CD40LG

Chr XXLR

CD40 ligand

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

NCBI Gene: 959 ENSG00000102245 UniProt: P29965 OMIM: 300386

The protein encoded by CD40LG is expressed on T cell surfaces and functions as a cytokine ligand for CD40, costimulating T cell proliferation and mediating immunoglobulin class switching in B cells. Mutations cause X-linked hyper-IgM syndrome, characterized by recurrent infections due to impaired antibody class switching. The gene shows X-linked recessive inheritance and is moderately constrained against loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Immunodeficiency, X-linked, with hyper-IgMMIM #308230

XLR

UniProtImmunodeficiency with hyper-IgM, type 1

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · hyper-IgM syndrome type 1 · XL · ClinGen 2021

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.56

LOEUF

—

Mechanism

📖

GeneReview available — CD40LG

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

1.30Z-score

OE missense 0.63 (0.51–0.78)

61 obs / 97.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.12 (0.04–0.56)

0≤0.351.4

Missense OE?0.63 (0.51–0.78)

0≤0.61.4

Synonymous OE?0.79

0≤1.21.6

LoF obs/exp: 1 / 8.5Missense obs/exp: 61 / 97.1Syn Z: 1.03

Background carrier burden — how many people carry a rare variant somewhere in CD40LG?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 310

150 rare PASS variants

Rare truncating (LoF)

1 in 62,000

3 rare PASS variants

Rare synonymous (reference)

1 in 680

70 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CD40LG. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 520	≈ 1 in 280,000
South Asian	~36k	1 in 410	none seen
Remaining (unassigned)	~31k	1 in 540	none seen
European (Finnish)	~27k	1 in 2,500	none seen
Admixed American	~23k	1 in 830	none seen
African / African American	~21k	1 in 370	≈ 1 in 20,000
East Asian	~20k	1 in 870	none seen
Ashkenazi Jewish	~13k	≈ 1 in 13,000	none seen
Middle Eastern	~2,758	1 in 460	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