Is COG6 p.Pro649= (c.1947G>A) pathogenic?

COG6 p.Pro649= (c.1947G>A) is classified Conflicting classifications of pathogenicity in COG6 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-15). Rare (popmax 0.121%, nfe); Associated with COG6-congenital disorder of glycosylation.

What condition is associated with COG6 p.Pro649= (c.1947G>A)?

COG6 p.Pro649= (c.1947G>A) is associated with COG6-congenital disorder of glycosylation, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome (ClinVar).

How common is COG6 p.Pro649= (c.1947G>A) in the general population?

COG6 p.Pro649= (c.1947G>A) is rare (popmax 0.121%, nfe) (gnomAD).

How is COG6-CGD inherited?

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

COG6 p.Pro649=

c.1947G>A · rs147311831 · VCV312150

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.121%, nfe)

Conditions

COG6-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -12	GERP -3.7
Overall
CADD	0.105	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.121% European (non-Finnish) · 1,423/1,179,718 alleles

Filtering AF 0.115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.113%

Overall 0.0977% 1,577/1,613,554 alleles · rare exomes 1,476/1,461,346 · genomes 101/152,208 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.121%	829
Amishnot grpmax-eligible	0.11%	912
Remaining individualsnot grpmax-eligible	0.0864%	1,157
African / African-American	0.072%	1,389
Admixed American	0.0367%	2,725
Finnishnot grpmax-eligible	0.0281%	3,555
South Asian	0.00439%	22,762
East Asian	0.00223%	44,804

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: COG6
Protein: p.Pro649=
Coding: c.1947G>A
MANE Select: NM_020751
dbSNP: rs147311831
Type: single nucleotide variant
Location: chr13:39751066 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.62

Full COG6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

COG6-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome

For COG6-CGD (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

COG6 p.Pro649Leu Uncertain significance ★★ ⚠ same residue
COG6 c.1167-24A>G Pathogenic/Likely pathogenic ★★ same condition
COG6 p.Arg171Ter Pathogenic ★★ same condition
COG6 p.Arg360Ter Pathogenic/Likely pathogenic ★★ same condition
COG6 p.Leu512Ter Pathogenic/Likely pathogenic ★★ same condition
COG6 c.*1532T>G Uncertain significance ★★ same condition
COG6 c.*52G>A Uncertain significance ★★ same condition
COG6 p.Ala13Thr 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/cog6-p-pro649 (accessed [today's date]).

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