PIK3C3

Chr 18

phosphatidylinositol 3-kinase catalytic subunit type 3

Also known as: VPS34, Vps34, hVps34

NCBI Gene: 5289 ENSG00000078142 UniProt: Q8NEB9 OMIM: 602609

PIK3C3 encodes a catalytic subunit that generates phosphatidylinositol 3-phosphate in different PI3K complexes, mediating autophagosome formation, endosomal trafficking, and cytokinesis. Mutations cause autosomal recessive neurodevelopmental disorders with seizures and intellectual disability, often with early childhood onset. The gene is highly constrained against loss-of-function variants in the population.

OMIM ResearchSummary from RefSeq, UniProt

Enables 1-phosphatidylinositol-3-kinase activity. Involved in several processes, including early endosome to late endosome transport; macroautophagy; and positive regulation of natural killer cell mediated cytotoxicity. Acts upstream of or within autophagy and positive regulation of protein lipidation. Located in autolysosome; late endosome; and midbody. Is active in plasma membrane. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Active trials

—

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.67

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.67LOEUF

pLI 0.000

Z-score 3.55

OE 0.48 (0.35–0.67)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.44Z-score

OE missense 0.68 (0.63–0.75)

325 obs / 474.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.48 (0.35–0.67)

0≤0.351.4

Missense OE?0.68 (0.63–0.75)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 26 / 54.2Missense obs/exp: 325 / 474.6Syn Z: -0.52

Background carrier burden — how many people carry a rare variant somewhere in PIK3C3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 100

945 rare PASS variants

Rare truncating (LoF)

1 in 700

214 rare PASS variants

Rare synonymous (reference)

1 in 140

422 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PIK3C3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 740
South Asian	~43k	1 in 110	1 in 550
Remaining (unassigned)	~30k	1 in 93	1 in 820
European (Finnish)	~27k	1 in 890	1 in 1,200
Admixed American	~22k	1 in 130	1 in 1,100
African / African American	~21k	1 in 110	1 in 710
East Asian	~20k	1 in 110	1 in 620
Ashkenazi Jewish	~13k	1 in 310	1 in 2,500
Middle Eastern	~2,884	1 in 170	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 12 of 25 coding exons well covered in gnomAD exomes; exons 5, 6, 7, 9, 11 and 8 more marginal. Genomes: all 25.? see exons ↓