PITX2 p.Ser226=
c.678C>T · VCV4968219
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
rare (popmax 0.232%, sas)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.158 | moderately benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 3.1 | GERP 0.7, phastCons 1 |
| Overall | ||
| CADD | 11.6 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.232%
South Asian · 211/91,072 alleles
Filtering AF
0.206%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.196%
Overall
0.014%
226/1,614,160 alleles · rare
exomes 214/1,461,882 · genomes 12/152,278 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.232% | 432 |
| Remaining individualsnot grpmax-eligible | 0.0176% | 5,683 |
| Middle Eastern | 0.0165% | 6,062 |
| European (non-Finnish) | 0.000254% | 393,345 |
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
- PITX2
- Protein
- p.Ser226=
- Coding
- c.678C>T
- MANE Select
- NM_000325
- Type
- single nucleotide variant
- Location
- chr4:110618422 (GRCh38)
- Gene constraint
- LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 62.59 · 3 PDB
- Residue 226
- a UniProt-annotated variant site (in rieg1)
Similar variants
- PITX2 c.411+1G>A Pathogenic ★★ same type
- PITX2 c.412-11A>G Pathogenic ★★ same type
- PITX2 c.412-2A>G Pathogenic/Likely pathogenic ★★ same type
- PITX2 p.Arg115His Pathogenic/Likely pathogenic ★★ same type
- PITX2 p.Arg122His Pathogenic ★★ same type
- PITX2 p.Arg144Pro Pathogenic/Likely pathogenic ★★ same type
- PITX2 p.Arg144Trp Pathogenic/Likely pathogenic ★★ same type
- PITX2 p.Arg96Trp Pathogenic/Likely pathogenic ★★ same type
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/pitx2-p-ser226 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown