Is TGFBR2 p.Lys124= (c.372G>A) pathogenic?

TGFBR2 p.Lys124= (c.372G>A) is classified Conflicting classifications of pathogenicity in TGFBR2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2017-05-25). Very rare (popmax 8.48e-05%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is TGFBR2 p.Lys124= (c.372G>A) in the general population?

TGFBR2 p.Lys124= (c.372G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

TGFBR2 p.Lys124=

Q: What condition is associated with TGFBR2 p.Lys124= (c.372G>A)?

TGFBR2 p.Lys124= (c.372G>A) is associated with familial thoracic aortic aneurysm and aortic dissection, diabetic retinopathy (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.372G>A · rs1212599579 · VCV477545

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

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 1.3	GERP -3.3, phastCons 1
Overall
CADD	7.102	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,446 alleles

Overall 0.000124% 2/1,612,306 alleles · very rare exomes 0/1,461,274 · genomes 2/151,032 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00157%	63,578
European (non-Finnish)grpmax	8.48e-05%	1,179,446

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Lys124=
Coding: c.372G>A
MANE Select: NM_003242
dbSNP: rs1212599579
Type: single nucleotide variant
Location: chr3:30650378 (GRCh38)
Gene constraint: LOEUF 0.531 · pLI 0.91 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.22 · 22 PDB
Residue 124: a β-strand

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: diabetic retinopathy

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

TGFBR2 p.Lys124Arg Uncertain significance ★★ ⚠ same residue
TGFBR2 p.Lys124Thr 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
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-lys124 (accessed [today's date]).

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