Is PITX2 p.Phe163= (c.489C>T) pathogenic?

PITX2 p.Phe163= (c.489C>T) is classified Likely benign in PITX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-30). Very rare (popmax 0.00333%, amr); Associated with anterior segment dysgenesis 4.

What condition is associated with PITX2 p.Phe163= (c.489C>T)?

PITX2 p.Phe163= (c.489C>T) is associated with anterior segment dysgenesis 4, Axenfeld-Rieger syndrome type 1 (ClinVar).

How common is PITX2 p.Phe163= (c.489C>T) in the general population?

PITX2 p.Phe163= (c.489C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

PITX2 p.Phe163=

c.489C>T · rs756196786 · VCV2155411

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

anterior segment dysgenesis 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.055	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.26	GERP -5.5, phastCons 0.009
Overall
CADD	12.02	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,022 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000372% 6/1,613,848 alleles · very rare exomes 6/1,461,568 · genomes 0/152,280 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,011
Remaining individualsnot grpmax-eligible	0.0016%	62,492
African / African-American	0.00133%	75,026
South Asian	0.0011%	91,008
European (non-Finnish)	8.48e-05%	1,179,852

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.Phe163=
Coding: c.489C>T
MANE Select: NM_000325
dbSNP: rs756196786
Type: single nucleotide variant
Location: chr4:110618611 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.59 · 3 PDB

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-phe163 (accessed [today's date]).

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