Is TGFBR2 p.Pro25= (c.75A>G) pathogenic?

TGFBR2 p.Pro25= (c.75A>G) is classified Benign/Likely benign in TGFBR2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-09). Rare (popmax 0.149%, mid); Associated with diabetic retinopathy.

What condition is associated with TGFBR2 p.Pro25= (c.75A>G)?

TGFBR2 p.Pro25= (c.75A>G) is associated with diabetic retinopathy, Loeys-Dietz syndrome 2, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is TGFBR2 p.Pro25= (c.75A>G) in the general population?

TGFBR2 p.Pro25= (c.75A>G) is rare (popmax 0.149%, mid) (gnomAD).

TGFBR2 p.Pro25=

c.75A>G · rs572435149 · VCV543908

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.149%, mid)

Conditions

diabetic retinopathy

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 -0.85	GERP -2.3, phastCons 0.001
Overall
CADD	8.52	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.149% Middle Eastern · 9/6,034 alleles

Filtering AF 0.0777% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0581%

Overall 0.00281% 45/1,601,084 alleles · rare exomes 42/1,449,112 · genomes 3/151,972 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.149%	670
European (non-Finnish)	0.00298%	33,550
Remaining individualsnot grpmax-eligible	0.00161%	61,932

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: TGFBR2
Protein: p.Pro25=
Coding: c.75A>G
MANE Select: NM_003242
dbSNP: rs572435149
Type: single nucleotide variant
Location: chr3:30606958 (GRCh38)
Gene constraint: LOEUF 0.531 · pLI 0.91 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.22 · 22 PDB

Full TGFBR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

diabetic retinopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Loeys-Dietz syndrome 2 familial thoracic aortic aneurysm and aortic dissection

Similar variants

TGFBR2 p.Pro25Ser Uncertain significance ★ ⚠ same residue
TGFBR2 p.Ala414Pro Pathogenic/Likely pathogenic ★★ same condition
TGFBR2 p.Ala527Thr Likely pathogenic ★★ same condition
TGFBR2 p.Ala527Val Pathogenic/Likely pathogenic ★★ same condition
TGFBR2 p.Arg356Pro Pathogenic/Likely pathogenic ★★ same condition
TGFBR2 p.Arg378Ser Pathogenic/Likely pathogenic ★★ same condition
TGFBR2 p.Arg460Cys Pathogenic ★★ same condition
TGFBR2 p.Arg460Gly 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/tgfbr2-p-pro25 (accessed [today's date]).

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