Is TGFB2 p.Arg328= (c.984G>A) pathogenic?

TGFB2 p.Arg328= (c.984G>A) is classified Likely benign in TGFB2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.0161%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is TGFB2 p.Arg328= (c.984G>A) in the general population?

TGFB2 p.Arg328= (c.984G>A) is ultra-rare (popmax 0.0161%, nfe) (gnomAD).

TGFB2 p.Arg328=

Q: What condition is associated with TGFB2 p.Arg328= (c.984G>A)?

TGFB2 p.Arg328= (c.984G>A) is associated with familial thoracic aortic aneurysm and aortic dissection, Loeys-Dietz syndrome 4 (ClinVar).

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.984G>A · rs147678881 · VCV997879

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0161%, 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 1.6	GERP -0.91, phastCons 1
Overall
CADD	9.423	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0161% European (non-Finnish) · 190/1,179,648 alleles

Filtering AF 0.0142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0134%

Overall 0.0118% 190/1,612,920 alleles · ultra-rare exomes 185/1,461,256 · genomes 5/151,664 · 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: TGFB2
Protein: p.Arg328=
Coding: c.984G>A
MANE Select: NM_003238
dbSNP: rs147678881
Type: single nucleotide variant
Location: chr1:218437394 (GRCh38)
Gene constraint: LOEUF 0.463 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.41 · 11 PDB
Residue 328: a UniProt-annotated variant site (in lds4); an α-helix

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

Also linked: Loeys-Dietz syndrome 4

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

TGFB2 p.Arg328Gly Uncertain significance ★ ⚠ same residue
TGFB2 p.Arg328Lys Uncertain significance ★ ⚠ same residue
TGFB2 p.Arg328Thr Uncertain significance ★ ⚠ same residue
TGFB2 p.Arg328_Asp329insTer Likely pathogenic ★ same residue
TGFB2 p.Arg328Ser Uncertain significance ★ ⚠ same residue
TGFB2 c.346+1G>A Pathogenic/Likely pathogenic ★★ same condition
TGFB2 c.346+1G>T Likely pathogenic ★★ same condition
TGFB2 c.510+1G>A 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-arg328 (accessed [today's date]).

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