PITX2 p.Val127fs
c.374_378dup · VCV4968226
Likely pathogenic
Single submitter
Classification
Likely pathogenic
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
Consequence
frameshift
predicted LoF
gnomAD v4.1
Rare
Conditions
1
PITX2-related disorder
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | frameshift | predicted loss-of-function in a haploinsufficient gene (ClinGen) |
|---|---|---|
| NMD | escapes | premature termination codon within the last 50 nt of the penultimate exon (2 of 3, 32 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 7.6 | GERP 1.6, phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Variant & gene context
- Gene
- PITX2
- Protein
- p.Val127fs
- Coding
- c.374_378dup
- MANE Select
- NM_000325
- Type
- Duplication
- Location
- chr4:110621196 (GRCh38)
- Gene constraint
- LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 62.59 · 3 PDB
- Residue 127
- a DNA-binding region; an α-helix
Disease context
PITX2-related disorder
Similar variants
- PITX2 p.Ser87fs Likely pathogenic ★ same condition
- PITX2 p.Arg122His Pathogenic ★★ same condition
- PITX2 c.*454C>T Benign ★★ same condition
- PITX2 p.Ser206= Benign/Likely benign ★★ same condition
- PITX2 p.Arg144Leu Likely pathogenic ★ same condition
- PITX2 p.Gln103Arg Likely pathogenic ★ same condition
- PITX2 p.Glu123Ter Likely pathogenic ★ same condition
- PITX2 p.Thr110fs 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-val127fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown