Is COG4 p.Val689= (c.2067C>T) pathogenic?

COG4 p.Val689= (c.2067C>T) is classified Likely benign in COG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-13). Ultra-rare (popmax 0.0156%, eas); Associated with COG4-congenital disorder of glycosylation.

What condition is associated with COG4 p.Val689= (c.2067C>T)?

COG4 p.Val689= (c.2067C>T) is associated with COG4-congenital disorder of glycosylation (ClinVar).

How common is COG4 p.Val689= (c.2067C>T) in the general population?

COG4 p.Val689= (c.2067C>T) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

How is COG4-CDG inherited?

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

COG4 p.Val689=

c.2067C>T · rs376705726 · VCV320367

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Conditions

COG4-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.1	GERP -3.5
Overall
CADD	0.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,884 alleles

Filtering AF 0.00844% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.00167% 27/1,613,958 alleles · ultra-rare exomes 25/1,461,792 · genomes 2/152,166 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,412
South Asian	0.0143%	7,005
Remaining individualsnot grpmax-eligible	0.008%	12,497
European (non-Finnish)	0.000169%	590,009

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.Val689=
Coding: c.2067C>T
MANE Select: NM_015386
dbSNP: rs376705726
Type: single nucleotide variant
Location: chr16:70481803 (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 689: an α-helix; the 'd domain' region

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.Val689Ala Uncertain significance ★ same residue
COG4 p.Val689Ile Uncertain significance ★ 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-val689 (accessed [today's date]).

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