NF-kappa-B signaling and anti-apoptotic signaling.

Subunit / interactions. Homotrimer. Interacts with isoform 3 of CD28. CD40 ligand, soluble form: Exists as either a monomer or a homotrimer. Forms a ternary complex between CD40 and integrins for CD40-CD40LG signaling.

Subcellular location. Cell membrane. Cell surface Secreted.

Tissue specificity. Specifically expressed on activated CD4+ T-lymphocytes.

Post-translational modifications. The soluble form derives from the membrane form by proteolytic processing. N-linked glycan is a mixture of high mannose and complex type. Glycan structure does not influence binding affinity to CD40. Not O-glycosylated.

Disease relevance. Immunodeficiency with hyper-IgM, type 1 (HIGM1) [MIM:308230] Immunoglobulin isotype switch defect characterized by elevated concentrations of serum IgM and decreased amounts of all other isotypes. Affected males present at an early age (usually within the first year of life) recurrent bacterial and opportunistic infections, including Pneumocystis carinii pneumonia and intractable diarrhea due to cryptosporidium infection. Despite substitution treatment with intravenous immunoglobulin, the overall prognosis is rather poor, with a death rate of about 10% before adolescence. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the tumor necrosis factor family.

RefSeq proteins (1): NP_000065* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003263	CD40L	Family
IPR006052	TNF_dom	Domain
IPR008983	Tumour_necrosis_fac-like_dom	Homologous_superfamily
IPR021184	TNF_CS	Conserved_site

Pfam: PF00229

UniProt features (65 total): sequence variant 35, strand 12, mutagenesis site 4, chain 2, topological domain 2, turn 2, helix 2, glycosylation site 2, transmembrane region 1, domain 1, site 1, disulfide bond 1

Structure

Experimental structures (PDB)

8 structures by resolution:

PDB	Title	Method	Resolution (Å)
6W9G	Crystal Structure of the Fab fragment of humanized 5c8 antibody containing the …	X-RAY DIFFRACTION	1.82
1ALY	CRYSTAL STRUCTURE OF HUMAN CD40 LIGAND	X-RAY DIFFRACTION	2
7SGM	Crystal structure of a Fab variant containing a fluorescent noncanonical amino acid with …	X-RAY DIFFRACTION	2
3LKJ	Small Molecule Inhibition of the TNF Family Cyokine CD40 Ligand Through a Subunit …	X-RAY DIFFRACTION	2.5
6BRB	Novel non-antibody protein scaffold targeting CD40L	X-RAY DIFFRACTION	2.82
1I9R	STRUCTURE OF CD40L IN COMPLEX WITH THE FAB FRAGMENT OF HUMANIZED 5C8 ANTIBODY	X-RAY DIFFRACTION	3.1
9I5N	Single particle cryo electron microscopy of a Fab fragment bound to recombinant human …	ELECTRON MICROSCOPY	3.4
3QD6	Crystal structure of the CD40 and CD154 (CD40L) complex	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P29965-F1	82.34	0.55

Antibody-complex structures (SAbDab)

4 antibodies co-crystallized with this protein: 1I9R, RUPLIZUMAB, TEGOPRUBART, VELAPRUMIG

Human Protein Atlas

Protein class: CD markers, Predicted membrane proteins, Predicted secreted proteins, Predicted intracellular proteins, Cancer-related genes, Candidate cancer biomarkers, Candidate cardiovascular disease genes, Disease related genes, Human disease related genes, Primary immunodeficiency

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): golgi apparatus; plasma membrane

Antibody reliability (HPA): IH enhanced · IF approved

Functional residue map

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

Catalytic / active sites (1)

Position	Role
112–113	cleavage

Disulfide bonds (1)

Type	Positions
Disulfide bond	178–218

Glycosylation sites (2)

Type	Positions
N-linked (glcnac…) (complex) asparagine	240
N-linked (glcnac…) (high mannose) asparagine	240

