Is COG8 p.Ser489= (c.1467C>T) pathogenic?

COG8 p.Ser489= (c.1467C>T) is classified Conflicting classifications of pathogenicity in COG8 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-23). Ultra-rare (popmax 0.0457%, nfe); Associated with COG8-congenital disorder of glycosylation.

What condition is associated with COG8 p.Ser489= (c.1467C>T)?

COG8 p.Ser489= (c.1467C>T) is associated with COG8-congenital disorder of glycosylation (ClinVar).

How common is COG8 p.Ser489= (c.1467C>T) in the general population?

COG8 p.Ser489= (c.1467C>T) is ultra-rare (popmax 0.0457%, nfe) (gnomAD).

How is COG8-CDG inherited?

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

COG8 p.Ser489=

c.1467C>T · rs138741747 · VCV508007

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0457%, nfe)

Conditions

COG8-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 0.45	GERP -4.9, phastCons 0.004
Overall
CADD	5.831	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0457% European (non-Finnish) · 539/1,180,034 alleles

Filtering AF 0.0425% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0412%

Overall 0.0452% 730/1,614,210 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.261%	383
European (non-Finnish)grpmax	0.0457%	2,189
Remaining individualsnot grpmax-eligible	0.032%	3,125
Admixed American	0.00333%	30,015
African / African-American	0.00266%	37,529

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: COG8
Protein: p.Ser489=
Coding: c.1467C>T
MANE Select: NM_032382
dbSNP: rs138741747
Type: single nucleotide variant
Location: chr16:69332829 (GRCh38)
Gene constraint: LOEUF 1.257 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.67

Full COG8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

COG8-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For COG8-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

COG8 p.Ser489Gly Uncertain significance ★ ⚠ same residue
COG8 c.1583-1G>A Pathogenic/Likely pathogenic ★★ same condition
COG8 p.Ala2Val Uncertain significance ★★ ⚠ same condition
COG8 p.Ala458Val Uncertain significance ★★ ⚠ same condition
COG8 p.Ala5Val Uncertain significance ★★ ⚠ same condition
COG8 p.Arg140Gln Uncertain significance ★★ ⚠ same condition
COG8 p.Arg244Lys Uncertain significance ★★ ⚠ same condition
COG8 p.Arg256Trp 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/cog8-p-ser489 (accessed [today's date]).

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