Is ALG8 p.Leu253= (c.757T>C) pathogenic?

ALG8 p.Leu253= (c.757T>C) is classified Likely benign in ALG8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-10). Very rare (popmax 0.00226%, sas); Associated with ALG8-congenital disorder of glycosylation.

What condition is associated with ALG8 p.Leu253= (c.757T>C)?

ALG8 p.Leu253= (c.757T>C) is associated with ALG8-congenital disorder of glycosylation (ClinVar).

How common is ALG8 p.Leu253= (c.757T>C) in the general population?

ALG8 p.Leu253= (c.757T>C) is very rare (popmax 0.00226%, sas) (gnomAD).

How is ALG8-CDG inherited?

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

ALG8 p.Leu253=

c.757T>C · rs768148587 · VCV1921619

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00226%, sas)

Conditions

ALG8-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 · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.58	GERP -4.3
Overall
CADD	2.729	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00226% South Asian · 2/88,616 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000904%

Overall 0.00156% 25/1,601,826 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00226%	44,308
Admixed American	0.00172%	58,188
European (non-Finnish)	0.0017%	58,712
Remaining individualsnot grpmax-eligible	0.00161%	62,136
African / African-American	0.00134%	74,414

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: ALG8
Protein: p.Leu253=
Coding: c.757T>C
MANE Select: NM_024079
dbSNP: rs768148587
Type: single nucleotide variant
Location: chr11:78113906 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07
Residue 253: a UniProt-annotated variant site (in pcld3)

Full ALG8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALG8-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For ALG8-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

ALG8 p.Leu253Met Uncertain significance ★ ⚠ same residue
ALG8 p.Leu253Val Uncertain significance ★ ⚠ same residue
ALG8 p.Leu253Ser Uncertain significance ★ ⚠ same residue
ALG8 c.368+2T>G Likely pathogenic ★★ same condition
ALG8 c.674-2A>G Likely pathogenic ★★ same condition
ALG8 c.777+1G>A Likely pathogenic ★★ same condition
ALG8 c.95+1G>A Likely pathogenic ★★ same condition
ALG8 p.Arg179Ter Pathogenic/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/alg8-p-leu253 (accessed [today's date]).

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