Is PITX2 p.Pro211Thr (c.631C>A) pathogenic?

PITX2 p.Pro211Thr (c.631C>A) is classified Uncertain significance in PITX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-10). AlphaMissense: likely benign (0.2471); Very rare (popmax 0.00333%, amr); Associated with anterior segment dysgenesis 4.

What condition is associated with PITX2 p.Pro211Thr (c.631C>A)?

PITX2 p.Pro211Thr (c.631C>A) is associated with anterior segment dysgenesis 4, Axenfeld-Rieger syndrome type 1 (ClinVar).

How common is PITX2 p.Pro211Thr (c.631C>A) in the general population?

PITX2 p.Pro211Thr (c.631C>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about PITX2 p.Pro211Thr (c.631C>A)?

AlphaMissense predicts likely benign (score 0.2471) — an in-silico prediction, not a clinical call.

PITX2 p.Pro211Thr

c.631C>A · rs893139859 · VCV3213312

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2471 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

anterior segment dysgenesis 4

Computational evidence

Protein change
AlphaMissense	0.2471	likely benign
REVEL	0.803	moderately pathogenic-leaning
SaProt	LLR -5.88	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	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 P204T vs ClinVar P211T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,006 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000248% 4/1,613,848 alleles · very rare exomes 1/1,461,726 · genomes 3/152,122 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,003
Remaining individualsnot grpmax-eligible	0.0016%	62,486
Finnishnot grpmax-eligible	0.00156%	64,040

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.Pro211Thr
Coding: c.631C>A
MANE Select: NM_000325
dbSNP: rs893139859
Type: single nucleotide variant
Location: chr4:110618469 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.59 · 3 PDB
Residue 204 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

anterior segment dysgenesis 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Axenfeld-Rieger syndrome type 1

Similar variants

PITX2 p.Pro211= Likely benign ★ same residue
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

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-pro211thr (accessed [today's date]).

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