Is TGFBR2 p.Arg495= (c.1483C>A) pathogenic?

TGFBR2 p.Arg495= (c.1483C>A) is classified Likely benign in TGFBR2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-20). Very rare (popmax 0.000593%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with TGFBR2 p.Arg495= (c.1483C>A)?

TGFBR2 p.Arg495= (c.1483C>A) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is TGFBR2 p.Arg495= (c.1483C>A) in the general population?

TGFBR2 p.Arg495= (c.1483C>A) is very rare (popmax 0.000593%, nfe) (gnomAD).

TGFBR2 p.Arg495=

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.1483C>A · rs104893819 · VCV1773619

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

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 2.4	GERP -0.096, phastCons 0.98
Overall
CADD	12.99	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,180,028 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,614,194 alleles · very rare exomes 7/1,461,866 · genomes 0/152,328 · 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.Arg495=
Coding: c.1483C>A
MANE Select: NM_003242
dbSNP: rs104893819
Type: single nucleotide variant
Location: chr3:30688470 (GRCh38)
Gene constraint: LOEUF 0.531 · pLI 0.91 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.22 · 22 PDB
Residue 495: the protein kinase domain; 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.Arg495Ter Pathogenic ★★ same residue
TGFBR2 p.Arg495Gln 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-arg495 (accessed [today's date]).

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