Is PITX2 p.Thr97Pro (c.289A>C) pathogenic?

PITX2 p.Thr97Pro (c.289A>C) is classified Uncertain significance in PITX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-09-28). AlphaMissense: likely pathogenic (0.9975); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PITX2 p.Thr97Pro (c.289A>C)?

PITX2 p.Thr97Pro (c.289A>C) is associated with Inborn genetic diseases (ClinVar).

How common is PITX2 p.Thr97Pro (c.289A>C) in the general population?

PITX2 p.Thr97Pro (c.289A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PITX2 p.Thr97Pro (c.289A>C)?

AlphaMissense predicts likely pathogenic (score 0.9975) — an in-silico prediction, not a clinical call.

PITX2 p.Thr97Pro

c.289A>C · rs1729005855 · VCV985657

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9975 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9975	likely pathogenic
REVEL	0.984	strongly pathogenic-leaning
SaProt	LLR -11.83	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 7.8	GERP 1.6, 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

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM T90P vs ClinVar T97P) — 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.Thr97Pro
Coding: c.289A>C
MANE Select: NM_000325
dbSNP: rs1729005855
Type: single nucleotide variant
Location: chr4:110621286 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.59 · 3 PDB
Residue 90 UniProt numbering: a DNA-binding region; the 'disordered' region; a β-strand; a modified residue (phosphothreonine; by pkb/akt2)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PITX2 p.Arg144Pro Pathogenic/Likely pathogenic ★★ same condition
PITX2 p.Ala263Pro Uncertain significance ★★ ⚠ same condition
PITX2 p.Lys72Arg Uncertain significance ★★ ⚠ same condition
PITX2 p.Ser314Asn Uncertain significance ★★ same condition
PITX2 p.Tyr271Phe Uncertain significance ★★ ⚠ same condition
PITX2 p.Ala156Thr Uncertain significance ★ ⚠ same condition
PITX2 p.Ala263Thr Uncertain significance ★ ⚠ same condition
PITX2 p.Arg281Gly Uncertain significance ★ ⚠ 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-thr97pro (accessed [today's date]).

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