Is TBX4 p.Ala92= (c.276T>G) pathogenic?

TBX4 p.Ala92= (c.276T>G) is classified Benign in TBX4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). Common (popmax 37.4%, eas) — too common for a highly-penetrant pathogenic allele; Associated with coxopodopatellar syndrome.

What condition is associated with TBX4 p.Ala92= (c.276T>G)?

TBX4 p.Ala92= (c.276T>G) is associated with coxopodopatellar syndrome (ClinVar).

How is Coxopodopatellar syndrome inherited?

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

TBX4 p.Ala92=

Q: How common is TBX4 p.Ala92= (c.276T>G) in the general population?

TBX4 p.Ala92= (c.276T>G) is common (popmax 37.4%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.276T>G · rs3744447 · VCV324249

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 37.4%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

coxopodopatellar syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.1	GERP -5.5, phastCons 0.18
Overall
CADD	11.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 37.4% East Asian · 16,758/44,772 alleles

Filtering AF 37% ClinGen BA1/BS1 input FAF95, joint · FAF99 36.8%

Overall 17.3% 278,997/1,612,722 alleles · common exomes 253,722/1,461,088 · genomes 25,275/151,634 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	37.4%	3
Finnishnot grpmax-eligible	27.9%	4
South Asian	20.1%	5
Middle Eastern	19.7%	5
Admixed American	19.2%	5
Amishnot grpmax-eligible	18.7%	5
Remaining individualsnot grpmax-eligible	18.1%	6
Ashkenazi Jewishnot grpmax-eligible	17.8%	6
European (non-Finnish)	16%	6
African / African-American	11.5%	9

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.Ala92=
Coding: c.276T>G
MANE Select: NM_001321120
dbSNP: rs3744447
Type: single nucleotide variant
Location: chr17:61457626 (GRCh38)
Gene constraint: LOEUF 0.379 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.96
Residue 92: a DNA-binding region

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 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
TBX4 p.Pro37Leu 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-ala92 (accessed [today's date]).

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