Is COG4 p.Arg177Ter (c.529C>T) pathogenic?

COG4 p.Arg177Ter (c.529C>T) is classified Pathogenic/Likely pathogenic in COG4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-06). Very rare (popmax 0.00134%, afr); Associated with COG4-Related Disorders.

What condition is associated with COG4 p.Arg177Ter (c.529C>T)?

COG4 p.Arg177Ter (c.529C>T) is associated with COG4-Related Disorders, COG4-congenital disorder of glycosylation (ClinVar).

How common is COG4 p.Arg177Ter (c.529C>T) in the general population?

COG4 p.Arg177Ter (c.529C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

COG4 p.Arg177Ter

c.529C>T · rs376663459 · VCV208568

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

COG4-Related Disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 19
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.24	loss · gain 0.03 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 0.65, phastCons 1
Overall
CADD	45.0	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 0.00134% African / African-American · 1/74,836 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,613,870 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,836
European (non-Finnish)	0.000593%	168,571

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.Arg177Ter
Coding: c.529C>T
MANE Select: NM_015386
dbSNP: rs376663459
Type: single nucleotide variant
Location: chr16:70514350 (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-Related Disorders

Also linked: COG4-congenital disorder of glycosylation

Similar variants

COG4 p.Arg177Gln Uncertain significance ★★ same residue
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-arg177ter (accessed [today's date]).

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