PITX2 p.Ala21=
c.63C>T · rs61756183 · VCV288932
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 4 submitters
gnomAD v4.1
Rare
rare (popmax 0.632%, nfe)
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 -2, phastCons 0.98 |
| Overall | ||
| CADD | 11.86 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.632%
European (non-Finnish) · 7,352/1,162,712 alleles
Filtering AF
0.62%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.615%
Overall
0.515%
8,126/1,579,196 alleles · rare
exomes 7,622/1,426,880 · genomes 504/152,316 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.632% | 158 |
| Remaining individualsnot grpmax-eligible | 0.36% | 278 |
| Finnishnot grpmax-eligible | 0.334% | 299 |
| Ashkenazi Jewishnot grpmax-eligible | 0.304% | 329 |
| Admixed American | 0.204% | 491 |
| Middle Eastern | 0.138% | 727 |
| African / African-American | 0.0876% | 1,141 |
| South Asian | 0.0858% | 1,165 |
| East Asian | 0.00234% | 42,690 |
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.Ala21=
- Coding
- c.63C>T
- MANE Select
- NM_000325
- dbSNP
- rs61756183
- Type
- single nucleotide variant
- Location
- chr4:110622398 (GRCh38)
- Gene constraint
- LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 62.59 · 3 PDB
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-ala21 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown