Is PITX2 p.Pro86fs (c.256_257insA) pathogenic?

PITX2 p.Pro86fs (c.256257insA) is classified Pathogenic in PITX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-08). Associated with anterior segment dysgenesis 4.

What condition is associated with PITX2 p.Pro86fs (c.256_257insA)?

PITX2 p.Pro86fs (c.256_257insA) is associated with anterior segment dysgenesis 4, Axenfeld-Rieger syndrome type 1 (ClinVar).

PITX2 p.Pro86fs

c.256_257insA · VCV4785512

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

anterior segment dysgenesis 4

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	predicted	premature termination codon in exon 2 of 3
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: PITX2
Protein: p.Pro86fs
Coding: c.256_257insA
MANE Select: NM_000325
Type: Insertion
Location: chr4:110621318 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.59 · 3 PDB
Residue 86: a DNA-binding region; the 'disordered' region; a β-strand

Full PITX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

anterior segment dysgenesis 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Axenfeld-Rieger syndrome type 1

Similar variants

PITX2 p.Pro86Leu Uncertain significance ★ ⚠ same residue
PITX2 p.Pro86Thr Uncertain significance ★ ⚠ same residue
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

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-pro86fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown