Is TGFB2 p.Ser377Pro (c.1129T>C) pathogenic?

TGFB2 p.Ser377Pro (c.1129T>C) is classified Uncertain significance in TGFB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-27). AlphaMissense: likely pathogenic (0.876); Very rare (popmax 8.48e-05%, nfe).

How common is TGFB2 p.Ser377Pro (c.1129T>C) in the general population?

TGFB2 p.Ser377Pro (c.1129T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about TGFB2 p.Ser377Pro (c.1129T>C)?

AlphaMissense predicts likely pathogenic (score 0.876) — an in-silico prediction, not a clinical call.

TGFB2 p.Ser377Pro

c.1129T>C · rs2464889965 · VCV2429194

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.876 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.876	likely pathogenic
REVEL	0.693	pathogenic-leaning
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.3	GERP 0.84, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 95 kb · p 2.1e-08 · regional, not allelic
Overall
CADD	23.0	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 8.48e-05% European (non-Finnish) · 1/1,179,920 alleles

Overall 6.2e-05% 1/1,613,824 alleles · very rare exomes 1/1,461,538 · genomes 0/152,286 · 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.Ser377Pro
Coding: c.1129T>C
MANE Select: NM_003238
dbSNP: rs2464889965
Type: single nucleotide variant
Location: chr1:218441246 (GRCh38)
Gene constraint: LOEUF 0.463 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.41 · 11 PDB
Residue 377: a UniProt-annotated variant site (in lds4)

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

Similar variants

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
TGFB2 c.933-1G>A Pathogenic/Likely pathogenic ★★ same type
TGFB2 p.Arg131Ter Pathogenic/Likely pathogenic ★★ same type
TGFB2 p.Arg299Gln 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-ser377pro (accessed [today's date]).

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