Is TBX3 p.Pro19= (c.57G>T) pathogenic?

TBX3 p.Pro19= (c.57G>T) is classified Likely benign in TBX3 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-28). Ultra-rare (popmax 0.0168%, mid); Associated with ulnar-mammary syndrome.

What condition is associated with TBX3 p.Pro19= (c.57G>T)?

TBX3 p.Pro19= (c.57G>T) is associated with ulnar-mammary syndrome (ClinVar).

How common is TBX3 p.Pro19= (c.57G>T) in the general population?

TBX3 p.Pro19= (c.57G>T) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

TBX3 p.Pro19=

c.57G>T · VCV3358446

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Conditions

ulnar-mammary syndrome

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 0.65	GERP -1.7, phastCons 1
Overall
CADD	11.99	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0168% Middle Eastern · 1/5,952 alleles

Overall 0.000205% 3/1,460,374 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,952
Remaining individualsnot grpmax-eligible	0.0016%	62,436
European (non-Finnish)	8.48e-05%	1,179,651

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: TBX3
Protein: p.Pro19=
Coding: c.57G>T
MANE Select: NM_005996
Type: single nucleotide variant
Location: chr12:114683144 (GRCh38)
Gene constraint: LOEUF 0.468 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.55 · 1 PDB

Full TBX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ulnar-mammary syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TBX3 p.Gln475Ter Pathogenic ★★ same condition
TBX3 c.1710+3A>G Uncertain significance ★★ same condition
TBX3 p.Ala158Thr Uncertain significance ★★ ⚠ same condition
TBX3 p.Ala336Val Uncertain significance ★★ ⚠ same condition
TBX3 p.Ala357Pro Uncertain significance ★★ ⚠ same condition
TBX3 p.Ala391Gly Uncertain significance ★★ ⚠ same condition
TBX3 p.Ala470Thr Uncertain significance ★★ ⚠ same condition
TBX3 p.Ala488Thr Uncertain significance ★★ ⚠ 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/tbx3-p-pro19 (accessed [today's date]).

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