Is ALG2 c.348+6G>A pathogenic?

ALG2 c.348+6G>A is classified Conflicting classifications of pathogenicity in ALG2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-27). Rare (popmax 0.215%, afr); Associated with ALG2-congenital disorder of glycosylation.

What condition is associated with ALG2 c.348+6G>A?

ALG2 c.348+6G>A is associated with ALG2-congenital disorder of glycosylation, congenital myasthenic syndrome 14 (ClinVar).

How common is ALG2 c.348+6G>A in the general population?

ALG2 c.348+6G>A is rare (popmax 0.215%, afr) (gnomAD).

How is ALG2-CDG inherited?

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

ALG2 c.348+6G>A

rs368075764 · VCV464895

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.215%, afr)

Conditions

ALG2-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +6	donor splice region (+6, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	phastCons 0.9
Non-coding constraint	Z -1.63	1 kb window · o/e 1.10 · regional · uncalibrated
Overall
CADD	19.48	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.215% African / African-American · 157/73,096 alleles

Filtering AF 0.187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.177%

Overall 0.0106% 164/1,542,878 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.215%	466
Admixed American	0.00785%	12,735
Remaining individualsnot grpmax-eligible	0.00334%	29,972
European (non-Finnish)	8.73e-05%	1,146,104

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
Coding: c.348+6G>A
MANE Select: NM_033087
dbSNP: rs368075764
Type: single nucleotide variant
Location: chr9:99221541 (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

ALG2-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myasthenic syndrome 14

For ALG2-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALG2 p.Ala29Pro Uncertain significance ★★ ⚠ same condition
ALG2 p.Ala36Val Uncertain significance ★★ ⚠ same condition
ALG2 p.Ala71Gly Uncertain significance ★★ ⚠ same condition
ALG2 p.Ala71Val Uncertain significance ★★ ⚠ same condition
ALG2 p.Arg129Gln Uncertain significance ★★ ⚠ same condition
ALG2 p.Arg130Gln Uncertain significance ★★ ⚠ same condition
ALG2 p.Arg251His Uncertain significance ★★ ⚠ same condition
ALG2 p.Arg378Cys 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-c-348-plus-6g-a (accessed [today's date]).

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