Is ALG8 p.Val133fs (c.396dup) pathogenic?

ALG8 p.Val133fs (c.396dup) is classified Conflicting classifications of pathogenicity in ALG8 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-03-25). Very rare (popmax 0.00833%, amr); Associated with ALG8-congenital disorder of glycosylation.

What condition is associated with ALG8 p.Val133fs (c.396dup)?

ALG8 p.Val133fs (c.396dup) is associated with ALG8-congenital disorder of glycosylation (ClinVar).

How common is ALG8 p.Val133fs (c.396dup) in the general population?

ALG8 p.Val133fs (c.396dup) is very rare (popmax 0.00833%, amr) (gnomAD).

How is ALG8-CDG inherited?

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

ALG8 p.Val133fs

c.396dup · rs753631154 · VCV2559

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Conditions

ALG8-congenital disorder of glycosylation

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 4 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.36	GERP 1.4, phastCons 0.97
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/59,996 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00031% 5/1,613,716 alleles · very rare exomes 4/1,461,474 · genomes 1/152,242 · joint denominator

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.Val133fs
Coding: c.396dup
MANE Select: NM_024079
dbSNP: rs753631154
Type: Duplication
Location: chr11:78121146 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.07

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.Val133Met Uncertain significance ★ ⚠ same residue
ALG8 p.Leu104fs Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Pro255fs Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Ser372fs Likely pathogenic ★★ same condition
ALG8 p.Val328fs Pathogenic/Likely pathogenic ★★ same condition
ALG8 p.Glu452fs Pathogenic ★ same condition
ALG8 p.Ile46fs Likely pathogenic ★ same condition
ALG8 p.Trp55fs 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-val133fs (accessed [today's date]).

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