CDIPT

Chr 16

CDP-diacylglycerol--inositol 3-phosphatidyltransferase

Also known as: PIS, PIS1

NCBI Gene: 10423 ENSG00000103502 UniProt: O14735 OMIM: 605893

The enzyme catalyzes the biosynthesis of phosphatidylinositol and performs phosphatidylinositol:inositol exchange reactions on the endoplasmic reticulum and Golgi apparatus. Mutations cause autosomal recessive congenital cataracts, facial dysmorphism, and neuropathy (CCFDN), a syndrome presenting in infancy with cataracts, distinctive facial features, progressive peripheral neuropathy, and developmental delays. The gene shows moderate tolerance to loss-of-function variants based on population genetics data.

OMIM ResearchSummary from RefSeq, UniProt

Phosphatidylinositol breakdown products are ubiquitous second messengers that function downstream of many G protein-coupled receptors and tyrosine kinases regulating cell growth, calcium metabolism, and protein kinase C activity. Two enzymes, CDP-diacylglycerol synthase and phosphatidylinositol synthase, are involved in the biosynthesis of phosphatidylinositol. Phosphatidylinositol synthase, a member of the CDP-alcohol phosphatidyl transferase class-I family, is an integral membrane protein found on the cytoplasmic side of the endoplasmic reticulum and the Golgi apparatus. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.79

Clinical Summary— CDIPT

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.79LOEUF

pLI 0.130

Z-score 2.01

OE 0.31 (0.14–0.79)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.72Z-score

OE missense 0.82 (0.70–0.97)

105 obs / 127.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.31 (0.14–0.79)

0≤0.351.4

Missense OE?0.82 (0.70–0.97)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 3 / 9.8Missense obs/exp: 105 / 127.9Syn Z: 0.73

This gene — mechanism propensity

0.80top 10%

GOF

0.6442th %ile

LOF

0.2680th %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.