Is COG5 p.Ile604Val (c.1810A>G) pathogenic?

COG5 p.Ile604Val (c.1810A>G) is classified Uncertain significance in COG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: likely benign (0.0566); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with COG5 p.Ile604Val (c.1810A>G)?

COG5 p.Ile604Val (c.1810A>G) is associated with Inborn genetic diseases (ClinVar).

How common is COG5 p.Ile604Val (c.1810A>G) in the general population?

COG5 p.Ile604Val (c.1810A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about COG5 p.Ile604Val (c.1810A>G)?

AlphaMissense predicts likely benign (score 0.0566) — an in-silico prediction, not a clinical call.

COG5 p.Ile604Val

c.1810A>G · VCV4004846

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0566 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0566	likely benign
REVEL	0.086	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -0.71, phastCons 0.99
Regional constraint	o/e 1.09	unconstrained · MANE · 360 kb · p 0.0042 · regional, not allelic
Overall
CADD	10.99	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I614V vs ClinVar I604V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,008 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,460,848 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,008
European (non-Finnish)	0.000254%	393,094

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: COG5
Protein: p.Ile604Val
Coding: c.1810A>G
MANE Select: NM_006348
Type: single nucleotide variant
Location: chr7:107248439 (GRCh38)
Gene constraint: LOEUF 1.026 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.37

Full COG5 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

COG5 p.Tyr416Ter Pathogenic ★★ same condition
COG5 c.-25C>A Uncertain significance ★★ ⚠ same condition
COG5 p.Ala15Gly Uncertain significance ★★ ⚠ same condition
COG5 p.Ala20Val Uncertain significance ★★ ⚠ same condition
COG5 p.Ala263Thr Uncertain significance ★★ ⚠ same condition
COG5 p.Ala409Thr Uncertain significance ★★ ⚠ same condition
COG5 p.Ala62Thr Uncertain significance ★★ ⚠ same condition
COG5 p.Arg214Cys 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/cog5-p-ile604val (accessed [today's date]).

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