PITX2 p.Leu196=
c.588A>C · rs749452484 · VCV2048618
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00667%, amr)
Conditions
2
anterior segment dysgenesis 4
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.052 | moderately benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 0.59 | GERP -0.58, phastCons 1 |
| Overall | ||
| CADD | 11.37 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00667%
Admixed American · 4/59,996 alleles
Filtering AF
0.00226%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00135%
Overall
0.000274%
4/1,460,986 alleles · very rare
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.Leu196=
- Coding
- c.588A>C
- MANE Select
- NM_000325
- dbSNP
- rs749452484
- Type
- single nucleotide variant
- Location
- chr4:110618512 (GRCh38)
- Gene constraint
- LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 62.59 · 3 PDB
- Residue 196
- a UniProt-annotated variant site (in rieg1)
Similar variants
- PITX2 c.411+1G>A Pathogenic ★★ same condition
- PITX2 c.412-11A>G Pathogenic ★★ same condition
- PITX2 c.412-2A>G Pathogenic/Likely pathogenic ★★ same condition
- PITX2 p.Arg115His Pathogenic/Likely pathogenic ★★ same condition
- PITX2 p.Arg122His Pathogenic ★★ same condition
- PITX2 p.Arg144Pro Pathogenic/Likely pathogenic ★★ same condition
- PITX2 p.Arg144Trp Pathogenic/Likely pathogenic ★★ same condition
- PITX2 p.Arg96Trp Pathogenic/Likely pathogenic ★★ 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/pitx2-p-leu196 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown