Is TGFB3 p.Asp355= (c.1065C>T) pathogenic?

TGFB3 p.Asp355= (c.1065C>T) is classified Likely benign in TGFB3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-24). Very rare (popmax 0.00133%, afr); Associated with Rienhoff syndrome.

What condition is associated with TGFB3 p.Asp355= (c.1065C>T)?

TGFB3 p.Asp355= (c.1065C>T) is associated with Rienhoff syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is TGFB3 p.Asp355= (c.1065C>T) in the general population?

TGFB3 p.Asp355= (c.1065C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

TGFB3 p.Asp355=

c.1065C>T · rs2035148398 · VCV2055002

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

Rienhoff syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2	GERP 0.93, phastCons 1
Overall
CADD	8.807	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,052 alleles

Overall 6.2e-05% 1/1,614,206 alleles · very rare exomes 1/1,461,880 · genomes 0/152,326 · 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.Asp355=
Coding: c.1065C>T
MANE Select: NM_003239
dbSNP: rs2035148398
Type: single nucleotide variant
Location: chr14:75960938 (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

Rienhoff syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

Similar variants

TGFB3 p.Asp355Gly Uncertain significance ★ ⚠ same residue
TGFB3 p.Asp355fs Uncertain significance ★ same residue
TGFB3 c.517-2A>G Likely pathogenic ★★ same condition
TGFB3 c.646+1G>C Likely pathogenic ★★ same condition
TGFB3 c.926+1G>A Likely pathogenic ★★ same condition
TGFB3 c.927-1G>C Likely pathogenic ★★ same condition
TGFB3 p.Arg148Ter Pathogenic/Likely pathogenic ★★ same condition
TGFB3 p.Arg300Gln 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/tgfb3-p-asp355 (accessed [today's date]).

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