Is ALG2 p.Leu254= (c.760T>C) pathogenic?

ALG2 p.Leu254= (c.760T>C) is classified Benign/Likely benign in ALG2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-04-01). Rare (popmax 0.605%, nfe); Associated with congenital myasthenic syndrome 14.

What condition is associated with ALG2 p.Leu254= (c.760T>C)?

ALG2 p.Leu254= (c.760T>C) is associated with congenital myasthenic syndrome 14, ALG2-congenital disorder of glycosylation (ClinVar).

How common is ALG2 p.Leu254= (c.760T>C) in the general population?

ALG2 p.Leu254= (c.760T>C) is rare (popmax 0.605%, nfe) (gnomAD).

How is ALG2-CDG inherited?

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

ALG2 p.Leu254=

c.760T>C · rs62562374 · VCV96238

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.605%, nfe)

Conditions

congenital myasthenic syndrome 14

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.64	GERP -5
Overall
CADD	2.49	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.605% European (non-Finnish) · 7,144/1,180,034 alleles

Filtering AF 0.594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.589%

Overall 0.491% 7,929/1,614,186 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.605%	165
Finnishnot grpmax-eligible	0.442%	226
Remaining individualsnot grpmax-eligible	0.368%	272
Amishnot grpmax-eligible	0.329%	304
Admixed American	0.207%	484
South Asian	0.0955%	1,047
Middle Eastern	0.066%	1,516
African / African-American	0.0626%	1,597
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,229

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: ALG2
Protein: p.Leu254=
Coding: c.760T>C
MANE Select: NM_033087
dbSNP: rs62562374
Type: single nucleotide variant
Location: chr9:99218425 (GRCh38)
Gene constraint: LOEUF 1.408 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.03

Full ALG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital myasthenic syndrome 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ALG2-congenital disorder of glycosylation

For ALG2-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALG2 p.Leu254Ser Uncertain significance ★ ⚠ same residue
ALG2 p.Leu254Val Uncertain significance ★ ⚠ same residue
ALG2 p.Ala29Pro Uncertain significance ★★ ⚠ same condition
ALG2 p.Ala36Val Uncertain significance ★★ ⚠ same condition
ALG2 p.Ala71Gly Uncertain significance ★★ ⚠ same condition
ALG2 p.Ala71Val Uncertain significance ★★ ⚠ same condition
ALG2 p.Arg129Gln Uncertain significance ★★ ⚠ same condition
ALG2 p.Arg130Gln Uncertain significance ★★ ⚠ 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/alg2-p-leu254 (accessed [today's date]).

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