Is TGFB2 p.Ala306= (c.918G>A) pathogenic?

TGFB2 p.Ala306= (c.918G>A) is classified Conflicting classifications of pathogenicity in TGFB2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-13). Ultra-rare (popmax 0.0166%, mid); Associated with Loeys-Dietz syndrome 4.

What condition is associated with TGFB2 p.Ala306= (c.918G>A)?

TGFB2 p.Ala306= (c.918G>A) is associated with Loeys-Dietz syndrome 4, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is TGFB2 p.Ala306= (c.918G>A) in the general population?

TGFB2 p.Ala306= (c.918G>A) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

TGFB2 p.Ala306=

c.918G>A · rs767936611 · VCV408430

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

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 -4.6	GERP -4.1
Overall
CADD	0.987	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,030 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000831%

Overall 0.0013% 21/1,610,604 alleles · ultra-rare exomes 21/1,458,356 · genomes 0/152,248 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,030
European (non-Finnish)	0.00161%	62,054
South Asian	0.00111%	90,074

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.Ala306=
Coding: c.918G>A
MANE Select: NM_003238
dbSNP: rs767936611
Type: single nucleotide variant
Location: chr1:218436133 (GRCh38)
Gene constraint: LOEUF 0.463 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.41 · 11 PDB
Residue 306: 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 p.Ala306Glu Uncertain significance ★★ ⚠ same residue
TGFB2 p.Ala306Val Uncertain significance ★★ same residue
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

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-ala306 (accessed [today's date]).

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