Is TGFB2 p.Pro321Thr (c.961C>A) pathogenic?

TGFB2 p.Pro321Thr (c.961C>A) is classified Uncertain significance in TGFB2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-12). AlphaMissense: likely benign (0.1586); Very rare (popmax 0.00338%, amr); Associated with Loeys-Dietz syndrome 4.

What condition is associated with TGFB2 p.Pro321Thr (c.961C>A)?

TGFB2 p.Pro321Thr (c.961C>A) is associated with Loeys-Dietz syndrome 4, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is TGFB2 p.Pro321Thr (c.961C>A) in the general population?

TGFB2 p.Pro321Thr (c.961C>A) is very rare (popmax 0.00338%, amr) (gnomAD).

What do computational predictors say about TGFB2 p.Pro321Thr (c.961C>A)?

AlphaMissense predicts likely benign (score 0.1586) — an in-silico prediction, not a clinical call.

TGFB2 p.Pro321Thr

c.961C>A · rs765295855 · VCV2452022

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1586 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00338%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Loeys-Dietz syndrome 4

Computational evidence

Protein change
AlphaMissense	0.1586	likely benign
REVEL	0.262	benign-leaning
SaProt	LLR -6.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 95 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00338% Admixed American · 2/59,126 alleles

Filtering AF 0.000561% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00021%

Overall 0.000311% 5/1,606,800 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00338%	29,563
European (non-Finnish)	0.000255%	392,489

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.Pro321Thr
Coding: c.961C>A
MANE Select: NM_003238
dbSNP: rs765295855
Type: single nucleotide variant
Location: chr1:218437371 (GRCh38)
Gene constraint: LOEUF 0.463 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.41 · 11 PDB
Residue 321: a UniProt-annotated variant site (in lds4); a disulfide bond

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.Pro321= Likely benign ★ 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
TGFB2 p.Arg299Gln 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-pro321thr (accessed [today's date]).

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