Is COG6 p.Pro641Ala (c.1921C>G) pathogenic?

COG6 p.Pro641Ala (c.1921C>G) is classified Uncertain significance in COG6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-26). AlphaMissense: likely benign (0.0639); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with COG6 p.Pro641Ala (c.1921C>G)?

COG6 p.Pro641Ala (c.1921C>G) is associated with Inborn genetic diseases (ClinVar).

How common is COG6 p.Pro641Ala (c.1921C>G) in the general population?

COG6 p.Pro641Ala (c.1921C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COG6 p.Pro641Ala (c.1921C>G)?

AlphaMissense predicts likely benign (score 0.0639) — an in-silico prediction, not a clinical call.

COG6 p.Pro641Ala

c.1921C>G · VCV3494988

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0639 · 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	0.0639	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -8.90	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 6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 95 kb · p 0.94 · regional, not allelic
Overall
CADD	20.8	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: COG6
Protein: p.Pro641Ala
Coding: c.1921C>G
MANE Select: NM_020751
Type: single nucleotide variant
Location: chr13:39751040 (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

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

Similar variants

COG6 p.Pro641Thr Uncertain significance ★ ⚠ same residue
COG6 c.1166+1G>A Likely pathogenic ★★ same condition
COG6 p.Ala13Thr Uncertain significance ★★ ⚠ same condition
COG6 p.Arg121His Uncertain significance ★★ ⚠ same condition
COG6 p.Arg201Leu Uncertain significance ★★ same condition
COG6 p.Arg466His Uncertain significance ★★ ⚠ same condition
COG6 p.Arg587His Uncertain significance ★★ ⚠ same condition
COG6 p.Asn18Ser 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-pro641ala (accessed [today's date]).

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