Is TGFB2 p.Pro119Ser (c.355C>T) pathogenic?

TGFB2 p.Pro119Ser (c.355C>T) is classified Conflicting classifications of pathogenicity in TGFB2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-10-02). AlphaMissense: likely benign (0.0895); Very rare (popmax 0.00175%, amr).

How common is TGFB2 p.Pro119Ser (c.355C>T) in the general population?

TGFB2 p.Pro119Ser (c.355C>T) is very rare (popmax 0.00175%, amr) (gnomAD).

What do computational predictors say about TGFB2 p.Pro119Ser (c.355C>T)?

AlphaMissense predicts likely benign (score 0.0895) — an in-silico prediction, not a clinical call.

TGFB2 p.Pro119Ser

c.355C>T · rs2464757454 · VCV2637753

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0895 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0895	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -5.60	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 95 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	21.8	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 0.00175% Admixed American · 1/57,150 alleles

Overall 6.32e-05% 1/1,582,982 alleles · very rare exomes 1/1,430,830 · genomes 0/152,152 · 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: TGFB2
Protein: p.Pro119Ser
Coding: c.355C>T
MANE Select: NM_003238
dbSNP: rs2464757454
Type: single nucleotide variant
Location: chr1:218405177 (GRCh38)
Gene constraint: LOEUF 0.463 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.41 · 11 PDB
Residue 119: a UniProt-annotated variant site (in lds4)

Full TGFB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TGFB2 p.Pro119= Benign/Likely benign ★★ same residue
TGFB2 p.Pro119Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TGFB2 p.Pro119fs Pathogenic ★★ same residue
TGFB2 c.1086+2T>C Likely pathogenic ★★ same type
TGFB2 c.346+1G>A Pathogenic/Likely pathogenic ★★ same type
TGFB2 c.346+1G>T Likely pathogenic ★★ same type
TGFB2 c.510+1G>A Likely pathogenic ★★ same type
TGFB2 c.932+1G>A Pathogenic/Likely pathogenic ★★ same type

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-pro119ser (accessed [today's date]).

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