PITX2 p.Arg45Trp
c.133C>T · VCV4968234
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00134%, afr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.699 | pathogenic-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 2.2, phastCons 1 |
| Regional constraint | o/e 1.13 | unconstrained · MANE · 1,135 bp · p 0.19 · regional, not allelic |
| Overall | ||
| CADD | 33.0 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00134%
African / African-American · 1/74,854 alleles
Overall
6.23e-05%
1/1,606,234 alleles · very rare
exomes 1/1,453,872 · genomes 0/152,362 · joint denominator
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.Arg45Trp
- Coding
- c.133C>T
- MANE Select
- NM_000325
- Type
- single nucleotide variant
- Location
- chr4:110622328 (GRCh38)
- Gene constraint
- LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 62.59 · 3 PDB
- Residue 45
- the 'disordered' region
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-arg45trp (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown