Is COG5 p.Val228= (c.684C>T) pathogenic?

COG5 p.Val228= (c.684C>T) is classified Likely benign in COG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-21). Very rare (popmax 0.00893%, eas); Associated with COG5-congenital disorder of glycosylation.

What condition is associated with COG5 p.Val228= (c.684C>T)?

COG5 p.Val228= (c.684C>T) is associated with COG5-congenital disorder of glycosylation (ClinVar).

How common is COG5 p.Val228= (c.684C>T) in the general population?

COG5 p.Val228= (c.684C>T) is very rare (popmax 0.00893%, eas) (gnomAD).

How is COG5-CDG inherited?

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

COG5 p.Val228=

c.684C>T · rs773862978 · VCV1667183

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00893%, eas)

Conditions

COG5-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 -3.2	GERP -4.3
Overall
CADD	0.96	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00893% East Asian · 4/44,798 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00211% 34/1,613,294 alleles · very rare exomes 28/1,461,322 · genomes 6/151,972 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00893%	11,200
African / African-American	0.00668%	14,965
South Asian	0.0033%	30,345
European (non-Finnish)	0.00178%	56,176
Finnishnot grpmax-eligible	0.00156%	63,944

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: COG5
Protein: p.Val228=
Coding: c.684C>T
MANE Select: NM_006348
dbSNP: rs773862978
Type: single nucleotide variant
Location: chr7:107372746 (GRCh38)
Gene constraint: LOEUF 1.026 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37

Full COG5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

COG5-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For COG5-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

COG5 p.Val228Leu Uncertain significance ★ ⚠ same residue
COG5 c.1475+1G>A Likely pathogenic ★★ same condition
COG5 c.2295+2T>C Pathogenic/Likely pathogenic ★★ same condition
COG5 p.Arg205Ter Pathogenic ★★ same condition
COG5 p.Arg283Ter Pathogenic ★★ same condition
COG5 p.Arg461Ter Pathogenic/Likely pathogenic ★★ same condition
COG5 p.Arg690Ter Pathogenic/Likely pathogenic ★★ same condition
COG5 p.Arg708Ter Pathogenic/Likely pathogenic ★★ 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/cog5-p-val228 (accessed [today's date]).

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