Mutagenesis-validated functional residues (4)

Position	Phenotype
170	decreases itga5:itgb1 binding, b-cell activation, activation of nf-kappa-b signaling, and anti-apoptotic signaling; in soluble form …
224	decreases itga5:itgb1 binding, b-cell activation, activation of nf-kappa-b signaling, and anti-apoptotic signaling; when associated with …
226	decreases itga5:itgb1 binding, b-cell activation, activation of nf-kappa-b signaling, and anti-apoptotic signaling; when associated with …
252	decreases itga5:itgb1 binding, b-cell activation, activation of nf-kappa-b signaling, and anti-apoptotic signaling; in soluble form. no …

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 7; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

7 pathways:

ID	Pathway	Evidence
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	curated
R-HSA-5676594	TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	curated
R-HSA-5668541	TNFR2 non-canonical NF-kB pathway	curated
R-HSA-1280218	Adaptive Immune System	—
R-HSA-9938027	Affinity selection of immunoglobulins	electronic
R-HSA-1280215	Cytokine Signaling in Immune system	—
R-HSA-168256	Immune System	—

MSigDB gene sets: 413 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_B_CELL_ACTIVATION, GCANCTGNY_MYOD_Q6, GOBP_PLATELET_ACTIVATION, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_LYMPHOCYTE_COSTIMULATION, GOCC_CELL_SURFACE, GOBP_B_CELL_PROLIFERATION, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY

GO Biological Process (23): inflammatory response (GO:0006954), leukocyte cell-cell adhesion (GO:0007159), cell surface receptor signaling pathway (GO:0007166), integrin-mediated signaling pathway (GO:0007229), CD40 signaling pathway (GO:0023035), platelet activation (GO:0030168), T cell costimulation (GO:0031295), positive regulation of interleukin-10 production (GO:0032733), positive regulation of interleukin-12 production (GO:0032735), positive regulation of interleukin-4 production (GO:0032753), B cell proliferation (GO:0042100), positive regulation of T cell proliferation (GO:0042102), negative regulation of apoptotic process (GO:0043066), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), isotype switching (GO:0045190), positive regulation of endothelial cell apoptotic process (GO:2000353), positive regulation of extrinsic apoptotic signaling pathway (GO:2001238), regulation of immune system process (GO:0002682), immune response (GO:0006955), cell communication (GO:0007154), signal transduction (GO:0007165), regulation of gene expression (GO:0010468), signaling (GO:0023052)

GO Molecular Function (7): cytokine activity (GO:0005125), tumor necrosis factor receptor binding (GO:0005164), CD40 receptor binding (GO:0005174), integrin binding (GO:0005178), protein serine/threonine kinase activator activity (GO:0043539), signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (5): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), membrane (GO:0016020), extracellular region (GO:0005576)

Reactome top-level categories

5 top-level categories:

Category	Pathways
Immune System	2
Adaptive Immune System	1
Cytokine Signaling in Immune system	1
TNFR2 non-canonical NF-kB pathway	1
Immunoglobulin maturation	1

GO top-level categories

53 GO namespaces:

Category	Terms
positive regulation of cytokine production	3
cellular anatomical structure	3
cell surface receptor signaling pathway	2
positive regulation of T cell activation	2
immune system process	2
tumor necrosis factor receptor superfamily binding	2
defense response	1
cell-cell adhesion	1
signal transduction	1
cell activation	1
blood coagulation	1
lymphocyte costimulation	1
interleukin-10 production	1
regulation of interleukin-10 production	1
interleukin-12 production	1
regulation of interleukin-12 production	1
interleukin-4 production	1
regulation of interleukin-4 production	1
B cell activation	1
lymphocyte proliferation	1
T cell proliferation	1
regulation of T cell proliferation	1
positive regulation of lymphocyte proliferation	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
somatic recombination of immunoglobulin genes involved in immune response	1
B cell activation involved in immune response	1
positive regulation of apoptotic process	1
endothelial cell apoptotic process	1
regulation of endothelial cell apoptotic process	1
extrinsic apoptotic signaling pathway	1
positive regulation of apoptotic signaling pathway	1
regulation of extrinsic apoptotic signaling pathway	1
regulation of biological process	1
response to stimulus	1
cellular process	1
receptor ligand activity	1
signaling receptor binding	1
protein-containing complex binding	1
cell adhesion molecule binding	1
protein serine/threonine kinase activity	1
protein kinase activator activity	1
protein binding	1
binding	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 17 of 36 annotations. The rest are phylogenetic / computational / electronic (IEA).

