Is PITX2 p.Pro235Ser (c.703C>T) pathogenic?

PITX2 p.Pro235Ser (c.703C>T) is classified Uncertain significance in PITX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-11). AlphaMissense: likely benign (0.1815); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PITX2 p.Pro235Ser (c.703C>T)?

PITX2 p.Pro235Ser (c.703C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PITX2 p.Pro235Ser (c.703C>T) in the general population?

PITX2 p.Pro235Ser (c.703C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PITX2 p.Pro235Ser (c.703C>T)?

AlphaMissense predicts likely benign (score 0.1815) — an in-silico prediction, not a clinical call.

PITX2 p.Pro235Ser

c.703C>T · VCV4841113

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1815 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1815	likely benign
REVEL	0.717	pathogenic-leaning
SaProt	LLR -5.82	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 532 bp · p 3.3e-06 · regional, not allelic
Overall
CADD	29.1	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 P228S vs ClinVar P235S) — 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.Pro235Ser
Coding: c.703C>T
MANE Select: NM_000325
Type: single nucleotide variant
Location: chr4:110618397 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.59 · 3 PDB
Residue 228 UniProt numbering: a UniProt-annotated variant site (in rieg1)

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-pro235ser (accessed [today's date]).

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