Is PITX2 p.Pro86Leu (c.257C>T) pathogenic?

PITX2 p.Pro86Leu (c.257C>T) is classified Uncertain significance in PITX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-08). AlphaMissense: likely benign (0.0979); Very rare (popmax 0.00439%, sas); Associated with Inborn genetic diseases.

What condition is associated with PITX2 p.Pro86Leu (c.257C>T)?

PITX2 p.Pro86Leu (c.257C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PITX2 p.Pro86Leu (c.257C>T) in the general population?

PITX2 p.Pro86Leu (c.257C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about PITX2 p.Pro86Leu (c.257C>T)?

AlphaMissense predicts likely benign (score 0.0979) — an in-silico prediction, not a clinical call.

PITX2 p.Pro86Leu

c.257C>T · rs1231505078 · VCV3213317

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0979 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0979	likely benign
REVEL	0.672	pathogenic-leaning
SaProt	LLR -8.52	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 1.6, phastCons 1
Regional constraint	o/e 0.28	constrained · MANE · 2,663 bp · p 1.5e-11 · regional, not allelic
Overall
CADD	26.7	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 P79L vs ClinVar P86L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,070 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000274% 4/1,461,596 alleles · very rare

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.Pro86Leu
Coding: c.257C>T
MANE Select: NM_000325
dbSNP: rs1231505078
Type: single nucleotide variant
Location: chr4:110621318 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.59 · 3 PDB
Residue 86: a DNA-binding region; the 'disordered' region; a β-strand

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.Pro86Thr Uncertain significance ★ ⚠ same residue
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.Pro86fs Pathogenic ★ same residue
PITX2 p.Ala156Thr 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-pro86leu (accessed [today's date]).

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