Is COG4 p.Leu552fs (c.1654_1655del) pathogenic?

COG4 p.Leu552fs (c.16541655del) is classified Pathogenic/Likely pathogenic in COG4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-27). Very rare (popmax 0.00133%, afr); Associated with COG4-related disorder.

What condition is associated with COG4 p.Leu552fs (c.1654_1655del)?

COG4 p.Leu552fs (c.1654_1655del) is associated with COG4-related disorder (ClinVar).

How common is COG4 p.Leu552fs (c.1654_1655del) in the general population?

COG4 p.Leu552fs (c.1654_1655del) is very rare (popmax 0.00133%, afr) (gnomAD).

COG4 p.Leu552fs

c.1654_1655del · rs1333878137 · VCV523959

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

COG4-related disorder

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 13 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.8	GERP 0.81, phastCons 1
Overall
CADD	35.0	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 0.00133% African / African-American · 1/74,918 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,614 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,918
European (non-Finnish)	0.000339%	294,928

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.Leu552fs
Coding: c.1654_1655del
MANE Select: NM_015386
dbSNP: rs1333878137
Type: Microsatellite
Location: chr16:70490385 (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 552: an α-helix

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

Disease context

COG4-related disorder

Similar variants

COG4 p.Arg177Ter Pathogenic/Likely pathogenic ★★ same condition
COG4 p.Arg468Gln Uncertain significance ★★ same condition
COG4 c.1828delG Pathogenic ★ same condition
COG4 p.Ala717fs Pathogenic ★ same condition
COG4 p.Gln311Ter Likely pathogenic ★ same condition
COG4 p.Glu711fs Pathogenic ★ same condition
COG4 c.844+5G>C Uncertain significance ★ same condition
COG4 p.Asp778His 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-leu552fs (accessed [today's date]).

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