Is TGFB1 p.Ser4Phe (c.11C>T) pathogenic?

TGFB1 p.Ser4Phe (c.11C>T) is classified Uncertain significance in TGFB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1754); Ultra-rare (popmax 0.012%, sas).

How common is TGFB1 p.Ser4Phe (c.11C>T) in the general population?

TGFB1 p.Ser4Phe (c.11C>T) is ultra-rare (popmax 0.012%, sas) (gnomAD).

What do computational predictors say about TGFB1 p.Ser4Phe (c.11C>T)?

AlphaMissense predicts likely benign (score 0.1754) — an in-silico prediction, not a clinical call.

TGFB1 p.Ser4Phe

c.11C>T · rs752190020 · VCV1898806

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1754 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1754	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -9.39	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 9.3	GERP 0.17, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 21 kb · p 0.0024 · regional, not allelic
Overall
CADD	23.7	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 0.012% South Asian · 10/83,582 alleles

Filtering AF 0.00643% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00489%

Overall 0.00085% 13/1,529,424 alleles · ultra-rare exomes 12/1,377,322 · genomes 1/152,102 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.012%	8,358
East Asian	0.00495%	20,196
European (non-Finnish)	8.75e-05%	1,142,582

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.Ser4Phe
Coding: c.11C>T
MANE Select: NM_000660
dbSNP: rs752190020
Type: single nucleotide variant
Location: chr19:41353034 (GRCh38)
Gene constraint: LOEUF 0.682 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 80.11 · 22 PDB

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

Similar variants

TGFB1 p.Ser4= Likely benign ★ same residue
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

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-ser4phe (accessed [today's date]).

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