Is ALG3 p.Leu223fs (c.668_669del) pathogenic?

ALG3 p.Leu223fs (c.668669del) is classified Likely pathogenic in ALG3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-05). Very rare (popmax 0.00839%, amr).

How common is ALG3 p.Leu223fs (c.668_669del) in the general population?

ALG3 p.Leu223fs (c.668_669del) is very rare (popmax 0.00839%, amr) (gnomAD).

ALG3 p.Leu223fs

c.668_669del · rs757912697 · VCV1695520

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00839%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.95	GERP 0.71, phastCons 0.001

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00839% Admixed American · 5/59,566 alleles

Filtering AF 0.00325% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00208%

Overall 0.000343% 5/1,458,878 alleles · very rare

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.Leu223fs
Coding: c.668_669del
MANE Select: NM_005787
dbSNP: rs757912697
Type: Deletion
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

Similar variants

ALG3 p.Leu223= Likely benign ★★ same residue
ALG3 p.Leu223del Uncertain significance ★ same residue
ALG3 p.His297fs Pathogenic ★ same type
ALG3 p.Lys72fs Likely pathogenic ★ same type
ALG3 p.Pro39fs Pathogenic ★ same type
ALG3 p.Tyr106fs Likely pathogenic ★ same type
ALG3 p.Val388fs Uncertain significance ★ same type
ALG3 c.196+19del Likely benign ★ same type

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-leu223fs (accessed [today's date]).

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