PITX3

Chr 10

paired like homeodomain 3

Also known as: ASGD1, ASMD, ASOD, CTPP4, CTRCT11

NCBI Gene: 5309 ENSG00000107859 UniProt: O75364

This gene encodes a transcription factor essential for lens development and the differentiation and maintenance of dopaminergic neurons in the brain. Mutations cause congenital cataracts and anterior segment dysgenesis affecting eye development, with inheritance patterns that can be either autosomal dominant or autosomal recessive depending on the specific mutation. The gene is highly constrained against loss-of-function variants (pLI 0.81, LOEUF 0.48), indicating that complete loss of protein function is likely not tolerated.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. Members of this family act as transcription factors. This protein is involved in lens formation during eye development. Mutations of this gene have been associated with anterior segment mesenchymal dysgenesis and congenital cataracts. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.48

Clinical Summary— PITX3

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.81) — some intolerance to loss-of-function variants.

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ClinVar Variants

8 unique Pathogenic / Likely Pathogenic· 60 VUS of 93 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.48LOEUF

pLI 0.813

Z-score 2.62

OE 0.10 (0.04–0.48)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.50Z-score

OE missense 0.68 (0.58–0.79)

115 obs / 170.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.10 (0.04–0.48)

0≤0.351.4

Missense OE?0.68 (0.58–0.79)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 1 / 9.9Missense obs/exp: 115 / 170.0Syn Z: 0.54

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePITX3-related cataract with or without ocular developmental defectsLOFAD

This gene — mechanism propensity

0.5868th %ile

GOF

0.3590th %ile

LOF

0.74top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 88% of P/LP variants are LoF · LOEUF 0.48

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

ClinVar Variant Classifications

93 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic5

VUS60

Likely Benign19

Benign4

Conflicting2

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	3	0	0	0	3
Likely Pathogenic	4	1	0	0	5
VUS	3	55	1	1	60
Likely Benign	0	0	2	17	19
Benign	0	0	3	1	4
Conflicting	—				2
Total	10	56	6	19	93

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap PITX3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →