Is ALG2 p.Cys59Tyr (c.176G>A) pathogenic?

ALG2 p.Cys59Tyr (c.176G>A) is classified Likely pathogenic in ALG2 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.8336); Very rare (popmax 0.00271%, nfe); Associated with ALG2-congenital disorder of glycosylation.

What condition is associated with ALG2 p.Cys59Tyr (c.176G>A)?

ALG2 p.Cys59Tyr (c.176G>A) is associated with ALG2-congenital disorder of glycosylation (ClinVar).

How common is ALG2 p.Cys59Tyr (c.176G>A) in the general population?

ALG2 p.Cys59Tyr (c.176G>A) is very rare (popmax 0.00271%, nfe) (gnomAD).

How is ALG2-CDG inherited?

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

What do computational predictors say about ALG2 p.Cys59Tyr (c.176G>A)?

AlphaMissense predicts likely pathogenic (score 0.8336) — an in-silico prediction, not a clinical call.

ALG2 p.Cys59Tyr

c.176G>A · rs757068626 · VCV1184506

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8336 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG2-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.8336	likely pathogenic ✓ concordant with ClinVar
REVEL	0.849	moderately pathogenic-leaning
SaProt	LLR -14.99	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 3,957 bp · p 0.038 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00271% European (non-Finnish) · 32/1,178,896 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00213% 34/1,597,562 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00271%	36,841
South Asian	0.0022%	45,390

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.Cys59Tyr
Coding: c.176G>A
MANE Select: NM_033087
dbSNP: rs757068626
Type: single nucleotide variant
Location: chr9:99221719 (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

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-p-cys59tyr (accessed [today's date]).

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