Is TBX3 p.Ser320Phe (c.959C>T) pathogenic?

TBX3 p.Ser320Phe (c.959C>T) is classified Uncertain significance in TBX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-20). AlphaMissense: ambiguous (0.5207); Very rare (popmax 0.00133%, afr); Associated with ulnar-mammary syndrome.

What condition is associated with TBX3 p.Ser320Phe (c.959C>T)?

TBX3 p.Ser320Phe (c.959C>T) is associated with ulnar-mammary syndrome (ClinVar).

How common is TBX3 p.Ser320Phe (c.959C>T) in the general population?

TBX3 p.Ser320Phe (c.959C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about TBX3 p.Ser320Phe (c.959C>T)?

AlphaMissense predicts ambiguous (score 0.5207) — an in-silico prediction, not a clinical call.

TBX3 p.Ser320Phe

c.959C>T · rs1396893876 · VCV1465536

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5207 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

ulnar-mammary syndrome

Computational evidence

Protein change
AlphaMissense	0.5207	ambiguous
REVEL	0.562	indeterminate
SaProt	LLR -8.58	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 146 bp · p 0.047 · regional, not allelic
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S340F vs ClinVar S320F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,932 alleles

Overall 0.000124% 2/1,614,086 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,932
European (non-Finnish)	8.47e-05%	1,180,048

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.Ser320Phe
Coding: c.959C>T
MANE Select: NM_005996
dbSNP: rs1396893876
Type: single nucleotide variant
Location: chr12:114676393 (GRCh38)
Gene constraint: LOEUF 0.468 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.55 · 1 PDB
Residue 320: 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-ser320phe (accessed [today's date]).

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