Is PITX2 p.Tyr271Phe (c.812A>T) pathogenic?

PITX2 p.Tyr271Phe (c.812A>T) is classified Uncertain significance in PITX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-13). AlphaMissense: likely benign (0.2738); Ultra-rare (popmax 0.0141%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PITX2 p.Tyr271Phe (c.812A>T)?

PITX2 p.Tyr271Phe (c.812A>T) is associated with Inborn genetic diseases (ClinVar).

How common is PITX2 p.Tyr271Phe (c.812A>T) in the general population?

PITX2 p.Tyr271Phe (c.812A>T) is ultra-rare (popmax 0.0141%, nfe) (gnomAD).

What do computational predictors say about PITX2 p.Tyr271Phe (c.812A>T)?

AlphaMissense predicts likely benign (score 0.2738) — an in-silico prediction, not a clinical call.

PITX2 p.Tyr271Phe

c.812A>T · rs371238455 · VCV96521

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2738 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0141%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2738	likely benign
REVEL	0.693	pathogenic-leaning
SaProt	LLR -6.89	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 6.2	GERP 2.8, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 532 bp · p 3.3e-06 · regional, not allelic
Overall
CADD	32.0	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 Y264F vs ClinVar Y271F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0141% European (non-Finnish) · 166/1,180,018 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0116%

Overall 0.0109% 176/1,613,898 alleles · ultra-rare exomes 171/1,461,886 · genomes 5/152,012 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0141%	7,109
Remaining individualsnot grpmax-eligible	0.0128%	7,810
African / African-American	0.00267%	37,426

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.Tyr271Phe
Coding: c.812A>T
MANE Select: NM_000325
dbSNP: rs371238455
Type: single nucleotide variant
Location: chr4:110618288 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.59 · 3 PDB
Residue 264 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.Ala156Thr Uncertain significance ★ ⚠ same condition
PITX2 p.Ala263Thr Uncertain significance ★ ⚠ same condition
PITX2 p.Arg281Gly Uncertain significance ★ ⚠ same condition
PITX2 p.Asn130Ser 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-tyr271phe (accessed [today's date]).

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