Is TGFB1 p.Ser288Phe (c.863C>T) pathogenic?

TGFB1 p.Ser288Phe (c.863C>T) is classified Uncertain significance in TGFB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-27). AlphaMissense: ambiguous (0.3595); Very rare (popmax 8.48e-05%, nfe).

How common is TGFB1 p.Ser288Phe (c.863C>T) in the general population?

TGFB1 p.Ser288Phe (c.863C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about TGFB1 p.Ser288Phe (c.863C>T)?

AlphaMissense predicts ambiguous (score 0.3595) — an in-silico prediction, not a clinical call.

TGFB1 p.Ser288Phe

c.863C>T · rs2037942138 · VCV2013824

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3595 · ACMG-weighted

gnomAD v4.1

Rare

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

Computational evidence

Protein change
AlphaMissense	0.3595	ambiguous
REVEL	0.532	indeterminate
SaProt	LLR -9.21	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP -0.47, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 21 kb · p 0.0024 · regional, not allelic
Overall
CADD	27.9	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) · 1/1,179,806 alleles

Overall 6.2e-05% 1/1,613,668 alleles · very rare exomes 1/1,461,418 · genomes 0/152,250 · 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: TGFB1
Protein: p.Ser288Phe
Coding: c.863C>T
MANE Select: NM_000660
dbSNP: rs2037942138
Type: single nucleotide variant
Location: chr19:41332279 (GRCh38)
Gene constraint: LOEUF 0.682 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 80.11 · 22 PDB
Residue 288: an α-helix

Full TGFB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TGFB1 p.Arg218Cys Pathogenic ★★ same type
TGFB1 p.Arg218His Pathogenic/Likely pathogenic ★★ ⚠ same type
TGFB1 p.Tyr171Cys Likely pathogenic ★★ same type
TGFB1 c.1014+5G>A Uncertain significance ★★ same type
TGFB1 p.Arg152Trp Uncertain significance ★★ ⚠ same type
TGFB1 p.Arg185Trp Uncertain significance ★★ ⚠ same type
TGFB1 p.Arg277Cys Uncertain significance ★★ ⚠ same type
TGFB1 p.Arg385Gly Uncertain significance ★★ 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/tgfb1-p-ser288phe (accessed [today's date]).

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