Is TGFB3 p.Lys331= (c.993G>A) pathogenic?

TGFB3 p.Lys331= (c.993G>A) is classified Likely benign in TGFB3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-21). Very rare (popmax 0.000169%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with TGFB3 p.Lys331= (c.993G>A)?

TGFB3 p.Lys331= (c.993G>A) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is TGFB3 p.Lys331= (c.993G>A) in the general population?

TGFB3 p.Lys331= (c.993G>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

TGFB3 p.Lys331=

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.993G>A · VCV3455812

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000169%, 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 -2	GERP -3.7
Overall
CADD	2.11	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,050 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,260 alleles · very rare exomes 2/1,461,894 · genomes 0/152,366 · joint denominator

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: TGFB3
Protein: p.Lys331=
Coding: c.993G>A
MANE Select: NM_003239
Type: single nucleotide variant
Location: chr14:75961010 (GRCh38)
Gene constraint: LOEUF 0.249 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.48 · 11 PDB

Full TGFB3 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

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

TGFB3 c.646+1G>C Likely pathogenic ★★ same condition
TGFB3 c.926+1G>A Likely pathogenic ★★ same condition
TGFB3 p.Arg148Ter Pathogenic/Likely pathogenic ★★ same condition
TGFB3 p.Arg300Trp Pathogenic/Likely pathogenic ★★ same condition
TGFB3 p.Arg325Ter Pathogenic/Likely pathogenic ★★ same condition
TGFB3 p.Lys37Ter Pathogenic/Likely pathogenic ★★ same condition
TGFB3 p.Ser345Ter Pathogenic/Likely pathogenic ★★ same condition
TGFB3 c.-1C>T Uncertain significance ★★ 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/tgfb3-p-lys331 (accessed [today's date]).

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