Is PITX2 p.Ala272= (c.816G>A) pathogenic?

PITX2 p.Ala272= (c.816G>A) is classified Likely benign in PITX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-15). Ultra-rare (popmax 0.0164%, nfe); Associated with Axenfeld-Rieger syndrome type 1.

What condition is associated with PITX2 p.Ala272= (c.816G>A)?

PITX2 p.Ala272= (c.816G>A) is associated with Axenfeld-Rieger syndrome type 1, anterior segment dysgenesis 4 (ClinVar).

How common is PITX2 p.Ala272= (c.816G>A) in the general population?

PITX2 p.Ala272= (c.816G>A) is ultra-rare (popmax 0.0164%, nfe) (gnomAD).

PITX2 p.Ala272=

c.816G>A · rs778779105 · VCV1660721

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, nfe)

Conditions

Axenfeld-Rieger syndrome type 1

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 -1.9	GERP -5.5
Overall
CADD	9.795	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% European (non-Finnish) · 194/1,180,044 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.0138% 222/1,614,046 alleles · ultra-rare exomes 211/1,461,890 · genomes 11/152,156 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0219%	4,573
European (non-Finnish)grpmax	0.0164%	6,083
Remaining individualsnot grpmax-eligible	0.0144%	6,943
African / African-American	0.004%	24,969
Admixed American	0.00167%	59,998
South Asian	0.0011%	91,086

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala272=
Coding: c.816G>A
MANE Select: NM_000325
dbSNP: rs778779105
Type: single nucleotide variant
Location: chr4:110618284 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.59 · 3 PDB
Residue 272: a UniProt-annotated variant site (in rieg1)

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

Disease context

Axenfeld-Rieger syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: anterior segment dysgenesis 4

Similar variants

PITX2 p.Ala272Thr 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
PITX2 p.Arg144Trp 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-ala272 (accessed [today's date]).

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