TGFBR1

Chr 9AD

transforming growth factor beta receptor 1

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

NCBI Gene: 7046ENSG00000106799UniProt: P36897

The protein encoded by this gene forms a heteromeric complex with type II TGF-beta receptors when bound to TGF-beta, transducing the TGF-beta signal from the cell surface to the cytoplasm. The encoded protein is a serine/threonine protein kinase. Mutations in this gene have been associated with Loeys-Dietz aortic aneurysm syndrome (LDAS). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

Primary Disease Associations & Inheritance

{Multiple self-healing squamous epithelioma, susceptibility to}MIM #132800
AD
Loeys-Dietz syndrome 1MIM #609192
AD
1254
ClinVar variants
58
Pathogenic / LP
0.85
pLI score
0
Active trials
Clinical Summary— TGFBR1
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.85) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
58 Pathogenic / Likely Pathogenic· 260 VUS of 1254 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.17 (0.08–0.38)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.51 (0.44–0.59)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 4 / 23.9Missense obs/exp: 133 / 259.7Syn Z: 0.05

ClinVar Variant Classifications

1254 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28
Likely Pathogenic30
VUS260
Likely Benign125
Benign8
Conflicting35
28
Pathogenic
30
Likely Pathogenic
260
VUS
125
Likely Benign
8
Benign
35
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
3
18
0
28
Likely Pathogenic
8
17
5
0
30
VUS
16
211
26
7
260
Likely Benign
1
3
45
76
125
Benign
0
0
8
0
8
Conflicting
—35
Total3223410283486

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.

Gene2Phenotype Curations

TGFBR1-related Loeys-Dietz syndrome

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. DisordersSkeletal
G2P ↗

TGFBR1-related multiple self-healing squamous epithelioma

definitive
ADLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure
SkinCancer
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Multiple self-healing squamous epithelioma, susceptibility to}

MIM #132800

Molecular basis of disorder known

Autosomal dominant

Loeys-Dietz syndrome 1

MIM #609192

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Single-Cell RNA Sequencing Reveals the Tissue Architecture in Human High-Grade Serous Ovarian Cancer.
Xu J et al.·Clin Cancer Res
2022
Single-cell tumor heterogeneity landscape of hepatocellular carcinoma: unraveling the pro-metastatic subtype and its interaction loop with fibroblasts.
Guo DZ et al.·Mol Cancer
2024
Clinical features and complications of Loeys-Dietz syndrome: A systematic review.
Gouda P et al.·Int J Cardiol
2022Review
Loeys-Dietz Syndrome.
Velchev JD et al.·Adv Exp Med Biol
2021
A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.
Loeys BL et al.·Nat Genet
2005
Aneurysm syndromes caused by mutations in the TGF-beta receptor.
Loeys BL et al.·N Engl J Med
2006
A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3.
Schepers D et al.·Hum Mutat
2018
Loeys-Dietz syndrome.
Van Laer L et al.·Adv Exp Med Biol
2014Review
Spatial transcriptomics reveals prognosis-associated cellular heterogeneity in the papillary thyroid carcinoma microenvironment.
Yan K et al.·Clin Transl Med
2024
M6A RNA methylation-mediated RMRP stability renders proliferation and progression of non-small cell lung cancer through regulating TGFBR1/SMAD2/SMAD3 pathway.
Yin H et al.·Cell Death Differ
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools