Is PITX2 p.Pro202fs (c.592_604dup) pathogenic?

PITX2 p.Pro202fs (c.592604dup) is classified Pathogenic in PITX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-07). Associated with anterior segment dysgenesis 4.

What condition is associated with PITX2 p.Pro202fs (c.592_604dup)?

PITX2 p.Pro202fs (c.592_604dup) is associated with anterior segment dysgenesis 4, Axenfeld-Rieger syndrome type 1 (ClinVar).

PITX2 p.Pro202fs

c.592_604dup · VCV4786493

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	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1

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

Variant & gene context

Gene: PITX2
Protein: p.Pro202fs
Coding: c.592_604dup
MANE Select: NM_000325
Type: Duplication
Location: chr4:110618495 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.59 · 3 PDB
Residue 202: a UniProt-annotated variant site (in rieg1)

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.Cys159Ter Pathogenic ★ same condition
PITX2 p.His98fs Pathogenic ★ same condition
PITX2 p.Pro265fs Pathogenic ★ same condition
PITX2 p.Pro274fs Likely pathogenic ★ same condition
PITX2 p.Thr121fs Likely pathogenic ★ same condition
PITX2 p.Thr132fs Likely pathogenic ★ same condition
PITX2 p.Thr239_Gly240insCysProGlnGlnTer Pathogenic ★ same condition
PITX2 p.Gln103_Leu104insThrHisPheThrSerGlnGln 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-pro202fs (accessed [today's date]).

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