PITX2

Chr 4AD

paired like homeodomain 2

Also known as: ARP1, ASGD4, Brx1, IDG2, IGDS, IGDS2, IHG2, IRID2

NCBI Gene: 5308 ENSG00000164093 UniProt: Q99697 OMIM: 601542

This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. The encoded protein acts as a transcription factor and regulates procollagen lysyl hydroxylase gene expression. This protein plays a role in the terminal differentiation of somatotroph and lactotroph cell phenotypes, is involved in the development of the eye, tooth and abdominal organs, and acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin. Mutations in this gene are associated with Axenfeld-Rieger syndrome, iridogoniodysgenesis syndrome, and sporadic cases of Peters anomaly. A similar protein in other vertebrates is involved in the determination of left-right asymmetry during development. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.263 OMIM phenotypes

Clinical Summary— PITX2

🧬

Gene-Disease Validity (ClinGen)

anterior segment dysgenesis 4 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

82 unique Pathogenic / Likely Pathogenic· 94 VUS of 258 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — PITX2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.26LOEUF

pLI 0.976

Z-score 3.14

OE 0.00 (0.00–0.26)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.55Z-score

OE missense 0.68 (0.58–0.79)

124 obs / 183.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.26)

0≤0.351.4

Missense OE?0.68 (0.58–0.79)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 0 / 11.5Missense obs/exp: 124 / 183.0Syn Z: -0.67

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePITX2-related anterior segment dysgenesisLOFAD

definitivePITX2-related Axenfeld-Rieger syndromeLOFAD

strongPITX2-related ring dermoid of corneaOTHERAD

This gene — mechanism propensity

0.6066th %ile

GOF

0.2696th %ile

LOF

0.81top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 62% of P/LP variants are LoF · LOEUF 0.26 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNExpression of the ARS dominant negative human PITX2A K50E allele also caused ARS-like phenotypes.1

GOFThe results indicate that the PITX2 C-terminal domain has inhibitory activity and support the notion that ARS may also be caused by gain-of-function mutations.2

LOFThis comparative study suggests both an incomplete penetrance of the ocular malformation pattern in patients carrying PITX2 deletions and a putative association between TOF and PITX2 haploinsufficiency.3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

258 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic58

Likely Pathogenic24

VUS94

Likely Benign43

Benign24

Conflicting14

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	40	13	5	0	58
Likely Pathogenic	11	11	2	0	24
VUS	2	52	36	4	94
Likely Benign	0	2	24	17	43
Benign	0	0	24	0	24
Conflicting	—				14
Total	53	78	91	21	257

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

15 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap PITX2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →