Is ALG3 p.Leu342Ile (c.1024C>A) pathogenic?

ALG3 p.Leu342Ile (c.1024C>A) is classified Conflicting classifications of pathogenicity in ALG3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-13). AlphaMissense: likely benign (0.2393); Rare (popmax 0.219%, sas); Associated with ALG3-congenital disorder of glycosylation.

What condition is associated with ALG3 p.Leu342Ile (c.1024C>A)?

ALG3 p.Leu342Ile (c.1024C>A) is associated with ALG3-congenital disorder of glycosylation (ClinVar).

How common is ALG3 p.Leu342Ile (c.1024C>A) in the general population?

ALG3 p.Leu342Ile (c.1024C>A) is rare (popmax 0.219%, sas) (gnomAD).

How is ALG3-CDG inherited?

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

What do computational predictors say about ALG3 p.Leu342Ile (c.1024C>A)?

AlphaMissense predicts likely benign (score 0.2393) — an in-silico prediction, not a clinical call.

ALG3 p.Leu342Ile

c.1024C>A · rs568371168 · VCV548540

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2393 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.219%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG3-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.2393	likely benign
REVEL	0.705	pathogenic-leaning
SaProt	LLR -6.66	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 2,165 bp · p 0.0031 · regional, not allelic
Overall
CADD	29.1	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 0.219% South Asian · 199/91,046 alleles

Filtering AF 0.194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.184%

Overall 0.0164% 264/1,613,524 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.219%	458
Middle Eastern	0.0663%	1,508
Remaining individualsnot grpmax-eligible	0.00961%	10,411
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,799
European (non-Finnish)	0.00449%	22,260

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.Leu342Ile
Coding: c.1024C>A
MANE Select: NM_005787
dbSNP: rs568371168
Type: single nucleotide variant
Location: chr3:184242943 (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-leu342ile (accessed [today's date]).

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