Is COG4 p.Arg221His (c.662G>A) pathogenic?

COG4 p.Arg221His (c.662G>A) is classified Uncertain significance in COG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-29). Ultra-rare (popmax 0.0187%, afr); Associated with Inborn genetic diseases.

What condition is associated with COG4 p.Arg221His (c.662G>A)?

COG4 p.Arg221His (c.662G>A) is associated with Inborn genetic diseases (ClinVar).

How common is COG4 p.Arg221His (c.662G>A) in the general population?

COG4 p.Arg221His (c.662G>A) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

COG4 p.Arg221His

c.662G>A · VCV3268477

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.658	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.4, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 43 kb · p 0.075 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% African / African-American · 14/74,914 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.00242% 39/1,613,994 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,351
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	0.00178%	56,191
Admixed American	0.00167%	59,982
South Asian	0.0011%	91,074

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.Arg221His
Coding: c.662G>A
MANE Select: NM_015386
Type: single nucleotide variant
Location: chr16:70512315 (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.Arg221Cys 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-arg221his (accessed [today's date]).

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