Is PITX2 p.Pro273= (c.819G>A) pathogenic?

PITX2 p.Pro273= (c.819G>A) is classified Benign/Likely benign in PITX2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-08-05). Low-frequency (popmax 2.19%, sas); Associated with cataract.

What condition is associated with PITX2 p.Pro273= (c.819G>A)?

PITX2 p.Pro273= (c.819G>A) is associated with cataract, anterior segment dysgenesis 4, Axenfeld-Rieger syndrome type 1 (ClinVar).

How common is PITX2 p.Pro273= (c.819G>A) in the general population?

PITX2 p.Pro273= (c.819G>A) is low-frequency (popmax 2.19%, sas) (gnomAD).

PITX2 p.Pro273=

c.819G>A · rs148191851 · VCV167472

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.19%, sas)

Conditions

cataract

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -4.8, phastCons 0.001
Overall
CADD	10.48	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.19% South Asian · 1,991/91,076 alleles

Filtering AF 2.11% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.07%

Overall 0.299% 4,829/1,614,162 alleles · low-frequency exomes 4,505/1,461,890 · genomes 324/152,272 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	2.19%	46
Middle Eastern	0.643%	155
Remaining individualsnot grpmax-eligible	0.339%	295
Ashkenazi Jewishnot grpmax-eligible	0.26%	384
European (non-Finnish)	0.205%	488
Admixed American	0.08%	1,250
African / African-American	0.0347%	2,886
Finnishnot grpmax-eligible	0.0312%	3,202

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.Pro273=
Coding: c.819G>A
MANE Select: NM_000325
dbSNP: rs148191851
Type: single nucleotide variant
Location: chr4:110618281 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.59 · 3 PDB
Residue 273: a UniProt-annotated variant site (in rieg1)

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

Disease context

cataract — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: anterior segment dysgenesis 4 Axenfeld-Rieger syndrome type 1 ring dermoid of cornea Peters anomaly

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-pro273 (accessed [today's date]).

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