Is TGFB2 p.His336= (c.1008C>T) pathogenic?

TGFB2 p.His336= (c.1008C>T) is classified Likely benign in TGFB2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-03). Ultra-rare (popmax 0.0329%, mid); Associated with Loeys-Dietz syndrome 4.

What condition is associated with TGFB2 p.His336= (c.1008C>T)?

TGFB2 p.His336= (c.1008C>T) is associated with Loeys-Dietz syndrome 4, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is TGFB2 p.His336= (c.1008C>T) in the general population?

TGFB2 p.His336= (c.1008C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

TGFB2 p.His336=

c.1008C>T · rs886038528 · VCV259004

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

Loeys-Dietz syndrome 4

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 -0.42	GERP -3.8, phastCons 0.19
Overall
CADD	6.434	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00248% 40/1,612,600 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Remaining individualsnot grpmax-eligible	0.0048%	20,819
East Asian	0.00446%	22,408
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
African / African-American	0.00268%	37,255
European (non-Finnish)	0.00237%	42,133
Finnishnot grpmax-eligible	0.00157%	63,736
South Asian	0.0011%	90,922

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.His336=
Coding: c.1008C>T
MANE Select: NM_003238
dbSNP: rs886038528
Type: single nucleotide variant
Location: chr1:218437418 (GRCh38)
Gene constraint: LOEUF 0.463 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.41 · 11 PDB
Residue 336: a UniProt-annotated variant site (in lds4); a β-strand; a disulfide bond

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

Disease context

Loeys-Dietz syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

Similar variants

TGFB2 c.346+1G>A Pathogenic/Likely pathogenic ★★ same condition
TGFB2 c.346+1G>T Likely pathogenic ★★ same condition
TGFB2 c.510+1G>A Likely pathogenic ★★ same condition
TGFB2 c.932+1G>A Pathogenic/Likely pathogenic ★★ same condition
TGFB2 c.933-1G>A Pathogenic/Likely pathogenic ★★ same condition
TGFB2 p.Arg131Ter Pathogenic/Likely pathogenic ★★ same condition
TGFB2 p.Arg299Gln Pathogenic/Likely pathogenic ★★ same condition
TGFB2 p.Arg299Trp Pathogenic/Likely 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/tgfb2-p-his336 (accessed [today's date]).

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