Is TGFBR1 p.Pro83= (c.249G>A) pathogenic?

TGFBR1 p.Pro83= (c.249G>A) is classified Likely benign in TGFBR1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-06-12). Ultra-rare (popmax 0.0165%, mid); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is TGFBR1 p.Pro83= (c.249G>A) in the general population?

TGFBR1 p.Pro83= (c.249G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

TGFBR1 p.Pro83=

Q: What condition is associated with TGFBR1 p.Pro83= (c.249G>A)?

TGFBR1 p.Pro83= (c.249G>A) is associated with familial thoracic aortic aneurysm and aortic dissection, Loeys-Dietz syndrome (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.249G>A · rs200091200 · VCV390446

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.2	GERP -3.8, phastCons 0.002
Overall
CADD	9.078	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00124% 20/1,613,970 alleles · ultra-rare exomes 20/1,461,704 · genomes 0/152,266 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
East Asian	0.00446%	22,437
South Asian	0.00329%	30,361
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)	0.0011%	90,766

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: TGFBR1
Protein: p.Pro83=
Coding: c.249G>A
MANE Select: NM_004612
dbSNP: rs200091200
Type: single nucleotide variant
Location: chr9:99129006 (GRCh38)
Gene constraint: LOEUF 0.509 · pLI 0.96 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.06 · 45 PDB
Residue 83: a UniProt-annotated variant site (in msse; hypomorphic variant)

Full TGFBR1 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

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

TGFBR1 p.Pro83Leu Uncertain significance ★ ⚠ same residue
TGFBR1 c.973+1G>A Likely pathogenic ★★ same condition
TGFBR1 c.974-1G>A Pathogenic ★★ same condition
TGFBR1 p.Ala355Thr Likely pathogenic ★★ same condition
TGFBR1 p.Arg225Gly Likely pathogenic ★★ same condition
TGFBR1 p.Arg487Gln Pathogenic ★★ same condition
TGFBR1 p.Arg487Trp Pathogenic/Likely pathogenic ★★ same condition
TGFBR1 p.Arg80Ter 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/tgfbr1-p-pro83 (accessed [today's date]).

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