Is ALG3 p.Trp396Ter (c.1188G>A) pathogenic?

ALG3 p.Trp396Ter (c.1188G>A) is classified Pathogenic in ALG3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-09). Ultra-rare (popmax 0.0171%, mid); Associated with ALG3-congenital disorder of glycosylation.

What condition is associated with ALG3 p.Trp396Ter (c.1188G>A)?

ALG3 p.Trp396Ter (c.1188G>A) is associated with ALG3-congenital disorder of glycosylation (ClinVar).

How common is ALG3 p.Trp396Ter (c.1188G>A) in the general population?

ALG3 p.Trp396Ter (c.1188G>A) is ultra-rare (popmax 0.0171%, mid) (gnomAD).

How is ALG3-CDG inherited?

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

ALG3 p.Trp396Ter

c.1188G>A · rs1287098925 · VCV2780035

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0171%, mid)

Conditions

ALG3-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (9 of 9) — the truncated protein is likely expressed. PVS1 input, not an applied code
REVEL	0.363	indeterminate
Splicing
SpliceAI	Δ0.20	acceptor gain · deltas
Pangolin	Δ0.23	loss · gain 0.06 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Overall
CADD	44.0	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 0.0171% Middle Eastern · 1/5,834 alleles

Filtering AF 0.000747% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000279%

Overall 0.000212% 3/1,412,942 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0171%	5,834
East Asian	0.00451%	22,191

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: ALG3
Protein: p.Trp396Ter
Coding: c.1188G>A
MANE Select: NM_005787
dbSNP: rs1287098925
Type: single nucleotide variant
Location: chr3:184242643 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.05

Full ALG3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALG3-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For ALG3-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALG3 c.444+1G>T Likely pathogenic ★★ same condition
ALG3 p.Arg171Gln Pathogenic/Likely pathogenic ★★ same condition
ALG3 p.Arg266Cys Pathogenic ★★ same condition
ALG3 p.Arg354Cys Likely pathogenic ★★ same condition
ALG3 p.Arg354His Pathogenic/Likely pathogenic ★★ same condition
ALG3 p.Asn174Ser Likely pathogenic ★★ ⚠ same condition
ALG3 p.Gly55= Pathogenic/Likely pathogenic ★★ same condition
ALG3 p.Ile69Thr 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/alg3-p-trp396ter (accessed [today's date]).

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