Is ALG1 p.Leu366fs (c.1095_1098del) pathogenic?

ALG1 p.Leu366fs (c.10951098del) is classified Pathogenic in ALG1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-25). Very rare (popmax 0.00223%, eas); Associated with ALG1-congenital disorder of glycosylation.

What condition is associated with ALG1 p.Leu366fs (c.1095_1098del)?

ALG1 p.Leu366fs (c.1095_1098del) is associated with ALG1-congenital disorder of glycosylation (ClinVar).

How common is ALG1 p.Leu366fs (c.1095_1098del) in the general population?

ALG1 p.Leu366fs (c.1095_1098del) is very rare (popmax 0.00223%, eas) (gnomAD).

How is ALG1-CDG inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ALG1 p.Leu366fs

c.1095_1098del · rs757512219 · VCV2442437

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

ALG1-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 11 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,882 alleles

Overall 0.000186% 3/1,612,020 alleles · very rare exomes 3/1,459,692 · genomes 0/152,328 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,882
South Asian	0.0011%	90,988
European (non-Finnish)	8.48e-05%	1,179,856

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ALG1
Protein: p.Leu366fs
Coding: c.1095_1098del
MANE Select: NM_019109
dbSNP: rs757512219
Type: Microsatellite
Location: chr16:5082575 (GRCh38)
Gene constraint: LOEUF 1.419 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.24
Residue 366: a UniProt-annotated variant site (in cdg1k; decreased function in protein glycosylation as shown by rescue assays in an alg1-deficient yeast strain)

Full ALG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALG1-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For ALG1-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALG1 p.Leu366Gln Pathogenic ★ same residue
ALG1 p.Leu366= Likely benign ★ same residue
ALG1 p.Leu20dup Uncertain significance ★★ same condition
ALG1 p.Glu405del Uncertain significance ★ same condition
ALG1 c.1073-12_1073-11del Likely benign ★ same condition
ALG1 c.1187+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALG1 c.1187+2T>C Pathogenic ★★ same condition
ALG1 c.1188-2A>G Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/alg1-p-leu366fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown