Is PITX2 p.Ser206= (c.618T>G) pathogenic?

PITX2 p.Ser206= (c.618T>G) is classified Benign/Likely benign in PITX2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-15). Low-frequency (popmax 3.68%, afr); Associated with PITX2-Related Eye Abnormalities.

What condition is associated with PITX2 p.Ser206= (c.618T>G)?

PITX2 p.Ser206= (c.618T>G) is associated with PITX2-Related Eye Abnormalities, cataract, anterior segment dysgenesis 4 (ClinVar).

How common is PITX2 p.Ser206= (c.618T>G) in the general population?

PITX2 p.Ser206= (c.618T>G) is low-frequency (popmax 3.68%, afr) (gnomAD).

PITX2 p.Ser206=

c.618T>G · rs35946364 · VCV262718

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.68%, afr)

Conditions

PITX2-Related Eye Abnormalities

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.276	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.83	GERP -5.5
Overall
CADD	4.595	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.68% African / African-American · 2,761/74,962 alleles

Filtering AF 3.57% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.52%

Overall 0.209% 3,367/1,613,886 alleles · low-frequency exomes 1,735/1,461,718 · genomes 1,632/152,168 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.68%	27
Middle Eastern	0.363%	276
Remaining individualsnot grpmax-eligible	0.272%	368
Ashkenazi Jewishnot grpmax-eligible	0.26%	384
Admixed American	0.233%	429
European (non-Finnish)	0.0158%	6,310
South Asian	0.011%	9,106

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.Ser206=
Coding: c.618T>G
MANE Select: NM_000325
dbSNP: rs35946364
Type: single nucleotide variant
Location: chr4:110618482 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.59 · 3 PDB
Residue 206: a UniProt-annotated variant site (in rieg1)

Full PITX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PITX2-Related Eye Abnormalities

Also linked: cataract anterior segment dysgenesis 4 Axenfeld-Rieger syndrome type 1 ring dermoid of cornea Peters anomaly

Similar variants

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
PITX2 p.Arg96Trp 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-ser206 (accessed [today's date]).

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