PDCD6IP

Chr 3

programmed cell death 6 interacting protein

Also known as: AIP1, ALIX, DRIP4, HP95, MCPH29

NCBI Gene: 10015 ENSG00000170248 UniProt: Q8WUM4

This gene encodes a multifunctional protein that operates within the ESCRT pathway for endocytosis and multivesicular body biogenesis, functions in cytokinesis completion, and maintains tight junction integrity in epithelial cells. Mutations cause primary microcephaly 29, an autosomal recessive disorder characterized by reduced brain size present from birth. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.36), consistent with its essential cellular functions.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that functions within the ESCRT pathway in the abscission stage of cytokinesis, in intralumenal endosomal vesicle formation, and in enveloped virus budding. Studies using mouse cells have shown that overexpression of this protein can block apoptosis. In addition, the product of this gene binds to the product of the PDCD6 gene, a protein required for apoptosis, in a calcium-dependent manner. This gene product also binds to endophilins, proteins that regulate membrane shape during endocytosis. Overexpression of this gene product and endophilins results in cytoplasmic vacuolization, which may be partly responsible for the protection against cell death. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. Related pseudogenes have been identified on chromosome 15. [provided by RefSeq, Jan 2012]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtMicrocephaly 29, primary, autosomal recessive

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.36

LOEUF

—

Mechanism

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?

0.36LOEUF

pLI 0.706

Z-score 4.85

OE 0.21 (0.12–0.36)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.98Z-score

OE missense 0.87 (0.80–0.95)

393 obs / 451.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.21 (0.12–0.36)

0≤0.351.4

Missense OE?0.87 (0.80–0.95)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 9 / 43.6Missense obs/exp: 393 / 451.4Syn Z: -0.24

Background carrier burden — how many people carry a rare variant somewhere in PDCD6IP?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 65

950 rare PASS variants

Rare truncating (LoF)

1 in 2,700

86 rare PASS variants

Rare synonymous (reference)

1 in 110

380 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PDCD6IP. 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 100	1 in 3,300
South Asian	~43k	1 in 87	1 in 970
Remaining (unassigned)	~30k	1 in 68	1 in 3,300
European (Finnish)	~27k	1 in 230	≈ 1 in 6,600
Admixed American	~22k	1 in 77	1 in 1,100
African / African American	~21k	1 in 70	1 in 1,400
East Asian	~20k	1 in 90	1 in 3,100
Ashkenazi Jewish	~13k	1 in 240	≈ 1 in 4,300
Middle Eastern	~2,884	1 in 84	≈ 1 in 960

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 18 coding exons well covered in gnomAD exomes; exons 3, 8, 10, 11, 15, 16 marginal. Genomes: all 18.? see exons ↓