Is COG4 p.Ala480fs (c.1434_1435del) pathogenic?

COG4 p.Ala480fs (c.14341435del) is classified Pathogenic in COG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-23). Very rare (popmax 8.47e-05%, nfe); Associated with COG4-congenital disorder of glycosylation.

What condition is associated with COG4 p.Ala480fs (c.1434_1435del)?

COG4 p.Ala480fs (c.1434_1435del) is associated with COG4-congenital disorder of glycosylation (ClinVar).

How common is COG4 p.Ala480fs (c.1434_1435del) in the general population?

COG4 p.Ala480fs (c.1434_1435del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is COG4-CDG inherited?

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

COG4 p.Ala480fs

c.1434_1435del · VCV4719224

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

COG4-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 11 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Overall
CADD	34.0	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 8.47e-05% European (non-Finnish) · 1/1,180,044 alleles

Overall 0.000657% 1/152,176 alleles · very rare

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: COG4
Protein: p.Ala480fs
Coding: c.1434_1435del
MANE Select: NM_015386
Type: Microsatellite
Location: chr16:70497267 (GRCh38)
Gene constraint: LOEUF 0.805 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.29 · 1 PDB

Full COG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

COG4-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For COG4-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

COG4 p.Arg177Ter Pathogenic/Likely pathogenic ★★ same condition
COG4 p.Arg733Trp Pathogenic/Likely pathogenic ★★ same condition
COG4 p.Glu614Ter Pathogenic ★★ same condition
COG4 p.Gly25Ter Pathogenic/Likely pathogenic ★★ same condition
COG4 p.Gly516Arg Pathogenic ★★ same condition
COG4 p.Ala251Thr Uncertain significance ★★ same condition
COG4 p.Ala544Val Uncertain significance ★★ same condition
COG4 p.Arg198His 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/cog4-p-ala480fs (accessed [today's date]).

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