Is PITX2 p.Ala263Pro (c.787G>C) pathogenic?

PITX2 p.Ala263Pro (c.787G>C) is classified Uncertain significance in PITX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-21). AlphaMissense: likely benign (0.1733); Very rare (popmax 0.00667%, amr); Associated with Inborn genetic diseases.

What condition is associated with PITX2 p.Ala263Pro (c.787G>C)?

PITX2 p.Ala263Pro (c.787G>C) is associated with Inborn genetic diseases (ClinVar).

How common is PITX2 p.Ala263Pro (c.787G>C) in the general population?

PITX2 p.Ala263Pro (c.787G>C) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about PITX2 p.Ala263Pro (c.787G>C)?

AlphaMissense predicts likely benign (score 0.1733) — an in-silico prediction, not a clinical call.

PITX2 p.Ala263Pro

c.787G>C · VCV4137294

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1733 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1733	likely benign
REVEL	0.579	indeterminate
SaProt	LLR -6.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.63, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 532 bp · p 3.3e-06 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 A256P vs ClinVar A263P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,006 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00031% 5/1,614,068 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,002
European (non-Finnish)	8.47e-05%	1,180,048

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.Ala263Pro
Coding: c.787G>C
MANE Select: NM_000325
Type: single nucleotide variant
Location: chr4:110618313 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.59 · 3 PDB
Residue 263: 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.Ala263Thr Uncertain significance ★ ⚠ same residue
PITX2 p.Ala263Ser Uncertain significance ★ ⚠ same residue
PITX2 p.Arg144Pro Pathogenic/Likely pathogenic ★★ 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.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-ala263pro (accessed [today's date]).

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