Is TGFB3 p.Pro319= (c.957C>T) pathogenic?

TGFB3 p.Pro319= (c.957C>T) is classified Likely benign in TGFB3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-30). Very rare (popmax 0.005%, amr); Associated with Rienhoff syndrome.

What condition is associated with TGFB3 p.Pro319= (c.957C>T)?

TGFB3 p.Pro319= (c.957C>T) is associated with Rienhoff syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is TGFB3 p.Pro319= (c.957C>T) in the general population?

TGFB3 p.Pro319= (c.957C>T) is very rare (popmax 0.005%, amr) (gnomAD).

TGFB3 p.Pro319=

c.957C>T · rs977821614 · VCV509913

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

Rienhoff syndrome

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 -0.098	GERP -3.7, phastCons 0.021
Overall
CADD	7.124	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,008 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000248% 4/1,614,062 alleles · very rare exomes 2/1,461,892 · genomes 2/152,170 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,003
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Pro319=
Coding: c.957C>T
MANE Select: NM_003239
dbSNP: rs977821614
Type: single nucleotide variant
Location: chr14:75961046 (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

Rienhoff syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

Similar variants

TGFB3 p.Pro319Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TGFB3 p.Pro319Arg Uncertain significance ★ ⚠ 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-pro319 (accessed [today's date]).

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