ALG2

Chr 9AR

programmed cell death 6

Also known as: ALG-2, ALG2, PEF1B

NCBI Gene: 10016ENSG00000119523UniProt: O75340

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]

Primary Disease Associations & Inheritance

Congenital disorder of glycosylation, type IiMIM #607906
AR
Myasthenic syndrome, congenital, 14, with tubular aggregatesMIM #616228
AR
404
ClinVar variants
45
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ALG2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
45 Pathogenic / Likely Pathogenic· 204 VUS of 404 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.18LOEUF
pLI 0.000
Z-score 1.13
OE 0.65 (0.38–1.18)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.08Z-score
OE missense 1.01 (0.91–1.13)
230 obs / 226.7 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.65 (0.38–1.18)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.01 (0.91–1.13)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.27
0≤1.21.6
LoF obs/exp: 8 / 12.3Missense obs/exp: 230 / 226.7Syn Z: -2.15

ClinVar Variant Classifications

404 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36
Likely Pathogenic9
VUS204
Likely Benign138
Benign9
Conflicting7
36
Pathogenic
9
Likely Pathogenic
204
VUS
138
Likely Benign
9
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
3
32
0
36
Likely Pathogenic
3
2
4
0
9
VUS
9
181
14
0
204
Likely Benign
0
4
18
116
138
Benign
0
3
3
3
9
Conflicting
—7
Total1319371119403

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

View in ClinVar →

Protein Context — Lollipop Plot

ALG2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ALG2-related congenital disorder of glycosylation

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Congenital disorder of glycosylation, type Ii

MIM #607906

Molecular basis of disorder known

Autosomal recessive

Myasthenic syndrome, congenital, 14, with tubular aggregates

MIM #616228

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review.
Ohno K et al.·Int J Mol Sci
2023Review
Ca(2+)-sensor ALG-2 engages ESCRTs to enhance lysosomal membrane resilience to osmotic stress.
Chen W et al.·Proc Natl Acad Sci U S A
2024
Novel pathogenic ALG2 mutation causing congenital myasthenic syndrome: A case report.
Ehrstedt C et al.·Neuromuscul Disord
2022Case report
Clinical and genetic characterization of congenital disorders of glycosylation in 20 Chinese patients.
Zhao P et al.·Orphanet J Rare Dis
2025Cohort
Mass spectrometry glycophenotype characterization of ALG2-CDG in Argentinean patients with a new genetic variant in homozygosis.
Papazoglu GM et al.·Glycoconj J
2021Cohort
Trouble at the junction: When myopathy and myasthenia overlap.
Nicolau S et al.·Muscle Nerve
2019Review
The spectrum of neuromuscular diseases with tubular aggregates.
Rashed HR et al.·Neuromuscul Disord
2025Review
Liposome-encapsulated mannose-1-phosphate therapy improves global N-glycosylation in different congenital disorders of glycosylation.
Budhraja R et al.·Mol Genet Metab
2024
Clinical and pathological heterogeneity of a congenital disorder of glycosylation manifesting as a myasthenic/myopathic syndrome.
Monies DM et al.·Neuromuscul Disord
2014Case report
Proteomic characterization of clinical Candida glabrata isolates with varying degrees of virulence and resistance to fluconazole.
El Khoury P et al.·PLoS One
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
In vitro cell model to dilucidate the underlying molecular mechanism associated with ophthalmic manifestation of congenital disorders of glycosylation: studying an ALG2-CDG patient.
Cubilla MA et al.·Front Genet
2025🔓 Open AccessFunctional
Case report: Novel genotype of ALG2-CDG and confirmation of the heptasaccharide glycan (NeuAc-Gal-GlcNAc-Man2-GlcNAc2) as a specific diagnostic biomarker.
Martínez Duncker I et al.·Front Genet
2024🔓 Open AccessCase report
COPII with ALG2 and ESCRTs control lysosome-dependent microautophagy of ER exit sites.
Liao YC et al.·Dev Cell
2024
ALG2 inhibits the epithelial-to-mesenchymal transition and stemness of ovarian granulosa cells through the Wnt/β-catenin signaling pathway in polycystic ovary syndrome.
Zheng Q et al.·Reprod Biol
2022
Oxidative stress-induced phosphorylation of JIP4 regulates lysosomal positioning in coordination with TRPML1 and ALG2.
Sasazawa Y et al.·EMBO J
2022🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools