Is COG5 p.Ala23Pro (c.67G>C) pathogenic?

COG5 p.Ala23Pro (c.67G>C) is classified Uncertain significance in COG5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-17). AlphaMissense: likely benign (0.1189); Ultra-rare (popmax 0.0183%, nfe); Associated with COG5-congenital disorder of glycosylation.

What condition is associated with COG5 p.Ala23Pro (c.67G>C)?

COG5 p.Ala23Pro (c.67G>C) is associated with COG5-congenital disorder of glycosylation (ClinVar).

How common is COG5 p.Ala23Pro (c.67G>C) in the general population?

COG5 p.Ala23Pro (c.67G>C) is ultra-rare (popmax 0.0183%, nfe) (gnomAD).

How is COG5-CDG inherited?

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

What do computational predictors say about COG5 p.Ala23Pro (c.67G>C)?

AlphaMissense predicts likely benign (score 0.1189) — an in-silico prediction, not a clinical call.

COG5 p.Ala23Pro

c.67G>C · rs146391348 · VCV358478

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1189 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

COG5-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.1189	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -10.02	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 0.16, phastCons 0.67
Regional constraint	o/e 1.09	unconstrained · MANE · 360 kb · p 0.0042 · regional, not allelic
Overall
CADD	19.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A54P vs ClinVar A23P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% European (non-Finnish) · 216/1,179,930 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0155%

Overall 0.0143% 231/1,613,694 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0183%	5,463
Remaining individualsnot grpmax-eligible	0.0112%	8,923
Admixed American	0.00667%	15,001
Finnishnot grpmax-eligible	0.0047%	21,265
African / African-American	0.00133%	74,934

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.Ala23Pro
Coding: c.67G>C
MANE Select: NM_006348
dbSNP: rs146391348
Type: single nucleotide variant
Location: chr7:107563830 (GRCh38)
Gene constraint: LOEUF 1.026 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37
Residue 23: the 'disordered' region

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.Ala23Gly Uncertain significance ★ ⚠ same residue
GPR22 p.Ile23Thr Uncertain significance ★ ⚠ same residue
GPR22 p.Ile23Val 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

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-ala23pro (accessed [today's date]).

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