Is COG2 p.Leu397= (c.1189T>C) pathogenic?

COG2 p.Leu397= (c.1189T>C) is classified Likely benign in COG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-25). Ultra-rare (popmax 0.067%, sas); Associated with congenital disorder of glycosylation, type IIq.

What condition is associated with COG2 p.Leu397= (c.1189T>C)?

COG2 p.Leu397= (c.1189T>C) is associated with congenital disorder of glycosylation, type IIq (ClinVar).

How common is COG2 p.Leu397= (c.1189T>C) in the general population?

COG2 p.Leu397= (c.1189T>C) is ultra-rare (popmax 0.067%, sas) (gnomAD).

How is COG2-CDG inherited?

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

COG2 p.Leu397=

c.1189T>C · rs372067889 · VCV720097

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.067%, sas)

Conditions

congenital disorder of glycosylation, type IIq

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 0.96	GERP 4.1, phastCons 1
Overall
CADD	8.22	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.067% South Asian · 61/91,038 alleles

Filtering AF 0.0535% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0486%

Overall 0.0355% 573/1,612,276 alleles · ultra-rare exomes 544/1,460,060 · genomes 29/152,216 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.067%	1,492
Middle Eastern	0.0661%	1,514
European (non-Finnish)	0.0412%	2,430
Remaining individualsnot grpmax-eligible	0.0208%	4,804
African / African-American	0.00667%	14,994
Admixed American	0.00667%	15,001
Finnishnot grpmax-eligible	0.00157%	63,860

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: COG2
Protein: p.Leu397=
Coding: c.1189T>C
MANE Select: NM_007357
dbSNP: rs372067889
Type: single nucleotide variant
Location: chr1:230683596 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.38

Full COG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For COG2-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

COG2 p.Ala160Val Uncertain significance ★★ ⚠ same condition
COG2 p.Ala339Pro Uncertain significance ★★ ⚠ same condition
COG2 p.Arg138Gln Uncertain significance ★★ ⚠ same condition
COG2 p.Arg241Gln Uncertain significance ★★ ⚠ same condition
COG2 p.Arg356Gln Uncertain significance ★★ ⚠ same condition
COG2 p.Arg356Trp Uncertain significance ★★ ⚠ same condition
COG2 p.Arg39Gln Uncertain significance ★★ ⚠ same condition
COG2 p.Arg39Trp 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/cog2-p-leu397 (accessed [today's date]).

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