17 experimentally-supported GO terms:

GO term	NS	Evidence
B cell proliferation	BP	direct assay
CD40 signaling pathway	BP	direct assay
inflammatory response	BP	direct assay
integrin-mediated signaling pathway	BP	mutant phenotype
negative regulation of apoptotic process	BP	direct assay
platelet activation	BP	direct assay
positive regulation of T cell proliferation	BP	direct assay
positive regulation of endothelial cell apoptotic process	BP	direct assay
positive regulation of interleukin-10 production	BP	direct assay
positive regulation of interleukin-12 production	BP	direct assay
positive regulation of interleukin-4 production	BP	direct assay
cell surface	CC	direct assay
plasma membrane	CC	direct assay
CD40 receptor binding	MF	mutant phenotype
cytokine activity	MF	direct assay
integrin binding	MF	mutant phenotype
protein serine/threonine kinase activator activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,818 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD40LG	CD40	P25942	981
CD40LG	CD4	P01730	935
CD40LG	IFNG	P01579	918
CD40LG	IL4	P05112	900
CD40LG	CD80	P33681	885
CD40LG	CD8A	P01732	879
CD40LG	CD86	P42081	878
CD40LG	IL2	P01585	868
CD40LG	TNF	P01375	867
CD40LG	IL10	P22301	866
CD40LG	ICOS	Q9Y6W8	862
CD40LG	CD28	P10747	857
CD40LG	AICDA	Q9GZX7	854
CD40LG	CD27	P26842	852
CD40LG	CXCR5	P32302	840

IntAct

Human interaction partners of CD40LG in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

1 partners by confidence:

Partner	Interaction type	MIscore	Records
CD40	direct interaction	0.440	1

BioGRID (12 interactions; top human partners by supporting records): RNF128 (Affinity Capture-Western; 2 records), APOA1 (Affinity Capture-Western), BIRC2 (Affinity Capture-Western), BIRC3 (Affinity Capture-Western), CD40 (Affinity Capture-Western), CRYAB (Affinity Capture-MS), DDX58 (Affinity Capture-RNA), HPR (Affinity Capture-Western), PHB (Reconstituted Complex), TRAF1 (Affinity Capture-Western), TRAF2 (Affinity Capture-Western)

SIGNOR signaling

showing 3 of 4 signaling interactions:

A	Effect	B	Mechanism
CD40LG	down-regulates	PTPN7
CD40LG	“up-regulates activity”	CD40	binding
CD40LG	“down-regulates quantity by repression”	IGSF6	“transcriptional regulation”

Ligand–receptor pairs (CellPhoneDB) (3)

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

3 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
ITGB1;ITGA5	ligand
ITGA2B;ITGB3	ligand
CD40	ligand

Disease & clinical

Genetic variants

Variant evidence for CD40LG: 355 ClinVar records (110 pathogenic / likely pathogenic); 4 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	79
Likely pathogenic	31
Uncertain significance	84
Likely benign	86
Benign	20

