Is COG1 p.Val689Ala (c.2066T>C) pathogenic?

COG1 p.Val689Ala (c.2066T>C) is classified Uncertain significance in COG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-07). AlphaMissense: likely benign (0.1463); Very rare (popmax 0.000169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with COG1 p.Val689Ala (c.2066T>C)?

COG1 p.Val689Ala (c.2066T>C) is associated with Inborn genetic diseases (ClinVar).

How common is COG1 p.Val689Ala (c.2066T>C) in the general population?

COG1 p.Val689Ala (c.2066T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about COG1 p.Val689Ala (c.2066T>C)?

AlphaMissense predicts likely benign (score 0.1463) — an in-silico prediction, not a clinical call.

COG1 p.Val689Ala

c.2066T>C · rs2511082997 · VCV2282025

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1463 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1463	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -8.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.63 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 15 kb · p 0.052 · regional, not allelic
Overall
CADD	21.1	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

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,952 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,702 alleles · very rare

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: COG1
Protein: p.Val689Ala
Coding: c.2066T>C
MANE Select: NM_018714
dbSNP: rs2511082997
Type: single nucleotide variant
Location: chr17:73201893 (GRCh38)
Gene constraint: LOEUF 0.718 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.82

Full COG1 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

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COG1 p.Ala385Thr Uncertain significance ★★ ⚠ same condition
COG1 p.Ala563Val Uncertain significance ★★ ⚠ same condition
COG1 p.Arg165Gln Uncertain significance ★★ ⚠ same condition
COG1 p.Arg172Trp Uncertain significance ★★ ⚠ same condition
COG1 p.Arg178Gln 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/cog1-p-val689ala (accessed [today's date]).

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