Is COG3 p.Leu592Phe (c.1776A>C) pathogenic?

COG3 p.Leu592Phe (c.1776A>C) is classified Uncertain significance in COG3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: likely pathogenic (0.9166); Very rare (popmax 0.00288%, nfe).

How common is COG3 p.Leu592Phe (c.1776A>C) in the general population?

COG3 p.Leu592Phe (c.1776A>C) is very rare (popmax 0.00288%, nfe) (gnomAD).

What do computational predictors say about COG3 p.Leu592Phe (c.1776A>C)?

AlphaMissense predicts likely pathogenic (score 0.9166) — an in-silico prediction, not a clinical call.

COG3 p.Leu592Phe

c.1776A>C · VCV4827785

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9166 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00288%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9166	likely pathogenic
REVEL	0.31	indeterminate
SaProt	LLR -14.32	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -4.2, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 43 kb · p 4.3e-11 · regional, not allelic
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00288% European (non-Finnish) · 34/1,179,908 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00211% 34/1,613,872 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: COG3
Protein: p.Leu592Phe
Coding: c.1776A>C
MANE Select: NM_031431
Type: single nucleotide variant
Location: chr13:45511821 (GRCh38)
Gene constraint: LOEUF 0.314 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.82

Full COG3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COG3 p.Leu592Val Uncertain significance ★ ⚠ same residue
COG3 p.Ala14Val Uncertain significance ★ ⚠ same type
COG3 p.Ala190Gly Uncertain significance ★ ⚠ same type
COG3 p.Ala227Asp Uncertain significance ★ ⚠ same type
COG3 p.Ala227Thr Uncertain significance ★ ⚠ same type
COG3 p.Ala2Val Uncertain significance ★ ⚠ same type
COG3 p.Ala302Gly Uncertain significance ★ ⚠ same type
COG3 p.Ala364Ser Uncertain significance ★ ⚠ same type

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/cog3-p-leu592phe (accessed [today's date]).

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