Is TGFB2 p.Leu366= (c.1098A>G) pathogenic?

TGFB2 p.Leu366= (c.1098A>G) is classified Likely benign in TGFB2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-23). Very rare (popmax 0.000339%, nfe); Associated with Loeys-Dietz syndrome 4.

What condition is associated with TGFB2 p.Leu366= (c.1098A>G)?

TGFB2 p.Leu366= (c.1098A>G) is associated with Loeys-Dietz syndrome 4, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is TGFB2 p.Leu366= (c.1098A>G) in the general population?

TGFB2 p.Leu366= (c.1098A>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

TGFB2 p.Leu366=

c.1098A>G · rs931960431 · VCV761789

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

Loeys-Dietz syndrome 4

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 0.032	GERP -4.1, phastCons 0.048
Overall
CADD	2.35	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,622 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,612,220 alleles · very rare exomes 3/1,460,044 · genomes 2/152,176 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,430
European (non-Finnish)grpmax	0.000339%	294,905

Remaining individuals 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: TGFB2
Protein: p.Leu366=
Coding: c.1098A>G
MANE Select: NM_003238
dbSNP: rs931960431
Type: single nucleotide variant
Location: chr1:218441215 (GRCh38)
Gene constraint: LOEUF 0.463 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.41 · 11 PDB
Residue 366: a UniProt-annotated variant site (in lds4); an α-helix

Full TGFB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Loeys-Dietz syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

Similar variants

TGFB2 c.346+1G>A Pathogenic/Likely pathogenic ★★ same condition
TGFB2 c.346+1G>T Likely pathogenic ★★ same condition
TGFB2 c.510+1G>A Likely pathogenic ★★ same condition
TGFB2 c.932+1G>A Pathogenic/Likely pathogenic ★★ same condition
TGFB2 c.933-1G>A Pathogenic/Likely pathogenic ★★ same condition
TGFB2 p.Arg131Ter Pathogenic/Likely pathogenic ★★ same condition
TGFB2 p.Arg299Gln Pathogenic/Likely pathogenic ★★ same condition
TGFB2 p.Arg299Trp 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/tgfb2-p-leu366 (accessed [today's date]).

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