Is TBX3 p.Phe459= (c.1377C>T) pathogenic?

TBX3 p.Phe459= (c.1377C>T) is classified Likely benign in TBX3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-01). Ultra-rare (popmax 0.0331%, amr); Associated with ulnar-mammary syndrome.

What condition is associated with TBX3 p.Phe459= (c.1377C>T)?

TBX3 p.Phe459= (c.1377C>T) is associated with ulnar-mammary syndrome (ClinVar).

How common is TBX3 p.Phe459= (c.1377C>T) in the general population?

TBX3 p.Phe459= (c.1377C>T) is ultra-rare (popmax 0.0331%, amr) (gnomAD).

TBX3 p.Phe459=

c.1377C>T · rs544127946 · VCV2196754

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, amr)

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 0.007	GERP -3.9, phastCons 0.46
Overall
CADD	8.108	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0331% Admixed American · 15/45,324 alleles

Filtering AF 0.0204% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0165%

Overall 0.00112% 17/1,518,554 alleles · ultra-rare exomes 15/1,366,226 · genomes 2/152,328 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0331%	3,022
European (non-Finnish)	0.000176%	568,133

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.Phe459=
Coding: c.1377C>T
MANE Select: NM_005996
dbSNP: rs544127946
Type: single nucleotide variant
Location: chr12:114674498 (GRCh38)
Gene constraint: LOEUF 0.468 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.55 · 1 PDB
Residue 459: the 'disordered' region

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-phe459 (accessed [today's date]).

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