ALG2

Chr 9AR

ALG2 alpha-1,3/1,6-mannosyltransferase

Also known as: CDG1I, CDGIi, CMS14, CMSTA3, NET38, hALPG2

NCBI Gene: 85365 ENSG00000119523 UniProt: O75340 OMIM: 607905

The protein functions as an alpha 1,3 mannosyltransferase in the endoplasmic reticulum, catalyzing the addition of mannose residues to dolichol-linked oligosaccharide precursors during N-linked glycosylation. Biallelic mutations cause congenital disorder of glycosylation type Ii and congenital myasthenic syndrome type 14 with tubular aggregates, both inherited in an autosomal recessive pattern. The pathogenic mechanism involves dominant-negative effects that disrupt normal protein glycosylation.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the glycosyltransferase 1 family. The encoded protein acts as an alpha 1,3 mannosyltransferase, mannosylating Man(2)GlcNAc(2)-dolichol diphosphate and Man(1)GlcNAc(2)-dolichol diphosphate to form Man(3)GlcNAc(2)-dolichol diphosphate. Defects in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ii). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.182 OMIM phenotypes

Clinical Summary— ALG2

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Gene-Disease Validity (ClinGen)

ALG2-congenital disorder of glycosylation · ARStrong

Strong evidence — appropriate for clinical testing

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

12 unique Pathogenic / Likely Pathogenic· 205 VUS of 371 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ALG2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

-0.08Z-score

OE missense 1.01 (0.91–1.13)

230 obs / 226.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.65 (0.38–1.18)

0≤0.351.4

Missense OE?1.01 (0.91–1.13)

0≤0.61.4

Synonymous OE?1.27

0≤1.21.6

LoF obs/exp: 8 / 12.3Missense obs/exp: 230 / 226.7Syn Z: -2.15

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongALG2-related congenital disorder of glycosylationLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6842th %ile

GOF

0.5954th %ile

LOF

0.2774th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

371 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic7

VUS205

Likely Benign137

Benign9

Conflicting7

Pathogenic

Likely Pathogenic

205

VUS

137

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	4	0	0	5
Likely Pathogenic	5	2	0	0	7
VUS	13	191	1	0	205
Likely Benign	0	4	17	116	137
Benign	0	3	3	3	9
Conflicting	—				7
Total	19	204	21	119	370

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

View in ClinVar →

34 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap ALG2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →