TGFBR1

Chr 9AD

transforming growth factor beta receptor 1

Also known as: AAT5, ACVRLK4, ALK-5, ALK5, ESS1, LDS1, LDS1A, LDS2A

NCBI Gene: 7046 ENSG00000106799 UniProt: P36897 OMIM: 190181

This gene encodes a transmembrane serine/threonine kinase that forms a receptor complex with TGFBR2 to transduce TGF-beta signaling from the cell surface to the cytoplasm, regulating cell proliferation, differentiation, and extracellular matrix production. Mutations cause Loeys-Dietz syndrome 1, a connective tissue disorder affecting the cardiovascular system, and increase susceptibility to multiple self-healing squamous epithelioma. The gene follows autosomal dominant inheritance and is highly constrained against loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.382 OMIM phenotypes

Clinical Summary— TGFBR1

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Gene-Disease Validity (ClinGen)

multiple self-healing squamous epithelioma · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.85) — some intolerance to loss-of-function variants.

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GeneReview available — TGFBR1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint

0.38LOEUF

pLI 0.854

Z-score 3.77

OE 0.17 (0.08–0.38)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

2.79Z-score

OE missense 0.51 (0.44–0.59)

133 obs / 259.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.17 (0.08–0.38)

0≤0.351.4

Missense OE0.51 (0.44–0.59)

0≤0.61.4

Synonymous OE0.99

0≤1.21.6

LoF obs/exp: 4 / 23.9Missense obs/exp: 133 / 259.7Syn Z: 0.05

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTGFBR1-related Loeys-Dietz syndromeGOFAD

definitiveTGFBR1-related multiple self-healing squamous epitheliomaLOFAD

0.5477th %ile

GOF

0.6931th %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

LOF1 literature citation · LOEUF 0.38

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 fact that the non-immune manifestations of the gain-of-function mutations of TGFBR1 and TGFBR2 are similar to the those of dominant negative mutations of STAT3 provide a clue to elucidate molecular mechanisms of non-immune manifestations of hyper-IgE syndrome.PMID:34419355

LOFHeterozygous loss-of-function mutations in TGF-? receptors 1 and 2 (TGFBR1 and TGFBR2) cause LDS, but TGF-? signaling is activated in the aorta (referred to as the TGF-? paradox) by mechanisms yet to be elucidated.PMID:30037098

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