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 110 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
35812	NM_000074.3(CD40LG):c.31C>T (p.Arg11Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
35814	NM_000074.3(CD40LG):c.761C>T (p.Thr254Met)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
426663	NM_000074.3(CD40LG):c.658C>T (p.Gln220Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
521393	NM_000074.3(CD40LG):c.559del (p.Ala187fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
595194	NM_000074.3(CD40LG):c.347-2A>G	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1327990	NM_000074.3(CD40LG):c.166G>T (p.Glu56Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1444168	NM_000074.3(CD40LG):c.478C>T (p.Gln160Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1997026	NM_000074.3(CD40LG):c.268C>T (p.Gln90Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2431619	NM_000074.3(CD40LG):c.654C>A (p.Cys218Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
191254	NM_000074.3(CD40LG):c.506A>G (p.Tyr169Cys)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
265075	NM_000074.3(CD40LG):c.431G>A (p.Gly144Glu)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
381653	NM_000074.3(CD40LG):c.767T>C (p.Phe256Ser)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
11160	NM_000074.3(CD40LG):c.464T>C (p.Leu155Pro)	Pathogenic	criteria provided, single submitter	2
11168	NM_000074.3(CD40LG):c.368C>A (p.Ala123Glu)	Pathogenic	criteria provided, single submitter	2
280565	NM_000074.3(CD40LG):c.638del (p.Ser213fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore CD40LG’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 33 predictions of 203):

Position(s)	Effect	Δscore	Sites
X:136650260	acceptor_gain	1.0000
X:136650264	acceptor_loss	1.0000	3
X:136650398–136650399	donor_loss	1.0000	5
X:136656354–136656355	acceptor_loss	1.0000	5
X:136648405–136648406	donor_loss	0.9900	5
X:136650265	acceptor_loss	0.9900	2
X:136656355	acceptor_loss	0.9900
X:136656419–136656420	donor_loss	0.9800	5
X:136650265	acceptor_loss	0.9700
X:136654431–136654432	donor_loss	0.9700	5

AlphaMissense

368 missense substitutions predicted likely pathogenic (of 1,733 scored), across 113 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
F229	8	0.863	0.979
F256	8	0.858	0.963
F189	8	0.834	0.956
H125	8	0.826	0.936
W140	7	0.970	0.996
C72	7	0.950	0.982
C84	7	0.920	0.959
F177	7	0.915	0.985
F238	7	0.819	0.959
C178	7	0.812	0.888
F253	7	0.747	0.919
C218	7	0.739	0.836
D62	7	0.706	0.847
G257	6	0.917	0.987
S128	6	0.874	0.983
V241	6	0.834	0.960
F42	6	0.775	0.891
V247	6	0.719	0.929
D51	6	0.635	0.685
Y169	5	0.908	0.977

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

1 prognostic cancer types:

Cancer	Prognostic	p-value
Breast Invasive Carcinoma (TCGA)	favorable	0.000215

Disease associations

OMIM: gene MIM:300386 | disease phenotypes: MIM:308230, MIM:607594

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
hyper-IgM syndrome type 1	Definitive	X-linked	4

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
hyper-IgM syndrome type 1	Definitive	XL

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (5 panels, 4 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

5 panels:

Panel	Rating
COVID-19 research	green
Gastrointestinal epithelial barrier disorders	green
Infantile enterocolitis & monogenic inflammatory bowel disease	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green
Fetal anomalies	amber

Mondo (3): hyper-IgM syndrome type 1 (MONDO:0010626), common variable immunodeficiency (MONDO:0015517), hyper-IgM syndrome (MONDO:0003947)

Orphanet (2): X-linked hyper-IgM syndrome (Orphanet:101088), OBSOLETE: Common variable immunodeficiency (Orphanet:1572)

HPO phenotypes

56 phenotypes (HPO-id order):

