Is ALG1 p.Tyr353Ter (c.1059C>A) pathogenic?

ALG1 p.Tyr353Ter (c.1059C>A) is classified Pathogenic/Likely pathogenic in ALG1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-08). Very rare (popmax 0.00223%, eas); Associated with ALG1-congenital disorder of glycosylation.

What condition is associated with ALG1 p.Tyr353Ter (c.1059C>A)?

ALG1 p.Tyr353Ter (c.1059C>A) is associated with ALG1-congenital disorder of glycosylation (ClinVar).

How common is ALG1 p.Tyr353Ter (c.1059C>A) in the general population?

ALG1 p.Tyr353Ter (c.1059C>A) 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.Tyr353Ter

c.1059C>A · rs1957009416 · VCV2825545

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

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	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 13
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.12	GERP 0.83, phastCons 0.46
Overall
CADD	37.0	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 0.00223% East Asian · 1/44,868 alleles

Overall 0.000138% 2/1,444,086 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,868
African / African-American	0.00133%	74,952

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.Tyr353Ter
Coding: c.1059C>A
MANE Select: NM_019109
dbSNP: rs1957009416
Type: single nucleotide variant
Location: chr16:5081043 (GRCh38)
Gene constraint: LOEUF 1.419 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.24
Residue 353: 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.Tyr353Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
ALG1 p.Tyr353= Likely benign ★ same residue
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
ALG1 c.209-2A>G Likely pathogenic ★★ same condition
ALG1 c.539+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALG1 c.630-2A>G 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-tyr353ter (accessed [today's date]).

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