Is COG4 p.Arg702Gln (c.2105G>A) pathogenic?

COG4 p.Arg702Gln (c.2105G>A) is classified Uncertain significance in COG4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-30). Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with COG4 p.Arg702Gln (c.2105G>A)?

COG4 p.Arg702Gln (c.2105G>A) is associated with Inborn genetic diseases (ClinVar).

How common is COG4 p.Arg702Gln (c.2105G>A) in the general population?

COG4 p.Arg702Gln (c.2105G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

COG4 p.Arg702Gln

c.2105G>A · VCV3494954

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.275	benign-leaning
Splicing
SpliceAI	Δ0.55	donor loss, 6 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 43 kb · p 0.075 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,892 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00205% 33/1,612,076 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,723
East Asian	0.00223%	44,872
European (non-Finnish)	0.00204%	49,100
Admixed American	0.00167%	59,988
Remaining individualsnot grpmax-eligible	0.0016%	62,412
Finnishnot grpmax-eligible	0.00156%	63,946
South Asian	0.0011%	90,994

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.Arg702Gln
Coding: c.2105G>A
MANE Select: NM_015386
Type: single nucleotide variant
Location: chr16:70481765 (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 702: an α-helix; the 'd domain' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COG4 p.Arg702Leu Uncertain significance ★ same residue
COG4 p.Arg702Trp Uncertain significance ★ same residue
COG4 p.Ala251Thr Uncertain significance ★★ same condition
COG4 p.Ala544Val Uncertain significance ★★ same condition
COG4 p.Ala599Thr Uncertain significance ★★ same condition
COG4 p.Arg177Gln Uncertain significance ★★ same condition
COG4 p.Arg198His Uncertain significance ★★ same condition
COG4 p.Arg266Gln 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-arg702gln (accessed [today's date]).

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