TGFBR2

Chr 3AD

transforming growth factor beta receptor 2

Also known as: AAT3, FAA3, LDS1B, LDS2, LDS2B, MFS2, RIIC, TAAD2

NCBI Gene: 7048 ENSG00000163513 UniProt: P37173 OMIM: 190182

The transmembrane serine/threonine kinase receptor forms complexes with TGF-beta cytokines and TGFBR1 to regulate cell proliferation, differentiation, wound healing, and immune responses through SMAD-dependent signaling pathways. Mutations cause Loeys-Dietz syndrome 2, a connective tissue disorder affecting the cardiovascular system, and hereditary nonpolyposis colorectal cancer type 6, both following autosomal dominant inheritance. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.52), reflecting its essential role in multiple developmental and physiological processes.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a transmembrane protein that has a protein kinase domain, forms a heterodimeric complex with TGF-beta receptor type-1, and binds TGF-beta. This receptor/ligand complex phosphorylates proteins, which then enter the nucleus and regulate the transcription of genes related to cell proliferation, cell cycle arrest, wound healing, immunosuppression, and tumorigenesis. Mutations in this gene have been associated with Marfan Syndrome, Loeys-Deitz Aortic Aneurysm Syndrome, and the development of various types of tumors. Alternatively spliced transcript variants encoding different isoforms have been characterized. [provided by RefSeq, Aug 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Colorectal cancer, hereditary nonpolyposis, type 6MIM #614331

Esophageal cancer, somaticMIM #133239

Loeys-Dietz syndrome 2MIM #610168

UniProtHereditary non-polyposis colorectal cancer 6

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Loeys-Dietz syndrome 2 · AD · ClinGen 2020

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

247

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.52

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — TGFBR2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.52LOEUF

pLI 0.125

Z-score 3.26

OE 0.26 (0.14–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.24Z-score

OE missense 0.65 (0.58–0.73)

215 obs / 329.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.26 (0.14–0.52)

0≤0.351.4

Missense OE?0.65 (0.58–0.73)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 6 / 22.8Missense obs/exp: 215 / 329.6Syn Z: -0.60

Background carrier burden — how many people carry a rare variant somewhere in TGFBR2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

595 rare PASS variants

Rare truncating (LoF)

1 in 1,400

53 rare PASS variants

Rare synonymous (reference)

1 in 200

323 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TGFBR2. 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 190	1 in 1,600
South Asian	~43k	1 in 100	1 in 550
Remaining (unassigned)	~30k	1 in 83	1 in 660
European (Finnish)	~27k	1 in 320	1 in 1,200
Admixed American	~22k	1 in 94	1 in 1,200
African / African American	~21k	1 in 100	1 in 980
East Asian	~20k	1 in 97	1 in 3,200
Ashkenazi Jewish	~13k	1 in 260	≈ 1 in 6,100
Middle Eastern	~2,884	1 in 120	≈ 1 in 910

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): All 7 coding exons well covered in gnomAD exomes and genomes.? see exons ↓