Is PITX2 p.Pro173Ser (c.517C>T) pathogenic?

PITX2 p.Pro173Ser (c.517C>T) is classified Uncertain significance in PITX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-05). AlphaMissense: likely benign (0.3342); Absent from gnomAD v4.1; Associated with Axenfeld-Rieger syndrome type 1.

What condition is associated with PITX2 p.Pro173Ser (c.517C>T)?

PITX2 p.Pro173Ser (c.517C>T) is associated with Axenfeld-Rieger syndrome type 1, anterior segment dysgenesis 4 (ClinVar).

How common is PITX2 p.Pro173Ser (c.517C>T) in the general population?

PITX2 p.Pro173Ser (c.517C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PITX2 p.Pro173Ser (c.517C>T)?

AlphaMissense predicts likely benign (score 0.3342) — an in-silico prediction, not a clinical call.

PITX2 p.Pro173Ser

c.517C>T · rs1728874429 · VCV2007681

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3342 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Axenfeld-Rieger syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.3342	likely benign
REVEL	0.843	moderately pathogenic-leaning
SaProt	LLR -11.21	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.8, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 532 bp · p 3.3e-06 · regional, not allelic
Overall
CADD	34.0	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 P166S vs ClinVar P173S) — 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.Pro173Ser
Coding: c.517C>T
MANE Select: NM_000325
dbSNP: rs1728874429
Type: single nucleotide variant
Location: chr4:110618583 (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

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 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-pro173ser (accessed [today's date]).

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