Is TBX3 p.Phe397= (c.1191C>T) pathogenic?

TBX3 p.Phe397= (c.1191C>T) is classified Likely benign in TBX3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-12-22). Very rare (popmax 0.00223%, eas); Associated with TBX3-related disorder.

What condition is associated with TBX3 p.Phe397= (c.1191C>T)?

TBX3 p.Phe397= (c.1191C>T) is associated with TBX3-related disorder (ClinVar).

How common is TBX3 p.Phe397= (c.1191C>T) in the general population?

TBX3 p.Phe397= (c.1191C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

TBX3 p.Phe397=

c.1191C>T · rs1380113912 · VCV3047437

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

TBX3-related disorder

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 0.99	GERP -2.4, phastCons 0.46
Overall
CADD	6.187	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,800 alleles

Overall 0.000275% 4/1,455,030 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,800
Remaining individualsnot grpmax-eligible	0.00161%	62,296
African / African-American	0.00133%	75,036
South Asian	0.0011%	90,682

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.Phe397=
Coding: c.1191C>T
MANE Select: NM_005996
dbSNP: rs1380113912
Type: single nucleotide variant
Location: chr12:114674684 (GRCh38)
Gene constraint: LOEUF 0.468 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.55 · 1 PDB
Residue 397: the 'disordered' region

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

Disease context

TBX3-related disorder

Similar variants

TBX3 p.Phe397Ser Uncertain significance ★ ⚠ same residue
TBX3 c.1710+1G>A Likely pathogenic ★ same condition
TBX3 p.Glu381Ter Pathogenic ★ same condition
TBX3 p.Met123Ile Likely pathogenic ★ same condition
TBX3 p.Phe397fs Likely pathogenic ★ same residue
TBX3 c.658-297G>A Uncertain significance ★ ⚠ same condition
TBX3 p.Ala192Thr Uncertain significance ★ ⚠ same condition
TBX3 c.390-1G>A 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/tbx3-p-phe397 (accessed [today's date]).

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