Is COG6 p.Pro290Ser (c.868C>T) pathogenic?

COG6 p.Pro290Ser (c.868C>T) is classified Uncertain significance in COG6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-07). AlphaMissense: likely benign (0.0855); Ultra-rare (popmax 0.03%, amr); Associated with hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome.

How common is COG6 p.Pro290Ser (c.868C>T) in the general population?

COG6 p.Pro290Ser (c.868C>T) is ultra-rare (popmax 0.03%, amr) (gnomAD).

What do computational predictors say about COG6 p.Pro290Ser (c.868C>T)?

AlphaMissense predicts likely benign (score 0.0855) — an in-silico prediction, not a clinical call.

COG6 p.Pro290Ser

Q: What condition is associated with COG6 p.Pro290Ser (c.868C>T)?

COG6 p.Pro290Ser (c.868C>T) is associated with hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, COG6-congenital disorder of glycosylation (ClinVar).

Q: How is Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome inherited?

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

c.868C>T · rs748959066 · VCV858496

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0855 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome

Computational evidence

Protein change
AlphaMissense	0.0855	likely benign
REVEL	0.193	benign-leaning
SaProt	LLR -10.82	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 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 95 kb · p 0.94 · regional, not allelic
Overall
CADD	20.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.03% Admixed American · 18/59,914 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00124% 20/1,613,300 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,329
Remaining individualsnot grpmax-eligible	0.0016%	62,472
African / African-American	0.00134%	74,600

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.Pro290Ser
Coding: c.868C>T
MANE Select: NM_020751
dbSNP: rs748959066
Type: single nucleotide variant
Location: chr13:39687582 (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

hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: COG6-congenital disorder of glycosylation

For Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

COG6 p.Pro290= Likely benign ★★ 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-pro290ser (accessed [today's date]).

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