Is TGFBR2 p.Pro558= (c.1674T>G) pathogenic?

TGFBR2 p.Pro558= (c.1674T>G) is classified Likely benign in TGFBR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-17). Very rare (popmax 0.00133%, afr); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with TGFBR2 p.Pro558= (c.1674T>G)?

TGFBR2 p.Pro558= (c.1674T>G) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is TGFBR2 p.Pro558= (c.1674T>G) in the general population?

TGFBR2 p.Pro558= (c.1674T>G) is very rare (popmax 0.00133%, afr) (gnomAD).

TGFBR2 p.Pro558=

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1674T>G · rs2125455752 · VCV1777767

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.7	GERP -3.5
Overall
CADD	1.727	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,036 alleles

Overall 6.2e-05% 1/1,614,146 alleles · very rare exomes 1/1,461,856 · genomes 0/152,290 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TGFBR2
Protein: p.Pro558=
Coding: c.1674T>G
MANE Select: NM_003242
dbSNP: rs2125455752
Type: single nucleotide variant
Location: chr3:30691569 (GRCh38)
Gene constraint: LOEUF 0.531 · pLI 0.91 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.22 · 22 PDB
Residue 558: the 'sufficient for interaction with clu' region

Full TGFBR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

TGFBR2 p.Pro558Ala Uncertain significance ★ ⚠ same residue
TGFBR2 p.Pro558Leu Uncertain significance ★ ⚠ same residue
TGFBR2 p.Ala414Pro Pathogenic/Likely pathogenic ★★ same condition
TGFBR2 p.Ala527Thr Likely pathogenic ★★ same condition
TGFBR2 p.Ala527Val Pathogenic/Likely pathogenic ★★ same condition
TGFBR2 p.Arg356Pro Pathogenic/Likely pathogenic ★★ same condition
TGFBR2 p.Arg378Ser Pathogenic/Likely pathogenic ★★ same condition
TGFBR2 p.Arg460Cys Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tgfbr2-p-pro558 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown