Is TBX4 p.Ser8= (c.24C>T) pathogenic?

TBX4 p.Ser8= (c.24C>T) is classified Benign/Likely benign in TBX4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-18). Ultra-rare (popmax 0.0337%, mid); Associated with coxopodopatellar syndrome.

What condition is associated with TBX4 p.Ser8= (c.24C>T)?

TBX4 p.Ser8= (c.24C>T) is associated with coxopodopatellar syndrome (ClinVar).

How common is TBX4 p.Ser8= (c.24C>T) in the general population?

TBX4 p.Ser8= (c.24C>T) is ultra-rare (popmax 0.0337%, mid) (gnomAD).

How is Coxopodopatellar syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

TBX4 p.Ser8=

c.24C>T · rs777880490 · VCV324242

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0337%, mid)

Conditions

coxopodopatellar 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 0.17	GERP -1.5, phastCons 0.9
Overall
CADD	10.55	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0337% Middle Eastern · 2/5,942 alleles

Filtering AF 0.0149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0141%

Overall 0.0133% 209/1,568,060 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0337%	2,971
European (non-Finnish)	0.0169%	5,934
Admixed American	0.00749%	13,348
African / African-American	0.00541%	18,498
Remaining individualsnot grpmax-eligible	0.00494%	20,233
East Asian	0.00236%	42,314

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: TBX4
Protein: p.Ser8=
Coding: c.24C>T
MANE Select: NM_001321120
dbSNP: rs777880490
Type: single nucleotide variant
Location: chr17:61456514 (GRCh38)
Gene constraint: LOEUF 0.379 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.96

Full TBX4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

coxopodopatellar syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Coxopodopatellar syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

TBX4 p.Ser8Phe Uncertain significance ★ ⚠ same residue
TBX4 c.1021+1G>A Pathogenic/Likely pathogenic ★★ same condition
TBX4 p.Arg250Trp Pathogenic ★★ same condition
TBX4 p.Arg261Ter Pathogenic ★★ same condition
TBX4 p.Arg340Ter Pathogenic/Likely pathogenic ★★ same condition
TBX4 p.Arg353Ter Pathogenic/Likely pathogenic ★★ same condition
TBX4 c.401+3A>T Uncertain significance ★★ same condition
TBX4 p.Asp253Glu 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/tbx4-p-ser8 (accessed [today's date]).

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