PITX2 p.Ala14=
c.42A>G · VCV4968238
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0168%, nfe)
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 0.27 | GERP -4, phastCons 1 |
| Overall | ||
| CADD | 10.77 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0168%
European (non-Finnish) · 194/1,156,046 alleles
Filtering AF
0.0148%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0141%
Overall
0.0129%
202/1,567,158 alleles · ultra-rare
exomes 192/1,414,954 · genomes 10/152,204 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.0168% | 5,959 |
| African / African-American | 0.00542% | 18,434 |
| Remaining individualsnot grpmax-eligible | 0.00494% | 20,226 |
| Admixed American | 0.00189% | 52,970 |
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.Ala14=
- Coding
- c.42A>G
- MANE Select
- NM_000325
- Type
- single nucleotide variant
- Location
- chr4:110622419 (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-ala14 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown