CD40LG

Chr XXLR

CD40 ligand

Also known as: CD154, CD40L, HIGM1, IGM, IMD3, T-BAM, TNFSF5, TRAP

NCBI Gene: 959ENSG00000102245UniProt: P29965

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. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Immunodeficiency, X-linked, with hyper-IgMMIM #308230
XLR
UniProtImmunodeficiency with hyper-IgM, type 1
410
ClinVar variants
199
Pathogenic / LP
0.72
pLI score
2
Active trials
Clinical Summary— CD40LG
🧬
Gene-Disease Validity (ClinGen)
hyper-IgM syndrome type 1 · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.72) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
199 Pathogenic / Likely Pathogenic· 82 VUS of 410 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.56LOEUF
pLI 0.721
Z-score 2.39
OE 0.12 (0.04–0.56)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.30Z-score
OE missense 0.63 (0.51–0.78)
61 obs / 97.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.12 (0.04–0.56)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.63 (0.51–0.78)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.79
0≤1.21.6
LoF obs/exp: 1 / 8.5Missense obs/exp: 61 / 97.1Syn Z: 1.03

ClinVar Variant Classifications

410 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic166
Likely Pathogenic33
VUS82
Likely Benign87
Benign31
Conflicting11
166
Pathogenic
33
Likely Pathogenic
82
VUS
87
Likely Benign
31
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
40
11
115
0
166
Likely Pathogenic
7
15
11
0
33
VUS
1
66
14
1
82
Likely Benign
0
3
40
44
87
Benign
0
11
7
13
31
Conflicting
—11
Total4810618758410

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CD40LG · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
CD40 LIGAND; CD40LG
MIM #300386 · *

Immunodeficiency, X-linked, with hyper-IgM

MIM #308230

Molecular basis of disorder known

X-linked recessive
📖
GeneReview available — CD40LG
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The shared circulating diagnostic biomarkers and molecular mechanisms of systemic lupus erythematosus and inflammatory bowel disease.
Sun HW et al.·Front Immunol
2024Functional
Pathomics predict CD40LG expression and clinical prognosis in lung adenocarcinoma based on haematoxylin-eosin-stained images.
Shi J et al.·Pathol Res Pract
2025
Role of Skewed X-Chromosome Inactivation in Common Variable Immunodeficiency.
Garcia-Prat M et al.·J Clin Immunol
2024
Exploring the potential mechanisms of Tongmai Jiangtang capsules in treating diabetic nephropathy through multi-dimensional data.
Liu Y et al.·Front Endocrinol (Lausanne)
2023Functional
BACH2-mediated CD28 and CD40LG axes contribute to pathogenesis and progression of T-cell lymphoblastic leukemia.
Feng M et al.·Cell Death Dis
2024
Case Report: CD40LG Arg203Ile variant underlies atypical phenotype of X-linked hyper IgM syndrome.
Nishikawa T et al.·Front Immunol
2025Case report
A Pyroptosis-Related Gene Signature Predicts Prognosis and Tumor Immune Microenvironment in Colorectal Cancer.
Li L et al.·Technol Cancer Res Treat
2024
Pathomics models for CD40LG expression and prognosis prediction in glioblastoma.
Li W et al.·Sci Rep
2024Functional
Genetics of Malaria Inflammatory Responses: A Pathogenesis Perspective.
Penha-Gonçalves C·Front Immunol
2019Review
Inherited and acquired clinical phenotypes associated with neuroendocrine tumors.
Nicolaides RE et al.·Curr Opin Allergy Clin Immunol
2017Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Systemic Lupus ErythematosusSystemic Scleroderma MeetingANCA Vasculitis

ROLE of PLATELETS in the PATHOPHYSIOLOGY of SYSTEMIC LUPUS

RECRUITING
NCT06593041University Hospital, Strasbourg, FranceStarted 2024-01-09
CD40L-HyperIgM Syndrome

Base Editing Hematopoietic Stem Cell and T Cell Gene Therapy for CD40L-HyperIgM Syndrome: Single Patient Study

RECRUITING
NCT06959771Phase PHASE1, PHASE2National Institute of Allergy and Infectious Diseases (NIAID)Started 2025-07-16
Base-edited hematopoietic stem and progenitor cellsAlemtuzumabSirolimus

External Resources

Links to major genomics databases and tools