Is COG4 p.Arg375His (c.1124G>A) pathogenic?

COG4 p.Arg375His (c.1124G>A) is classified Uncertain significance in COG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-13). Very rare (popmax 0.00333%, amr); Associated with COG4-congenital disorder of glycosylation.

What condition is associated with COG4 p.Arg375His (c.1124G>A)?

COG4 p.Arg375His (c.1124G>A) is associated with COG4-congenital disorder of glycosylation (ClinVar).

How common is COG4 p.Arg375His (c.1124G>A) in the general population?

COG4 p.Arg375His (c.1124G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

How is COG4-CDG inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

COG4 p.Arg375His

c.1124G>A · rs762087790 · VCV1366494

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

COG4-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.453	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 43 kb · p 0.075 · regional, not allelic
Overall
CADD	30.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,992 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000889% 13/1,461,520 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,996
African / African-American	0.00267%	37,450
Remaining individualsnot grpmax-eligible	0.0016%	62,472
European (non-Finnish)	0.000678%	147,473

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.Arg375His
Coding: c.1124G>A
MANE Select: NM_015386
dbSNP: rs762087790
Type: single nucleotide variant
Location: chr16:70501029 (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

COG4-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For COG4-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

COG4 p.Arg375Cys Conflicting classifications of pathogenicity ★ same residue
COG4 p.Arg375fs Pathogenic ★ same residue
COG4 p.Arg177Ter Pathogenic/Likely pathogenic ★★ same condition
COG4 p.Arg733Trp Pathogenic/Likely pathogenic ★★ same condition
COG4 p.Glu614Ter Pathogenic ★★ same condition
COG4 p.Gly25Ter Pathogenic/Likely pathogenic ★★ same condition
COG4 p.Gly516Arg Pathogenic ★★ same condition
COG4 p.Ala251Thr 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-arg375his (accessed [today's date]).

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