Is TGFBR2 p.Arg3Pro (c.8G>C) pathogenic?

TGFBR2 p.Arg3Pro (c.8G>C) is classified Uncertain significance in TGFBR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-07). AlphaMissense: likely benign (0.1864); Very rare (popmax 0.00173%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is TGFBR2 p.Arg3Pro (c.8G>C) in the general population?

TGFBR2 p.Arg3Pro (c.8G>C) is very rare (popmax 0.00173%, nfe) (gnomAD).

What do computational predictors say about TGFBR2 p.Arg3Pro (c.8G>C)?

AlphaMissense predicts likely benign (score 0.1864) — an in-silico prediction, not a clinical call.

TGFBR2 p.Arg3Pro

Q: What condition is associated with TGFBR2 p.Arg3Pro (c.8G>C)?

TGFBR2 p.Arg3Pro (c.8G>C) is associated with familial thoracic aortic aneurysm and aortic dissection, Loeys-Dietz syndrome 2 (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.8G>C · rs780267559 · VCV3072678

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1864 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00173%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.1864	likely benign
REVEL	0.458	indeterminate
SaProt	LLR -6.20	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 65 kb · p 3e-06 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00173% European (non-Finnish) · 20/1,154,940 alleles

Filtering AF 0.00113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000919%

Overall 0.00127% 20/1,569,918 alleles · very rare exomes 20/1,417,618 · genomes 0/152,300 · 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: TGFBR2
Protein: p.Arg3Pro
Coding: c.8G>C
MANE Select: NM_003242
dbSNP: rs780267559
Type: single nucleotide variant
Location: chr3:30606891 (GRCh38)
Gene constraint: LOEUF 0.531 · pLI 0.91 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.22 · 22 PDB

Full TGFBR2 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 2

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

TGFBR2 p.Arg3Trp Uncertain significance ★★ same residue
TGFBR2 p.Arg3= Conflicting classifications of pathogenicity ★ same residue
TGFBR2 p.Arg3Leu Uncertain significance ★ ⚠ same residue
TGFBR2 p.Ala414Pro Pathogenic/Likely pathogenic ★★ same condition
TGFBR2 p.Ala527Thr Likely pathogenic ★★ same condition
TGFBR2 p.Ala527Val Pathogenic/Likely pathogenic ★★ same condition
TGFBR2 p.Arg356Pro Pathogenic/Likely pathogenic ★★ same condition
TGFBR2 p.Arg378Ser 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/tgfbr2-p-arg3pro (accessed [today's date]).

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