Is ALG3 p.Leu223= (c.669C>T) pathogenic?

ALG3 p.Leu223= (c.669C>T) is classified Likely benign in ALG3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-11). Rare (popmax 0.429%, mid); Associated with ALG3-congenital disorder of glycosylation.

What condition is associated with ALG3 p.Leu223= (c.669C>T)?

ALG3 p.Leu223= (c.669C>T) is associated with ALG3-congenital disorder of glycosylation (ClinVar).

How common is ALG3 p.Leu223= (c.669C>T) in the general population?

ALG3 p.Leu223= (c.669C>T) is rare (popmax 0.429%, mid) (gnomAD).

How is ALG3-CDG inherited?

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

ALG3 p.Leu223=

c.669C>T · rs146607327 · VCV382025

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.429%, mid)

Conditions

ALG3-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.01	strongly benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.019	GERP -2
Overall
CADD	8.355	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.429% Middle Eastern · 26/6,062 alleles

Filtering AF 0.301% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.258%

Overall 0.0169% 272/1,611,058 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.429%	233
African / African-American	0.18%	555
Remaining individualsnot grpmax-eligible	0.0481%	2,080
Ashkenazi Jewishnot grpmax-eligible	0.00677%	14,768
European (non-Finnish)	0.00619%	16,147
Admixed American	0.00503%	19,870
South Asian	0.00332%	30,085

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.Leu223=
Coding: c.669C>T
MANE Select: NM_005787
dbSNP: rs146607327
Type: single nucleotide variant
Location: chr3:184244658 (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 p.Leu223del Uncertain significance ★ same residue
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

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-leu223 (accessed [today's date]).

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