HPO	Term
HP:0000155	Oral ulcer
HP:0000230	Gingivitis
HP:0000403	Recurrent otitis media
HP:0000629	Periorbital fullness
HP:0001080	Biliary tract abnormality
HP:0001263	Global developmental delay
HP:0001287	Meningitis
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0001394	Cirrhosis
HP:0001419	X-linked recessive inheritance
HP:0001508	Failure to thrive
HP:0001609	Hoarse voice
HP:0001618	Dysphonia
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001878	Hemolytic anemia
HP:0002014	Diarrhea
HP:0002240	Hepatomegaly
HP:0002376	Developmental regression
HP:0002718	Recurrent bacterial infections
HP:0002720	Decreased circulating IgA concentration
HP:0002721	Immunodeficiency
HP:0002783	Recurrent lower respiratory tract infections
HP:0002847	Impaired memory B cell generation
HP:0002849	Absence of lymph node germinal center
HP:0002959	Impaired Ig class switch recombination
HP:0003261	Increased circulating IgA concentration
HP:0003326	Myalgia
HP:0003496	Increased circulating IgM concentration
HP:0003593	Infantile onset
HP:0004315	Decreased circulating IgG concentration
HP:0005419	Decreased T cell activation
HP:0005479	Decreased circulating IgE concentration
HP:0009071	Inflammatory myopathy
HP:0009098	Recurrent oral thrush
HP:0010280	Stomatitis
HP:0010783	Erythema
HP:0010976	Decreased total B cell count
HP:0011448	Ankle clonus
HP:0011463	Childhood onset
HP:0012115	Hepatitis
HP:0012418	Hypoxemia
HP:0020102	Pneumocystis jirovecii pneumonia
HP:0030234	Highly elevated creatine kinase
HP:0030388	Decreased class-switched memory B cell proportion
HP:0030812	Enlarged tonsils
HP:0030991	Sclerosing cholangitis
HP:0033222	Inverted CD4:CD8 ratio
HP:0034285	Enteroviral encephalitis
HP:0040218	Reduced total natural killer cell count
HP:0100806	Sepsis
HP:0200123	Chronic hepatitis
HP:0410243	Abnormal circulating IgM concentration
HP:5210131	Severe Leishmania infection

GWAS associations

4 associations:

Study	Trait	p-value
GCST009565_1	CD40 ligand levels	1e-25
GCST90002388_378	Lymphocyte count	1e-11
GCST90002400_557	Plateletcrit	5e-10
GCST003097_45	Pediatric autoimmune diseases	1e-8

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0004790	CD40 ligand measurement
EFO:0004587	lymphocyte count
EFO:0007985	platelet crit

MeSH disease descriptors

2 disease descriptors:

Descriptor	Name	Tree numbers
D017074	Common Variable Immunodeficiency	C20.673.330
D053306	Hyper-IgM Immunodeficiency Syndrome	C15.378.147.333.249; C16.320.413; C16.320.798.625; C20.673.430.250; C20.673.795.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL3580491 (SINGLE PROTEIN), CHEMBL4106121 (PROTEIN-PROTEIN INTERACTION), CHEMBL4106122 (PROTEIN-PROTEIN INTERACTION)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the CD40LG 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.

6 curated-mechanism drugs:

Drug	Modality	Max phase
DAPIROLIZUMAB PEGOL	Antibody	3
DAZODALIBEP	Protein	3
RUPLIZUMAB	Antibody	3
RAVAGALIMAB	Antibody	2
TEGOPRUBART	Antibody	2
TORALIZUMAB	Antibody	2

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs1126535	adalimumab	Efficacy	Allele T is associated with increased response to adalimumab in people with Arthritis, Rheumatoid as compared to allele C.	PMID:28639493

Binding affinities (BindingDB)

1 measured of 2 human assays (2 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

8 potent at pChembl≥5 of 13 total, top 8 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.77	IC50	170	nM	CHEMBL4080373
6.51	IC50	310	nM	CHEMBL4060985
6.44	IC50	360	nM	CHEMBL4090673
6.00	IC50	990	nM	CHEMBL4098397
5.65	IC50	2260	nM	CHEMBL4082979
5.63	IC50	2330	nM	CHEMBL4072368
5.35	IC50	4500	nM	CHEMBL4080373
5.03	IC50	9400	nM	CHEMBL4090673

