TNFSF18

Chr 1

TNF superfamily member 18

Also known as: AITRL, GITRL, TL6, TNLG2A, hGITRL

NCBI Gene: 8995 ENSG00000120337 UniProt: Q9UNG2 OMIM: 603898

The protein encoded by TNFSF18 is a cytokine that binds to the TNFRSF18 receptor and regulates T-cell activation, proliferation, and survival, while also promoting leukocyte adhesion to endothelial cells. This gene is highly tolerant to loss-of-function variants based on population genetics data, and no Mendelian diseases have been definitively associated with TNFSF18 mutations to date. The gene's role in immune cell regulation suggests that if pathogenic variants were identified, they would likely affect immunological function.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This cytokine is a ligand for receptor TNFRSF18/AITR/GITR. It has been shown to modulate T lymphocyte survival in peripheral tissues. This cytokine is also found to be expressed in endothelial cells, and is thought to be important for interaction between T lymphocytes and endothelial cells. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.63

Clinical Summary— TNFSF18

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

15 VUS of 18 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.63LOEUF

pLI 0.000

Z-score 0.35

OE 0.86 (0.47–1.63)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.56Z-score

OE missense 1.16 (0.99–1.35)

115 obs / 99.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.86 (0.47–1.63)

0≤0.351.4

Missense OE?1.16 (0.99–1.35)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 6 / 7.0Missense obs/exp: 115 / 99.4Syn Z: 0.30

This gene — mechanism propensity

0.6743th %ile

GOF

0.6345th %ile

LOF

0.2971th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

18 submitted variants in ClinVar

ClinVar

Classification Summary

VUS15

Likely Benign2

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	12	3	15
Likely Benign	1	1	2
Benign	0	0	0
Total	13	4	17

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap TNFSF18 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →