Is COG4 p.Pro20Ser (c.58C>T) pathogenic?

COG4 p.Pro20Ser (c.58C>T) is classified Uncertain significance in COG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-22). Very rare (popmax 8.47e-05%, nfe); Associated with COG4-congenital disorder of glycosylation.

What condition is associated with COG4 p.Pro20Ser (c.58C>T)?

COG4 p.Pro20Ser (c.58C>T) is associated with COG4-congenital disorder of glycosylation (ClinVar).

How common is COG4 p.Pro20Ser (c.58C>T) in the general population?

COG4 p.Pro20Ser (c.58C>T) 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.Pro20Ser

c.58C>T · VCV3673993

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

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.
REVEL	0.04	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.91	GERP -1.7, phastCons 0.001
Regional constraint	o/e 1.06	unconstrained · MANE · 43 kb · p 0.075 · regional, not allelic
Overall
CADD	12.18	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,042 alleles

Overall 0.00118% 19/1,613,950 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0203%	4,920
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,402
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)grpmax	8.47e-05%	1,180,043

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: COG4
Protein: p.Pro20Ser
Coding: c.58C>T
MANE Select: NM_015386
Type: single nucleotide variant
Location: chr16:70523486 (GRCh38)
Gene constraint: LOEUF 0.805 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.29 · 1 PDB
Residue 20: the 'disordered' region; the 'interaction with scfd1' region

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.Pro20Leu Uncertain significance ★★ same residue
COG4 p.Pro20= Likely benign same residue
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

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-pro20ser (accessed [today's date]).

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