PubChem BioAssay actives

8 with measured affinity, of 46 total; 6 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
8-[[4-[4-[(4-methoxycarbonylbenzoyl)amino]phenyl]benzoyl]amino]naphthalene-1-sulfonic acid	1465876: Inhibition of human Fc-conjugated CD40/FLAG-tagged biotinylated CD40L costimulatory protein-protein interaction incubated for 1 hr by ELISA-type assay	ic50	0.1700	uM
8-[[4-[4-[(4-nitrobenzoyl)amino]phenyl]benzoyl]amino]naphthalene-1-sulfonic acid	1465876: Inhibition of human Fc-conjugated CD40/FLAG-tagged biotinylated CD40L costimulatory protein-protein interaction incubated for 1 hr by ELISA-type assay	ic50	0.3100	uM
4-[[4-[4-[(4-nitrobenzoyl)amino]phenyl]benzoyl]amino]naphthalene-1-carboxylic acid	1465876: Inhibition of human Fc-conjugated CD40/FLAG-tagged biotinylated CD40L costimulatory protein-protein interaction incubated for 1 hr by ELISA-type assay	ic50	0.3600	uM
8-[[4-[4-(1H-benzotriazole-5-carbonylamino)phenyl]benzoyl]amino]naphthalene-1-sulfonic acid	1465876: Inhibition of human Fc-conjugated CD40/FLAG-tagged biotinylated CD40L costimulatory protein-protein interaction incubated for 1 hr by ELISA-type assay	ic50	0.9900	uM
4-hydroxy-7-[[5-hydroxy-7-sulfo-6-[[2-sulfo-4-[(4-sulfophenyl)diazenyl]phenyl]diazenyl]naphthalen-2-yl]carbamoylamino]-3-[[2-sulfo-4-[(4-sulfophenyl)diazenyl]phenyl]diazenyl]naphthalene-2-sulfonic acid	1465876: Inhibition of human Fc-conjugated CD40/FLAG-tagged biotinylated CD40L costimulatory protein-protein interaction incubated for 1 hr by ELISA-type assay	ic50	2.2600	uM
4-[[4-[4-[(4-nitrobenzoyl)amino]phenyl]benzoyl]amino]naphthalene-1-sulfonic acid	1465876: Inhibition of human Fc-conjugated CD40/FLAG-tagged biotinylated CD40L costimulatory protein-protein interaction incubated for 1 hr by ELISA-type assay	ic50	2.3300	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	affects cotreatment, increases expression, decreases expression	3
Air Pollutants	affects expression, increases abundance, increases expression	3
Tetrachlorodibenzodioxin	affects cotreatment, decreases reaction, increases expression, affects activity, increases reaction (+1 more)	3
Atorvastatin	decreases expression	2
Aspirin	decreases expression	2
Doxorubicin	increases expression, decreases reaction, increases cleavage, increases reaction, decreases response to substance (+1 more)	2
Erythrosine	affects binding, decreases reaction	2
Paclitaxel	increases cleavage, increases reaction, decreases response to substance, affects cotreatment, decreases expression (+1 more)	2
Reactive Oxygen Species	decreases expression, affects binding, increases reaction, increases expression, affects cotreatment (+4 more)	2
Particulate Matter	affects expression, decreases methylation, increases expression	2
bisphenol F	decreases expression	1
aminomethylphosphonic acid (AMPA)	increases expression	1
diphenyleneiodonium	affects binding, affects cotreatment, decreases reaction, increases abundance	1
emulphogene BC 720	increases expression	1
gallein	affects binding, decreases reaction	1
3,3’-diindolylmethane	increases expression	1
sodium arsenite	decreases expression	1
indirubin	affects cotreatment, decreases reaction, increases expression	1
diphenyliodonium	affects cotreatment, decreases reaction, increases abundance, increases reaction, increases expression (+1 more)	1
candesartan	decreases expression, increases reaction	1
lipopolysaccharide, E. coli O26-B6	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	increases expression, increases reaction, affects cotreatment, decreases reaction	1
bisphenol S	increases expression	1
Aspirin, Dipyridamole Drug Combination	decreases expression	1
Fingolimod Hydrochloride	decreases expression	1
Clopidogrel	decreases reaction, increases expression	1
Zoledronic Acid	decreases expression	1
Arsenic Trioxide	affects cotreatment, increases expression	1
Vemurafenib	affects cotreatment, increases expression	1
Eptifibatide	decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4688318	Binding	Inhibition of CD40L (unknown origin)	Biologic-like In Vivo Efficacy with Small Molecule Inhibitors of TNFα Identified Using Scaffold Hopping and Structure-Based Drug Design Approaches. — *J Med Chem*

