Is TBX3 p.Pro178= (c.534C>T) pathogenic?

TBX3 p.Pro178= (c.534C>T) is classified Likely benign in TBX3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-08-29). Very rare (popmax 0.00267%, afr); Associated with TBX3-related disorder.

What condition is associated with TBX3 p.Pro178= (c.534C>T)?

TBX3 p.Pro178= (c.534C>T) is associated with TBX3-related disorder (ClinVar).

How common is TBX3 p.Pro178= (c.534C>T) in the general population?

TBX3 p.Pro178= (c.534C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

TBX3 p.Pro178=

c.534C>T · rs757541848 · VCV3046481

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

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 -1.6	GERP -3.8
Overall
CADD	10.62	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,862 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000992% 16/1,613,662 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
African / African-Americangrpmax	0.00267%	37,431
East Asian	0.00223%	44,858
Remaining individualsnot grpmax-eligible	0.0016%	62,486
Finnishnot grpmax-eligible	0.00156%	63,898
European (non-Finnish)	0.000847%	117,997

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro178=
Coding: c.534C>T
MANE Select: NM_005996
dbSNP: rs757541848
Type: single nucleotide variant
Location: chr12:114681002 (GRCh38)
Gene constraint: LOEUF 0.468 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.55 · 1 PDB
Residue 178: a DNA-binding region; an α-helix

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

Disease context

TBX3-related disorder

Similar variants

TBX3 c.1710+1G>A Likely pathogenic ★ same condition
TBX3 p.Glu381Ter Pathogenic ★ same condition
TBX3 p.Met123Ile Likely pathogenic ★ same condition
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
TBX3 c.657+1G>A Pathogenic same condition
TBX3 c.658-262G>A 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-pro178 (accessed [today's date]).

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