Is ALG3 p.Leu223del (c.664CTC[1]) pathogenic?

ALG3 p.Leu223del (c.664CTC[1]) is classified Uncertain significance in ALG3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-25). Very rare (popmax 0.00134%, afr); Associated with ALG3-congenital disorder of glycosylation.

What condition is associated with ALG3 p.Leu223del (c.664CTC[1])?

ALG3 p.Leu223del (c.664CTC[1]) is associated with ALG3-congenital disorder of glycosylation (ClinVar).

How common is ALG3 p.Leu223del (c.664CTC[1]) in the general population?

ALG3 p.Leu223del (c.664CTC[1]) is very rare (popmax 0.00134%, afr) (gnomAD).

How is ALG3-CDG inherited?

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

ALG3 p.Leu223del

c.664CTC[1] · rs1399225021 · VCV3064907

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

ALG3-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.95	GERP 0.71, phastCons 0.001
Overall
CADD	19.49	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,626 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000931% 15/1,610,456 alleles · very rare exomes 13/1,458,876 · genomes 2/151,580 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,368
African / African-Americangrpmax	0.00134%	74,626
European (non-Finnish)	0.0011%	90,663

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu223del
Coding: c.664CTC[1]
MANE Select: NM_005787
dbSNP: rs1399225021
Type: Microsatellite
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.Leu223= Likely benign ★★ same residue
ALG3 p.Leu223fs Likely pathogenic ★ 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

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-leu223del (accessed [today's date]).

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