Is ALG12 p.Arg486fs (c.1456del) pathogenic?

ALG12 p.Arg486fs (c.1456del) is classified Uncertain significance in ALG12 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-31). Ultra-rare (popmax 0.0586%, afr); Associated with ALG12-congenital disorder of glycosylation.

What condition is associated with ALG12 p.Arg486fs (c.1456del)?

ALG12 p.Arg486fs (c.1456del) is associated with ALG12-congenital disorder of glycosylation (ClinVar).

How common is ALG12 p.Arg486fs (c.1456del) in the general population?

ALG12 p.Arg486fs (c.1456del) is ultra-rare (popmax 0.0586%, afr) (gnomAD).

How is ALG12-CDG inherited?

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

ALG12 p.Arg486fs

c.1456del · rs768823564 · VCV1348932

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0586%, afr)

Conditions

ALG12-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	escapes	premature termination codon in the last exon (10 of 10) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.016	GERP -0.82
Overall
CADD	12.3	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 0.0586% African / African-American · 44/75,076 alleles

Filtering AF 0.0448% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.04%

Overall 0.00316% 51/1,614,164 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0586%	1,706
Admixed American	0.00833%	12,006
Remaining individualsnot grpmax-eligible	0.0032%	31,251

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: ALG12
Protein: p.Arg486fs
Coding: c.1456del
MANE Select: NM_024105
dbSNP: rs768823564
Type: Deletion
Location: chr22:49903849 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.26
Residue 486: a UniProt-annotated variant site (in cdg1g)

Full ALG12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALG12-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For ALG12-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALG12 p.Arg486Trp Uncertain significance ★★ ⚠ same residue
ALG12 p.Arg486Gln Uncertain significance ★ ⚠ same residue
ALG12 p.Arg486= Likely benign ★ same residue
ALG12 p.Arg311fs Pathogenic ★★ same condition
ALG12 p.Asn334fs Pathogenic/Likely pathogenic ★★ same condition
ALG12 p.Gln40fs Pathogenic ★★ same condition
ALG12 p.Leu12fs Pathogenic/Likely pathogenic ★★ same condition
ALG12 p.Lys416fs 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/alg12-p-arg486fs (accessed [today's date]).

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