Is TGFB3 p.Pro57= (c.171T>C) pathogenic?

TGFB3 p.Pro57= (c.171T>C) is classified Likely benign in TGFB3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-23). Ultra-rare (popmax 0.0165%, mid); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with TGFB3 p.Pro57= (c.171T>C)?

TGFB3 p.Pro57= (c.171T>C) is associated with familial thoracic aortic aneurysm and aortic dissection, Rienhoff syndrome (ClinVar).

How common is TGFB3 p.Pro57= (c.171T>C) in the general population?

TGFB3 p.Pro57= (c.171T>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

TGFB3 p.Pro57=

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.171T>C · rs768225719 · VCV1155657

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.3	GERP -3.7
Overall
CADD	5.44	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000743% 12/1,614,158 alleles · ultra-rare exomes 12/1,461,892 · genomes 0/152,266 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
South Asian	0.00549%	18,217
Remaining individualsnot grpmax-eligible	0.0032%	31,254
European (non-Finnish)	0.000339%	295,005

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: TGFB3
Protein: p.Pro57=
Coding: c.171T>C
MANE Select: NM_003239
dbSNP: rs768225719
Type: single nucleotide variant
Location: chr14:75980723 (GRCh38)
Gene constraint: LOEUF 0.249 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.48 · 11 PDB

Full TGFB3 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: Rienhoff syndrome

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

TGFB3 p.Pro57_Glu58insTer Pathogenic ★ same residue
TGFB3 p.Pro57fs Pathogenic ★ same residue
TGFB3 c.517-2A>G Likely pathogenic ★★ same condition
TGFB3 c.646+1G>C Likely pathogenic ★★ same condition
TGFB3 c.926+1G>A Likely pathogenic ★★ same condition
TGFB3 c.927-1G>C Likely pathogenic ★★ same condition
TGFB3 p.Arg148Ter Pathogenic/Likely pathogenic ★★ same condition
TGFB3 p.Arg300Gln 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/tgfb3-p-pro57 (accessed [today's date]).

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