Is PITX2 p.Phe99Ser (c.296T>C) pathogenic?

PITX2 p.Phe99Ser (c.296T>C) is classified Likely pathogenic in PITX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-23). AlphaMissense: likely pathogenic (1); Absent from gnomAD v4.1; Associated with Axenfeld-Rieger syndrome type 1.

What condition is associated with PITX2 p.Phe99Ser (c.296T>C)?

PITX2 p.Phe99Ser (c.296T>C) is associated with Axenfeld-Rieger syndrome type 1 (ClinVar).

How common is PITX2 p.Phe99Ser (c.296T>C) in the general population?

PITX2 p.Phe99Ser (c.296T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PITX2 p.Phe99Ser (c.296T>C)?

AlphaMissense predicts likely pathogenic (score 1) — an in-silico prediction, not a clinical call.

PITX2 p.Phe99Ser

c.296T>C · rs2529773099 · VCV1693131

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

1 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Axenfeld-Rieger syndrome type 1

Computational evidence

Protein change
AlphaMissense	1	likely pathogenic ✓ concordant with ClinVar · top 6% in PITX2
REVEL	0.951	strongly pathogenic-leaning
SaProt	LLR -14.70	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.28	constrained · MANE · 2,663 bp · p 1.5e-11 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F92S vs ClinVar F99S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PITX2
Protein: p.Phe99Ser
Coding: c.296T>C
MANE Select: NM_000325
dbSNP: rs2529773099
Type: single nucleotide variant
Location: chr4:110621279 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.59 · 3 PDB
Residue 92 UniProt numbering: 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

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

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.Arg144Pro Pathogenic/Likely pathogenic ★★ same condition
PITX2 p.Arg144Trp Pathogenic/Likely pathogenic ★★ same condition
PITX2 p.Arg96Trp Pathogenic/Likely pathogenic ★★ same condition
PITX2 p.Trp139Ser 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-phe99ser (accessed [today's date]).

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