Is COG8 p.Pro581Thr (c.1741C>A) pathogenic?

COG8 p.Pro581Thr (c.1741C>A) is classified Benign/Likely benign in COG8 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-12-23). AlphaMissense: likely benign (0.0702); Low-frequency (popmax 1.11%, sas); Associated with Inborn genetic diseases.

What condition is associated with COG8 p.Pro581Thr (c.1741C>A)?

COG8 p.Pro581Thr (c.1741C>A) is associated with Inborn genetic diseases, COG8-congenital disorder of glycosylation (ClinVar).

How common is COG8 p.Pro581Thr (c.1741C>A) in the general population?

COG8 p.Pro581Thr (c.1741C>A) is low-frequency (popmax 1.11%, sas) (gnomAD).

What do computational predictors say about COG8 p.Pro581Thr (c.1741C>A)?

AlphaMissense predicts likely benign (score 0.0702) — an in-silico prediction, not a clinical call.

COG8 p.Pro581Thr

c.1741C>A · rs548002506 · VCV597494

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0702 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.11%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0702	likely benign
REVEL	0.027	moderately benign-leaning
SaProt	LLR -7.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.6, phastCons 0.29
Regional constraint	o/e 0.97	unconstrained · MANE · 8,710 bp · p 0.33 · regional, not allelic
Overall
CADD	4.603	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 1.11% South Asian · 946/85,488 alleles

Filtering AF 1.05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.02%

Overall 0.0873% 1,362/1,560,794 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.11%	90
Middle Eastern	0.45%	222
Remaining individualsnot grpmax-eligible	0.121%	829
Admixed American	0.0795%	1,257
Ashkenazi Jewishnot grpmax-eligible	0.0244%	4,104
European (non-Finnish)	0.0227%	4,401
African / African-American	0.00543%	18,430
Finnishnot grpmax-eligible	0.00339%	29,531

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: COG8
Protein: p.Pro581Thr
Coding: c.1741C>A
MANE Select: NM_032382
dbSNP: rs548002506
Type: single nucleotide variant
Location: chr16:69330937 (GRCh38)
Gene constraint: LOEUF 1.257 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.67
Residue 581: the 'disordered' region

Full COG8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: COG8-congenital disorder of glycosylation

Similar variants

COG8 c.1583-1G>A Pathogenic/Likely pathogenic ★★ same condition
COG8 p.Ala16Gly Uncertain significance ★★ ⚠ same condition
COG8 p.Ala2Val Uncertain significance ★★ ⚠ same condition
COG8 p.Ala458Val Uncertain significance ★★ ⚠ same condition
COG8 p.Ala5Val Uncertain significance ★★ ⚠ same condition
COG8 p.Arg102Cys Uncertain significance ★★ ⚠ same condition
COG8 p.Arg140Gln Uncertain significance ★★ ⚠ same condition
COG8 p.Arg244Lys 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/cog8-p-pro581thr (accessed [today's date]).

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