Cellosaurus cell lines

14 cell lines: 10 transformed cell line, 2 cancer cell line, 1 telomerase immortalized cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_2Z02	ID00002	Transformed cell line	Male
CVCL_2Z27	ID00063	Transformed cell line	Male
CVCL_2Z28	ID00064	Transformed cell line	Male
CVCL_4V25	293-CD40L	Transformed cell line	Female
CVCL_4V26	293-CD40L-sCD40L	Transformed cell line	Female
CVCL_A2XK	YK6-CD40Lg-IL21	Telomerase immortalized cell line	Male
CVCL_B8D3	Abcam HCT 116 CD40LG KO	Cancer cell line	Male
CVCL_B9FA	Abcam A-549 CD40LG KO	Cancer cell line	Male
CVCL_E3RF	HS5-CD40L	Transformed cell line	Male
CVCL_E3RI	HS5-CD40L-IL4	Transformed cell line	Male

Clinical trials (associated diseases)

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

45 trials:

NCT	Phase	Status	Title
NCT00520494	Phase 4	COMPLETED	Efficacy and Safety of Vivaglobin® in Previously Untreated Patients With Primary Immunodeficiency
NCT01289847	Phase 4	COMPLETED	A Study to Find Out How Safe and Effective Gammaplex® is in Young People With Primary Immunodeficiency
NCT01946906	Phase 4	COMPLETED	The Rifaximin Study in CVID
NCT05193552	Phase 4	RECRUITING	Usage of Spirometry in Managing IgG Therapy in CVID With Airway Disease
NCT01884311	Phase 3	COMPLETED	Pharmacokinetics (PK) and Safety of Subgam-VF in Primary Immunodeficiency Diseases
NCT00168012	Phase 3	COMPLETED	Efficacy and Safety of Intravenous Immunoglobulin IVIG-F10 in Patients With Primary Immunodeficiencies (PID)
NCT00168025	Phase 3	COMPLETED	Efficacy and Safety of Intravenous Immunoglobulin IgPro10 in Patients With Primary Immunodeficiencies (PID)
NCT00220766	Phase 3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT00322556	Phase 3	COMPLETED	Safety and Efficacy of Intravenous Immunoglobulin IgPro10 in Patients With Primary Immunodeficiencies (PID)
NCT00542997	Phase 3	COMPLETED	Study of Subcutaneous Immune Globulin in Patients Requiring IgG Replacement Therapy
NCT01963143	Phase 3	COMPLETED	Bioequivalence Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Gammaplex® 10 and Gammaplex® 5% in Primary Immunodeficiency Diseases
NCT02247141	Phase 3	COMPLETED	A Multi-centre Open Study to Assess the Safety and Efficacy of Subgam®
NCT00278954	Phase 3	COMPLETED	Efficacy, Safety and Pharmacokinetics of Gammaplex in Primary Immunodeficiency Diseases.
NCT01489618	Phase 2	TERMINATED	Prime Boost Vaccination Strategy Combining Conjugated Anti- Pneumococcal Vaccine (s0) and Polysaccharide Anti- Pneumococcal Vaccine (s4) Compared to Polysaccharide Anti- Pneumococcal Vaccine Alone (s4) In Patients With Common Variable Immunodeficiency
NCT01821781	Phase 2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT02579967	Phase 2	RECRUITING	Pilot Trial of Allogeneic Blood or Marrow Transplantation for Primary Immunodeficiencies
NCT03663933	Phase 2	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Cell Transplantation for Disorders of T-cell Proliferation and/or Dysregulation
NCT04339777	Phase 2	RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Inborn Errors of Immunity
NCT04925375	Phase 2	RECRUITING	Abatacept for the Treatment of Common Variable Immunodeficiency With Interstitial Lung Disease
