Is TGFBR2 p.Cys61Tyr (c.182G>A) pathogenic?

TGFBR2 p.Cys61Tyr (c.182G>A) is classified Uncertain significance in TGFBR2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-11-15). AlphaMissense: likely pathogenic (0.9958); Absent from gnomAD v4.1; Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with TGFBR2 p.Cys61Tyr (c.182G>A)?

TGFBR2 p.Cys61Tyr (c.182G>A) is associated with familial thoracic aortic aneurysm and aortic dissection, Loeys-Dietz syndrome 2 (ClinVar).

How common is TGFBR2 p.Cys61Tyr (c.182G>A) in the general population?

TGFBR2 p.Cys61Tyr (c.182G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TGFBR2 p.Cys61Tyr (c.182G>A)?

AlphaMissense predicts likely pathogenic (score 0.9958) — an in-silico prediction, not a clinical call.

TGFBR2 p.Cys61Tyr

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.182G>A · rs2125404783 · VCV1312557

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9958 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.9958	likely pathogenic · top 9% in TGFBR2
REVEL	0.947	strongly pathogenic-leaning
SaProt	LLR -12.91	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 2.4, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 65 kb · p 3e-06 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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.Cys61Tyr
Coding: c.182G>A
MANE Select: NM_003242
dbSNP: rs2125404783
Type: single nucleotide variant
Location: chr3:30644834 (GRCh38)
Gene constraint: LOEUF 0.531 · pLI 0.91 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.22 · 22 PDB
Residue 61: a disulfide bond; a UniProt-annotated variant site (in a gastric adenocarcinoma sample; somatic mutation)

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.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
TGFBR2 p.Arg460Cys Pathogenic ★★ same condition
TGFBR2 p.Arg460Gly Pathogenic ★★ same condition
TGFBR2 p.Arg460His 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-cys61tyr (accessed [today's date]).

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