Is TBX3 p.Phe397Ser (c.1190T>C) pathogenic?

TBX3 p.Phe397Ser (c.1190T>C) is classified Uncertain significance in TBX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-04). AlphaMissense: likely benign (0.1626); Absent from gnomAD v4.1; Associated with ulnar-mammary syndrome.

What condition is associated with TBX3 p.Phe397Ser (c.1190T>C)?

TBX3 p.Phe397Ser (c.1190T>C) is associated with ulnar-mammary syndrome (ClinVar).

How common is TBX3 p.Phe397Ser (c.1190T>C) in the general population?

TBX3 p.Phe397Ser (c.1190T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TBX3 p.Phe397Ser (c.1190T>C)?

AlphaMissense predicts likely benign (score 0.1626) — an in-silico prediction, not a clinical call.

TBX3 p.Phe397Ser

c.1190T>C · rs761584262 · VCV2070375

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1626 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ulnar-mammary syndrome

Computational evidence

Protein change
AlphaMissense	0.1626	likely benign
REVEL	0.451	indeterminate
SaProt	LLR -2.39	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP -0.21, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 2,991 bp · p 0.023 · regional, not allelic
Overall
CADD	19.94	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F417S vs ClinVar F397S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TBX3
Protein: p.Phe397Ser
Coding: c.1190T>C
MANE Select: NM_005996
dbSNP: rs761584262
Type: single nucleotide variant
Location: chr12:114674685 (GRCh38)
Gene constraint: LOEUF 0.468 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.55 · 1 PDB
Residue 417 UniProt numbering: 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.Phe397= Likely benign same residue
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

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-phe397ser (accessed [today's date]).

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