Is TGFBR2 p.Arg460Pro (c.1379G>C) pathogenic?

TGFBR2 p.Arg460Pro (c.1379G>C) is classified Pathogenic/Likely pathogenic in TGFBR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-06). AlphaMissense: likely pathogenic (0.999); Absent from gnomAD v4.1; Associated with Loeys-Dietz syndrome 2.

What condition is associated with TGFBR2 p.Arg460Pro (c.1379G>C)?

TGFBR2 p.Arg460Pro (c.1379G>C) is associated with Loeys-Dietz syndrome 2 (ClinVar).

How common is TGFBR2 p.Arg460Pro (c.1379G>C) in the general population?

TGFBR2 p.Arg460Pro (c.1379G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TGFBR2 p.Arg460Pro (c.1379G>C)?

AlphaMissense predicts likely pathogenic (score 0.999) — an in-silico prediction, not a clinical call.

TGFBR2 p.Arg460Pro

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.1379G>C · rs104893816 · VCV1332771

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Loeys-Dietz syndrome 2

Computational evidence

Protein change
AlphaMissense	0.999	likely pathogenic ✓ concordant with ClinVar · top 4% in TGFBR2
REVEL	0.937	strongly pathogenic-leaning
SaProt	LLR -18.64	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 4.1, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 1,936 bp · p 3.8e-10 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TGFBR2
Protein: p.Arg460Pro
Coding: c.1379G>C
MANE Select: NM_003242
dbSNP: rs104893816
Type: single nucleotide variant
Location: chr3:30674229 (GRCh38)
Gene constraint: LOEUF 0.531 · pLI 0.91 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.22 · 22 PDB
Residue 460: the protein kinase domain; a UniProt-annotated variant site (in lds2); the 'sufficient for interaction with clu' region

Full TGFBR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Loeys-Dietz syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

TGFBR2 p.Arg460Cys Pathogenic ★★ same residue
TGFBR2 p.Arg460His Pathogenic ★★ same residue
TGFBR2 p.Arg460Leu Pathogenic/Likely pathogenic ★★ same residue
TGFBR2 p.Arg460Ser Likely pathogenic ★ same residue
TGFBR2 p.Arg460Gly Pathogenic ★★ same residue
TGFBR2 p.Arg460= Likely benign ★ same residue
TGFBR2 p.Ala527Val Pathogenic/Likely pathogenic ★★ same condition
TGFBR2 p.Arg356Pro 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-arg460pro (accessed [today's date]).

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