TGFBR1

Chr 9AD

transforming growth factor beta receptor 1

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

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.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismADLOEUF 0.382 OMIM phenotypes
Clinical SummaryTGFBR1
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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

Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.85) — some intolerance to loss-of-function variants.
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ClinVar Variants
45 unique Pathogenic / Likely Pathogenic· 271 VUS of 500 total submissions
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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

Moderate LoF intolerance
LoF Constraint
0.38LOEUF
pLI 0.854
Z-score 3.77
OE 0.17 (0.080.38)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.79Z-score
OE missense 0.51 (0.440.59)
133 obs / 259.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.17 (0.080.38)
00.351.4
Missense OE0.51 (0.440.59)
00.61.4
Synonymous OE0.99
01.21.6
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
DN
0.5477th %ile
GOF
0.6931th %ile
LOF
0.55top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 56% of P/LP variants are LoF · LOEUF 0.38
GOFprediction above median · 1 literature citation

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.

ClinVar Variant Classifications

500 submitted variants in ClinVar

Classification Summary

Pathogenic24
Likely Pathogenic21
VUS271
Likely Benign153
Benign7
Conflicting10
24
Pathogenic
21
Likely Pathogenic
271
VUS
153
Likely Benign
7
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
14
4
6
0
24
Likely Pathogenic
11
9
1
0
21
VUS
17
221
23
10
271
Likely Benign
1
4
58
90
153
Benign
0
0
7
0
7
Conflicting
10
Total4323895100486

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

View in ClinVar →

Protein Context — Lollipop Plot

TGFBR1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
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