Is TGFB2 p.Lys49= (c.147G>A) pathogenic?

TGFB2 p.Lys49= (c.147G>A) is classified Likely benign in TGFB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-11). Very rare (popmax 0.000254%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with TGFB2 p.Lys49= (c.147G>A)?

TGFB2 p.Lys49= (c.147G>A) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is TGFB2 p.Lys49= (c.147G>A) in the general population?

TGFB2 p.Lys49= (c.147G>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

TGFB2 p.Lys49=

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.147G>A · rs1656699232 · VCV2586620

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000254%, 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 5	GERP 1.1, phastCons 1
Overall
CADD	12.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,040 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,894 alleles · very rare

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: TGFB2
Protein: p.Lys49=
Coding: c.147G>A
MANE Select: NM_003238
dbSNP: rs1656699232
Type: single nucleotide variant
Location: chr1:218346848 (GRCh38)
Gene constraint: LOEUF 0.463 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.41 · 11 PDB

Full TGFB2 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

TGFB2 p.Lys49Ter Pathogenic ★★ same residue
TGFB2 c.346+1G>T Likely pathogenic ★★ same condition
TGFB2 p.Arg131Ter Pathogenic/Likely pathogenic ★★ same condition
TGFB2 p.Arg299Gln Pathogenic/Likely pathogenic ★★ same condition
TGFB2 p.Arg299Trp Pathogenic/Likely pathogenic ★★ same condition
TGFB2 p.Arg302Cys Pathogenic/Likely pathogenic ★★ same condition
TGFB2 p.Arg302His Pathogenic/Likely pathogenic ★★ same condition
TGFB2 p.Arg320Cys Pathogenic/Likely 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/tgfb2-p-lys49 (accessed [today's date]).

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