Is TGFBR2 p.Arg356Pro (c.1067G>C) pathogenic?

TGFBR2 p.Arg356Pro (c.1067G>C) is classified Pathogenic/Likely pathogenic in TGFBR2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-23). AlphaMissense: likely pathogenic (0.9269); No allele count reported in gnomAD v4.1 (AN 1,603,152); Associated with Loeys-Dietz syndrome.

What condition is associated with TGFBR2 p.Arg356Pro (c.1067G>C)?

TGFBR2 p.Arg356Pro (c.1067G>C) is associated with Loeys-Dietz syndrome, Loeys-Dietz syndrome 2, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is TGFBR2 p.Arg356Pro (c.1067G>C) in the general population?

TGFBR2 p.Arg356Pro (c.1067G>C) is no allele count reported in gnomAD v4.1 (AN 1,603,152) (gnomAD).

What do computational predictors say about TGFBR2 p.Arg356Pro (c.1067G>C)?

AlphaMissense predicts likely pathogenic (score 0.9269) — an in-silico prediction, not a clinical call.

TGFBR2 p.Arg356Pro

c.1067G>C · rs727504292 · VCV177704

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9269 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,603,152)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Loeys-Dietz syndrome

Computational evidence

Protein change
AlphaMissense	0.9269	likely pathogenic ✓ concordant with ClinVar
REVEL	0.652	pathogenic-leaning
SaProt	LLR -13.20	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 10	GERP 3.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 65 kb · p 3e-06 · regional, not allelic
Overall
CADD	29.1	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

No allele count reported in gnomAD v4.1 (AN 1,603,152). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TGFBR2
Protein: p.Arg356Pro
Coding: c.1067G>C
MANE Select: NM_003242
dbSNP: rs727504292
Type: single nucleotide variant
Location: chr3:30672250 (GRCh38)
Gene constraint: LOEUF 0.531 · pLI 0.91 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.22 · 22 PDB
Residue 356: the protein kinase domain; an α-helix

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

Disease context

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

Also linked: Loeys-Dietz syndrome 2 familial thoracic aortic aneurysm and aortic dissection

Similar variants

TGFBR2 p.Arg356Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
TGFBR2 p.Arg356Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
TGFBR2 p.Arg356Trp Conflicting classifications of pathogenicity ★ ⚠ 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.Arg378Ser Pathogenic/Likely pathogenic ★★ same condition
TGFBR2 p.Arg460Cys 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-arg356pro (accessed [today's date]).

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