Is ALG1 p.Leu332= (c.996C>T) pathogenic?

ALG1 p.Leu332= (c.996C>T) is classified Likely benign in ALG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-26). Ultra-rare (popmax 0.0714%, sas); Associated with ALG1-congenital disorder of glycosylation.

What condition is associated with ALG1 p.Leu332= (c.996C>T)?

ALG1 p.Leu332= (c.996C>T) is associated with ALG1-congenital disorder of glycosylation (ClinVar).

How common is ALG1 p.Leu332= (c.996C>T) in the general population?

ALG1 p.Leu332= (c.996C>T) is ultra-rare (popmax 0.0714%, sas) (gnomAD).

How is ALG1-CDG inherited?

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

ALG1 p.Leu332=

c.996C>T · rs529867921 · VCV2199872

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0714%, sas)

Conditions

ALG1-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.20	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 1.8	GERP -0.29, phastCons 1
Overall
CADD	9.274	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0714% South Asian · 65/90,992 alleles

Filtering AF 0.0575% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0524%

Overall 0.00733% 117/1,596,354 alleles · ultra-rare exomes 109/1,444,076 · genomes 8/152,278 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0714%	1,400
Middle Eastern	0.0226%	4,428
European (non-Finnish)	0.00407%	24,577
Admixed American	0.00167%	60,022
Remaining individualsnot grpmax-eligible	0.00161%	62,220
African / African-American	0.00133%	74,958

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: ALG1
Protein: p.Leu332=
Coding: c.996C>T
MANE Select: NM_019109
dbSNP: rs529867921
Type: single nucleotide variant
Location: chr16:5080980 (GRCh38)
Gene constraint: LOEUF 1.419 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.24

Full ALG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALG1-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For ALG1-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALG1 p.Leu332Val Uncertain significance ★ ⚠ same residue
ALG1 c.1187+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALG1 c.1187+2T>C Pathogenic ★★ same condition
ALG1 c.1188-2A>G Pathogenic/Likely pathogenic ★★ same condition
ALG1 c.209-2A>G Likely pathogenic ★★ same condition
ALG1 c.539+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALG1 c.630-2A>G Likely pathogenic ★★ same condition
ALG1 c.863-2A>G 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/alg1-p-leu332 (accessed [today's date]).

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