TNFRSF9

Chr 1AR

TNF receptor superfamily member 9

Also known as: 4-1BB, CD137, CDw137, ILA, IMD109

NCBI Gene: 3604 ENSG00000049249 OMIM: 602250

The protein is a TNF receptor superfamily member that enhances CD8+ T-cell survival and cytotoxicity, contributing to clonal expansion and development of T cells while promoting Th1 cell responses and immunity against viruses and tumors. Autosomal recessive mutations cause immunodeficiency 109 with lymphoproliferation, affecting the immune system. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.606).

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contributes to the clonal expansion, survival, and development of T cells. It can also induce proliferation in peripheral monocytes, enhance T cell apoptosis induced by TCR/CD3 triggered activation, and regulate CD28 co-stimulation to promote Th1 cell responses. The expression of this receptor is induced by lymphocyte activation. TRAF adaptor proteins have been shown to bind to this receptor and transduce the signals leading to activation of NF-kappaB. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.611 OMIM phenotype

Clinical Summary— TNFRSF9

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Gene-Disease Validity (ClinGen)

immunodeficiency 109 with lymphoproliferation · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

15 unique Pathogenic / Likely Pathogenic· 86 VUS of 209 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.61LOEUF

pLI 0.322

Z-score 2.54

OE 0.23 (0.11–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.36Z-score

OE missense 0.92 (0.80–1.06)

134 obs / 146.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.23 (0.11–0.61)

0≤0.351.4

Missense OE?0.92 (0.80–1.06)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 3 / 12.8Missense obs/exp: 134 / 146.4Syn Z: -0.01

This gene — mechanism propensity

0.6840th %ile

GOF

0.6638th %ile

LOF

0.2873th %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

209 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic5

VUS86

Likely Benign83

Benign12

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	0	1	0	10
Likely Pathogenic	4	0	1	0	5
VUS	2	72	10	2	86
Likely Benign	0	3	36	44	83
Benign	0	1	8	3	12
Conflicting	—				2
Total	15	76	56	49	198

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

View in ClinVar →

42 pathogenic / likely-pathogenic (of 51) ClinVar copy-number / structural variants overlap TNFRSF9 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →