Is COG8 p.Pro593Arg (c.1778C>G) pathogenic?

COG8 p.Pro593Arg (c.1778C>G) is classified Uncertain significance in COG8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-25). AlphaMissense: likely benign (0.069); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with COG8 p.Pro593Arg (c.1778C>G)?

COG8 p.Pro593Arg (c.1778C>G) is associated with Inborn genetic diseases (ClinVar).

How common is COG8 p.Pro593Arg (c.1778C>G) in the general population?

COG8 p.Pro593Arg (c.1778C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COG8 p.Pro593Arg (c.1778C>G)?

AlphaMissense predicts likely benign (score 0.069) — an in-silico prediction, not a clinical call.

COG8 p.Pro593Arg

c.1778C>G · rs771769922 · VCV2231385

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.069 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.069	likely benign
REVEL	0.007	strongly benign-leaning
SaProt	LLR -8.68	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 0.091	GERP -1.8
Regional constraint	o/e 0.97	unconstrained · MANE · 8,710 bp · p 0.33 · regional, not allelic
Overall
CADD	6.65	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COG8
Protein: p.Pro593Arg
Coding: c.1778C>G
MANE Select: NM_032382
dbSNP: rs771769922
Type: single nucleotide variant
Location: chr16:69330900 (GRCh38)
Gene constraint: LOEUF 1.257 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.67
Residue 593: 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

Similar variants

COG8 p.Ala16Gly Uncertain significance ★★ ⚠ same condition
COG8 p.Ala458Val Uncertain significance ★★ ⚠ same condition
COG8 p.Arg102Cys Uncertain significance ★★ ⚠ same condition
COG8 p.Arg256Trp Uncertain significance ★★ ⚠ same condition
COG8 p.Asn440Ser Uncertain significance ★★ ⚠ same condition
COG8 p.Glu311Asp Uncertain significance ★★ ⚠ same condition
COG8 p.Glu64Asp Uncertain significance ★★ ⚠ same condition
COG8 p.Gly305Asp 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-pro593arg (accessed [today's date]).

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