PDCD6

Chr 5

programmed cell death 6

Also known as: ALG-2, ALG2, PEF1B

NCBI Gene: 10016 ENSG00000249915 UniProt: O75340 OMIM: 601057

PDCD6 encodes a calcium-binding protein that functions as a calcium sensor regulating ER-Golgi vesicular transport, endosomal biogenesis, membrane repair, and apoptosis. Mutations cause autosomal recessive primary microcephaly with seizures and developmental delay. The gene shows low constraint against loss-of-function variants, consistent with its autosomal recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a calcium-binding protein belonging to the penta-EF-hand protein family. Calcium binding is important for homodimerization and for conformational changes required for binding to other protein partners. This gene product participates in T cell receptor-, Fas-, and glucocorticoid-induced programmed cell death. In mice deficient for this gene product, however, apoptosis was not blocked suggesting this gene product is functionally redundant. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is also located on the short arm of chromosome 5. [provided by RefSeq, May 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.94

Clinical Summary— PDCD6

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

26 VUS of 37 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.94LOEUF

pLI 0.009

Z-score 1.70

OE 0.45 (0.23–0.94)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.45Z-score

OE missense 0.89 (0.76–1.04)

111 obs / 125.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.45 (0.23–0.94)

0≤0.351.4

Missense OE?0.89 (0.76–1.04)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 5 / 11.1Missense obs/exp: 111 / 125.3Syn Z: 0.15

This gene — mechanism propensity

0.86top 5%

GOF

0.85top 5%

LOF

0.2288th %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.

ClinVar Variant Classifications

37 submitted variants in ClinVar

ClinVar

Classification Summary

VUS26

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	26	0	26
Likely Benign	0	1	1
Benign	0	0	0
Total	26	1	27

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

View in ClinVar →

135 pathogenic / likely-pathogenic (of 170) ClinVar copy-number / structural variants overlap PDCD6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →