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

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

{Multiple self-healing squamous epithelioma, susceptibility to}MIM #132800

Loeys-Dietz syndrome 1MIM #609192

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Curated mechanisms (Gene2Phenotype) include both loss of function and gain of function. Which applies is variant-dependent — do not assume a null variant is, or isn’t, the pathogenic class without checking the specific variant.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

232

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.38

LOEUF

Multiple*

Mechanism· G2P

📖

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 OE?0.17 (0.08–0.38)

0≤0.351.4

Missense OE?0.51 (0.44–0.59)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

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

Background carrier burden — how many people carry a rare variant somewhere in TGFBR1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 220

432 rare PASS variants

Rare truncating (LoF)

1 in 5,600

56 rare PASS variants

Rare synonymous (reference)

1 in 200

245 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TGFBR1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 250	1 in 4,500
South Asian	~43k	1 in 160	1 in 1,600
Remaining (unassigned)	~30k	1 in 190	≈ 1 in 17,000
European (Finnish)	~27k	1 in 640	1 in 5,300
Admixed American	~22k	1 in 180	≈ 1 in 22,000
African / African American	~21k	1 in 170	≈ 1 in 9,300
East Asian	~20k	1 in 270	≈ 1 in 6,300
Ashkenazi Jewish	~13k	1 in 600	none seen
Middle Eastern	~2,884	1 in 160	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 8 of 9 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: 8 of 9 (exon 1 below).? see exons ↓