Is TGFBR2 p.Ser486= (c.1458C>T) pathogenic?

TGFBR2 p.Ser486= (c.1458C>T) is classified Benign/Likely benign in TGFBR2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-14). Rare (popmax 0.272%, afr); Associated with colorectal cancer, hereditary nonpolyposis, type 6.

What condition is associated with TGFBR2 p.Ser486= (c.1458C>T)?

TGFBR2 p.Ser486= (c.1458C>T) is associated with colorectal cancer, hereditary nonpolyposis, type 6, esophageal cancer, Loeys-Dietz syndrome 2 (ClinVar).

How common is TGFBR2 p.Ser486= (c.1458C>T) in the general population?

TGFBR2 p.Ser486= (c.1458C>T) is rare (popmax 0.272%, afr) (gnomAD).

TGFBR2 p.Ser486=

c.1458C>T · rs139881155 · VCV263413

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.272%, afr)

Conditions

colorectal cancer, hereditary nonpolyposis, type 6

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 1.8	GERP 4.2, phastCons 1
Overall
CADD	11.63	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.272% African / African-American · 204/75,062 alleles

Filtering AF 0.241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.229%

Overall 0.016% 258/1,614,208 alleles · rare exomes 148/1,461,866 · genomes 110/152,342 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.272%	368
Middle Eastern	0.214%	466
Remaining individualsnot grpmax-eligible	0.0416%	2,404
Admixed American	0.0133%	7,504
South Asian	0.0011%	91,090
European (non-Finnish)	0.000508%	196,670

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.Ser486=
Coding: c.1458C>T
MANE Select: NM_003242
dbSNP: rs139881155
Type: single nucleotide variant
Location: chr3:30688445 (GRCh38)
Gene constraint: LOEUF 0.531 · pLI 0.91 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 81.22 · 22 PDB
Residue 486: an α-helix; the protein kinase domain; the 'sufficient for interaction with clu' region

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

Disease context

colorectal cancer, hereditary nonpolyposis, type 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

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
TGFBR2 p.Arg460His 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-ser486 (accessed [today's date]).

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