Is COG8 p.Arg183Ter (c.547C>T) pathogenic?

COG8 p.Arg183Ter (c.547C>T) is classified Likely pathogenic in COG8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-22). Very rare (popmax 0.00167%, amr); Associated with COG8-related disorder.

What condition is associated with COG8 p.Arg183Ter (c.547C>T)?

COG8 p.Arg183Ter (c.547C>T) is associated with COG8-related disorder (ClinVar).

How common is COG8 p.Arg183Ter (c.547C>T) in the general population?

COG8 p.Arg183Ter (c.547C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

COG8 p.Arg183Ter

c.547C>T · rs201289118 · VCV2628993

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

COG8-related disorder

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 2 of 6
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 1.5, phastCons 1
Overall
CADD	37.0	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 0.00167% Admixed American · 1/60,002 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00143% 23/1,614,000 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00937%	10,670
Admixed Americangrpmax	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.00127%	78,669

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.Arg183Ter
Coding: c.547C>T
MANE Select: NM_032382
dbSNP: rs201289118
Type: single nucleotide variant
Location: chr16:69336543 (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-related disorder

Similar variants

COG8 p.Arg183Gln Uncertain significance ★ ⚠ same residue
COG8 p.Arg183= Likely benign ★ same residue
COG8 p.Arg600Ter Uncertain significance ★ same condition
COG8 p.Glu560fs Pathogenic/Likely pathogenic ★★ same condition
COG8 p.Phe563fs Likely pathogenic ★★ same condition
COG8 c.1583-1G>A Pathogenic/Likely pathogenic ★★ same type
COG8 p.Ala16Gly Uncertain significance ★★ ⚠ same type
COG8 p.Ala2Val Uncertain significance ★★ ⚠ same type

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-arg183ter (accessed [today's date]).

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