NCT05593588	Phase 2	ACTIVE_NOT_RECRUITING	Senolytics Treatment of Interstitial Lung Disease in Common Variable Immunodeficiency
NCT06897358	Phase 2	COMPLETED	Leniolisib for Immune Dysregulation in CVID
NCT07284641	Phase 2	RECRUITING	Hematopoietic Stem Cell Transplantation (HSCT) for Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD)
NCT00263237	Phase 1	COMPLETED	STA-5326 Meslylate to Treat Gut Inflammation Associated With Common Variable Immunodeficiency
NCT00004341	Not specified	UNKNOWN	Study of Genetic and Molecular Defects in Primary Immunodeficiency Disorders
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT01852370	Phase 1/2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT03513328	Phase 1/2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT00004695	Not specified	COMPLETED	Randomized Study of Polyethylene-Glycol-Conjugated Interleukin 2 in Patients With Common Variable Immunodeficiency
NCT00015431	Not specified	COMPLETED	Immune System and Gut Abnormalities in Patients With Common Variable Immunodeficiency With and Without Gastrointestinal Symptoms
NCT00661401	Not specified	COMPLETED	Specific IgG Antibody in Patients With Primary Antibody Deficiencies Treated With Subcutaneous Immunoglobulin
NCT00943514	Not specified	RECRUITING	Natural History of Bronchiectasis
NCT01196702	Not specified	COMPLETED	Lymphocyte Immunophenotyping in Common Variable Immunodeficiency
NCT01981785	Not specified	UNKNOWN	Investigation of Immune Disorders and Deficiencies
NCT02960399	Not specified	TERMINATED	Assessment of Immunogenicity of Zostavax® in Patients With Antibody Deficiency 60 Years of Age and Older
NCT03188419	Not specified	COMPLETED	Breadth of Donor Options for People With Inherited Diseases Requiring Allogeneic Hematopoietic Stem Cell Transplant in the Era of Alternative Donor Transplants Using Post-Transplantation Cyclophosphamide
NCT03211689	Not specified	COMPLETED	The Impact of Exercise on Stress, Fatigue, and Quality of Life in Individuals With Primary Immunodeficiency Disease
NCT03534479	Not specified	COMPLETED	Human IgGs and Endothelial Function in Vivo in Humans
NCT05310604	Not specified	COMPLETED	Early Detection of Primary Antibody Deficiencies in Primary Care Facilities by an Algorithm Driven Selection of Serologic Testing in Individuals at Risk.
NCT05321407	Not specified	ACTIVE_NOT_RECRUITING	COVID-19 Vaccine Responses in PIDD Subjects
NCT05481554	Not specified	UNKNOWN	Composition and Function of Gut Microbiota in Porto-sinusoidal Vascular Disease Associated With Variable Common Immunodeficiency
NCT06145100	Not specified	COMPLETED	Prediction of Portal Hypertension in Patients With CVID (CVID-pHT)
NCT06355323	Not specified	COMPLETED	Bronchiectasis Prevalence in Patients With Primary Humoral Immunodefiency in Champagne-Ardenne Region, France
NCT07255157	Not specified	RECRUITING	Peripheral Helper T-cells in Common Variable ImmunoDeficiency
NCT00266513	Not specified	TERMINATED	Studies of Disorders in Antibody Production and Related Primary Immunodeficiency States

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CD40LG across ~30M SureChEMBL compounds — explore on Sugi Predict.