Is TGFB2 p.Ala306Val (c.917C>T) pathogenic?

TGFB2 p.Ala306Val (c.917C>T) is classified Uncertain significance in TGFB2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-18). AlphaMissense: ambiguous (0.4019); Very rare (popmax 0.00136%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with TGFB2 p.Ala306Val (c.917C>T)?

TGFB2 p.Ala306Val (c.917C>T) is associated with familial thoracic aortic aneurysm and aortic dissection, Loeys-Dietz syndrome 4 (ClinVar).

How common is TGFB2 p.Ala306Val (c.917C>T) in the general population?

TGFB2 p.Ala306Val (c.917C>T) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about TGFB2 p.Ala306Val (c.917C>T)?

AlphaMissense predicts ambiguous (score 0.4019) — an in-silico prediction, not a clinical call.

TGFB2 p.Ala306Val

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.917C>T · rs989462091 · VCV1766066

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4019 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.4019	ambiguous
REVEL	0.315	indeterminate
SaProt	LLR -7.68	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 95 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	22.5	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

Grpmax group 0.00136% European (non-Finnish) · 16/1,178,736 alleles

Filtering AF 0.000804% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00118% 19/1,609,182 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,127
European (non-Finnish)grpmax	0.00136%	73,671
South Asian	0.00111%	89,770

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.Ala306Val
Coding: c.917C>T
MANE Select: NM_003238
dbSNP: rs989462091
Type: single nucleotide variant
Location: chr1:218436132 (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

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Loeys-Dietz syndrome 4

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

TGFB2 p.Ala306Glu Uncertain significance ★★ ⚠ same residue
TGFB2 p.Ala306= Conflicting classifications of pathogenicity ★ 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-ala306val (accessed [today's date]).

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