TNFRSF1A

Chr 12AD

TNF receptor superfamily member 1A

Also known as: CD120a, FPF, TBP1, TNF-R, TNF-R-I, TNF-R55, TNFAR, TNFR1

NCBI Gene: 7132 ENSG00000067182 UniProt: P19438

This gene encodes a TNF receptor that binds tumor necrosis factor alpha to regulate cell survival, apoptosis, and inflammation through caspase activation and other signaling pathways. Mutations cause tumor necrosis factor receptor-associated periodic syndrome (TRAPS), characterized by recurrent fever and abdominal pain, and may contribute to multiple sclerosis susceptibility. The gene follows autosomal dominant inheritance and is highly constrained against loss-of-function variants.

Summary from RefSeq, OMIM, UniProt

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Primary Disease Associations & Inheritance

{Multiple sclerosis, susceptibility to, 5}MIM #614810

Periodic fever, familialMIM #142680

Active trials

Pubs (1 yr)

P/LP submissions

38%

P/LP missense

0.24

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

Clinical Summary— TNFRSF1A

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Gene-Disease Validity (ClinGen)

TNF receptor 1-associated periodic fever syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

53 unique Pathogenic / Likely Pathogenic· 234 VUS of 600 total submissions

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Clinical Trials

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

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GeneReview available — TNFRSF1A

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.24LOEUF

pLI 0.995

Z-score 3.94

OE 0.05 (0.02–0.24)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

2.10Z-score

OE missense 0.64 (0.56–0.72)

170 obs / 266.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.05 (0.02–0.24)

0≤0.351.4

Missense OE0.64 (0.56–0.72)

0≤0.61.4

Synonymous OE0.97

0≤1.21.6

LoF obs/exp: 1 / 20.1Missense obs/exp: 170 / 266.5Syn Z: 0.25

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTNFRSF1A-related periodic fever, familialOTHERAD

0.4488th %ile

GOF

0.7030th %ile

LOF

0.55top 25%

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

GOFprediction above median · 1 literature citation

LOFLOEUF 0.24

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.

Literature Evidence

GOFThe novel S59P mutation in the TNFRSF1A gene identified in an adult onset TNF receptor associated periodic syndrome (TRAPS) constitutively activates NF-kB pathwayPMID:25888769

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.