Is COG1 p.Val180Glu (c.539T>A) pathogenic?

COG1 p.Val180Glu (c.539T>A) is classified Uncertain significance in COG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-22). AlphaMissense: ambiguous (0.3949); Very rare (popmax 0.00769%, sas); Associated with Inborn genetic diseases.

What condition is associated with COG1 p.Val180Glu (c.539T>A)?

COG1 p.Val180Glu (c.539T>A) is associated with Inborn genetic diseases (ClinVar).

How common is COG1 p.Val180Glu (c.539T>A) in the general population?

COG1 p.Val180Glu (c.539T>A) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about COG1 p.Val180Glu (c.539T>A)?

AlphaMissense predicts ambiguous (score 0.3949) — an in-silico prediction, not a clinical call.

COG1 p.Val180Glu

c.539T>A · rs749267657 · VCV3147077

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3949 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3949	ambiguous
REVEL	0.364	indeterminate
SaProt	LLR -5.80	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 15 kb · p 0.052 · regional, not allelic
Overall
CADD	27.0	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 0.00769% South Asian · 7/91,084 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000547% 8/1,461,506 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,012
Remaining individualsnot grpmax-eligible	0.0016%	62,494

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.Val180Glu
Coding: c.539T>A
MANE Select: NM_018714
dbSNP: rs749267657
Type: single nucleotide variant
Location: chr17:73196730 (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

COG1 p.Ala209Val Uncertain significance ★★ ⚠ same condition
COG1 p.Ala27Ser Uncertain significance ★★ ⚠ same condition
COG1 p.Ala380Val Uncertain significance ★★ ⚠ same condition
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-val180glu (accessed [today's date]).

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