TGFB2

Chr 1AD

transforming growth factor beta 2

Also known as: CAEND2, G-TSF, LDS4, TGF-beta2

NCBI Gene: 7042 ENSG00000092969 UniProt: P61812 OMIM: 190220

The protein functions as a secreted ligand that binds TGF-beta receptors to activate SMAD transcription factors and regulate gene expression throughout development. Mutations cause Camurati-Engelmann disease 2 (a bone dysplasia) and Loeys-Dietz syndrome 4 (a connective tissue disorder affecting the cardiovascular system, skeleton, and other organs), both inherited in an autosomal dominant pattern. This gene is highly constrained against loss-of-function variation in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF-beta family members. Disruption of the TGF-beta/SMAD pathway has been implicated in a variety of human cancers. A chromosomal translocation that includes this gene is associated with Peters' anomaly, a congenital defect of the anterior chamber of the eye. Mutations in this gene may be associated with Loeys-Dietz syndrome. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.152 OMIM phenotypes

Clinical Summary— TGFB2

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Gene-Disease Validity (ClinGen)

familial thoracic aortic aneurysm and aortic dissection · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

131 unique Pathogenic / Likely Pathogenic· 409 VUS of 869 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.15LOEUF

pLI 0.999

Z-score 4.16

OE 0.00 (0.00–0.15)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

2.13Z-score

OE missense 0.62 (0.54–0.71)

153 obs / 247.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.15)

0≤0.351.4

Missense OE?0.62 (0.54–0.71)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 0 / 20.1Missense obs/exp: 153 / 247.3Syn Z: -0.15

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTGFB2-related Loeys-Dietz syndromeLOFAD

This gene — mechanism propensity

0.3495th %ile

GOF

0.2497th %ile

LOF

0.66top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 76% of P/LP variants are LoF · LOEUF 0.15

Literature Evidence

LOFLoss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm.1

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

References

1.PMID 22772368 ↗

ClinVar Variant Classifications

869 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic76

Likely Pathogenic55

VUS409

Likely Benign257

Benign37

Conflicting27

Pathogenic

Likely Pathogenic

409

VUS

257

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	60	3	13	0	76
Likely Pathogenic	39	10	6	0	55
VUS	11	322	70	6	409
Likely Benign	0	7	86	164	257
Benign	0	0	37	0	37
Conflicting	—				27
Total	110	342	212	170	861

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

View in ClinVar →

35 pathogenic / likely-pathogenic (of 44) ClinVar copy-number / structural variants overlap TGFB2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →