PTP4A3

Chr 8

protein tyrosine phosphatase 4A3

ENSG00000184489 UniProt: O75365 OMIM: 606449

The protein is a tyrosine phosphatase that regulates cell cycle progression from G1 to S phase and enhances cell proliferation and motility. Mutations cause autosomal recessive intellectual disability with neurodegeneration and brain atrophy, typically presenting in early childhood. The gene shows low constraint to loss-of-function variants, consistent with a recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

Protein tyrosine phosphatase which stimulates progression from G1 into S phase during mitosis. Enhances cell proliferation, cell motility and invasive activity, and promotes cancer metastasis. May be involved in the progression of cardiac hypertrophy by inhibiting intracellular calcium mobilization in response to angiotensin II

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.12

Clinical Summary— PTP4A3

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Population Constraint (gnomAD)

Low constraint (pLI 0.05) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.12LOEUF

pLI 0.045

Z-score 1.38

OE 0.43 (0.20–1.12)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.06Z-score

OE missense 0.73 (0.62–0.87)

93 obs / 126.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.20–1.12)

0≤0.351.4

Missense OE?0.73 (0.62–0.87)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 3 / 6.9Missense obs/exp: 93 / 126.6Syn Z: 0.78

This gene — mechanism propensity

0.76top 25%

GOF

0.73top 25%

LOF

0.2483th %ile

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

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.