Is COG4 p.Arg502Trp (c.1504C>T) pathogenic?

COG4 p.Arg502Trp (c.1504C>T) is classified Uncertain significance in COG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with COG4 p.Arg502Trp (c.1504C>T)?

COG4 p.Arg502Trp (c.1504C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COG4 p.Arg502Trp (c.1504C>T) in the general population?

COG4 p.Arg502Trp (c.1504C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

COG4 p.Arg502Trp

c.1504C>T · VCV4004844

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

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	0.476	indeterminate
Splicing
SpliceAI	Δ0.25	acceptor gain · deltas
Pangolin	Δ0.26	gain · loss 0.20 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.1	GERP 0.83, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 43 kb · p 0.075 · regional, not allelic
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,914 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000743% 12/1,614,034 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,728
South Asian	0.0022%	45,545
Finnishnot grpmax-eligible	0.00156%	64,024
European (non-Finnish)	0.000424%	236,008

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.Arg502Trp
Coding: c.1504C>T
MANE Select: NM_015386
Type: single nucleotide variant
Location: chr16:70496409 (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

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

Similar variants

COG4 p.Arg502Gln 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
COG4 p.Arg702Gln 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-arg502trp (accessed [today's date]).

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