Is PITX2 p.Arg91= (c.273G>A) pathogenic?

PITX2 p.Arg91= (c.273G>A) is classified Conflicting classifications of pathogenicity in PITX2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-08-31). Rare (popmax 0.111%, afr); Associated with anterior segment dysgenesis 4.

What condition is associated with PITX2 p.Arg91= (c.273G>A)?

PITX2 p.Arg91= (c.273G>A) is associated with anterior segment dysgenesis 4, Axenfeld-Rieger syndrome type 1 (ClinVar).

How common is PITX2 p.Arg91= (c.273G>A) in the general population?

PITX2 p.Arg91= (c.273G>A) is rare (popmax 0.111%, afr) (gnomAD).

PITX2 p.Arg91=

c.273G>A · rs149288560 · VCV596328

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.111%, afr)

Conditions

anterior segment dysgenesis 4

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 -0.18	GERP -0.56, phastCons 0.34
Overall
CADD	12.21	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.111% African / African-American · 83/74,948 alleles

Filtering AF 0.0915% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0844%

Overall 0.00595% 96/1,613,780 alleles · rare exomes 35/1,461,538 · genomes 61/152,242 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.111%	903
Admixed American	0.01%	9,998
Remaining individualsnot grpmax-eligible	0.008%	12,494
South Asian	0.0022%	45,535

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.Arg91=
Coding: c.273G>A
MANE Select: NM_000325
dbSNP: rs149288560
Type: single nucleotide variant
Location: chr4:110621302 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.59 · 3 PDB
Residue 91: 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 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-arg91 (accessed [today's date]).

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