Is ALG2 p.Gly347fs (c.1040del) pathogenic?

ALG2 p.Gly347fs (c.1040del) is classified Pathogenic/Likely pathogenic in ALG2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-18). Very rare (popmax 0.00705%, nfe); Associated with congenital myasthenic syndrome 14.

What condition is associated with ALG2 p.Gly347fs (c.1040del)?

ALG2 p.Gly347fs (c.1040del) is associated with congenital myasthenic syndrome 14, ALG2-congenital disorder of glycosylation (ClinVar).

How common is ALG2 p.Gly347fs (c.1040del) in the general population?

ALG2 p.Gly347fs (c.1040del) is very rare (popmax 0.00705%, nfe) (gnomAD).

How is ALG2-CDG inherited?

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

ALG2 p.Gly347fs

c.1040del · rs387906281 · VCV2699

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00705%, nfe)

Conditions

congenital myasthenic syndrome 14

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -4.6	GERP -5.3
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00705% European (non-Finnish) · 83/1,177,870 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00534%

Overall 0.00552% 89/1,611,228 alleles · very rare exomes 78/1,459,032 · genomes 11/152,196 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00705%	14,191
Remaining individualsnot grpmax-eligible	0.00481%	20,777
African / African-American	0.00267%	37,423
Finnishnot grpmax-eligible	0.00156%	63,978

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: ALG2
Protein: p.Gly347fs
Coding: c.1040del
MANE Select: NM_033087
dbSNP: rs387906281
Type: Deletion
Location: chr9:99218145 (GRCh38)
Gene constraint: LOEUF 1.408 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.03

Full ALG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital myasthenic syndrome 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ALG2-congenital disorder of glycosylation

For ALG2-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALG2 p.Ala119_Cys120insTer Likely pathogenic ★ same condition
ALG2 p.Asp10_Ser11delinsAla Uncertain significance ★ same condition
ALG2 p.Cys45fs Uncertain significance ★ same condition
ALG2 p.Glu30fs Uncertain significance ★ same condition
ALG2 p.Lys308fs Uncertain significance ★ same condition
ALG2 p.Met386fs Uncertain significance ★ same condition
ALG2 p.Phe103fs Uncertain significance ★ same condition
ALG2 p.Ser11fs Uncertain significance ★ 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/alg2-p-gly347fs (accessed [today's date]).

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