Is COG3 p.Ala575Val (c.1724C>T) pathogenic?

COG3 p.Ala575Val (c.1724C>T) is classified Uncertain significance in COG3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-01). AlphaMissense: likely benign (0.1149); Very rare (popmax 0.00223%, eas).

How common is COG3 p.Ala575Val (c.1724C>T) in the general population?

COG3 p.Ala575Val (c.1724C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about COG3 p.Ala575Val (c.1724C>T)?

AlphaMissense predicts likely benign (score 0.1149) — an in-silico prediction, not a clinical call.

COG3 p.Ala575Val

c.1724C>T · VCV4004835

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1149 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1149	likely benign
REVEL	0.134	moderately benign-leaning
SaProt	LLR -5.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.25	acceptor loss, 4 bp away · masked 0 · deltas
Pangolin	Δ0.32	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 43 kb · p 4.3e-11 · regional, not allelic
Overall
CADD	23.6	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 0.00223% East Asian · 1/44,852 alleles

Overall 0.00131% 2/152,102 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,852
European (non-Finnish)	8.49e-05%	1,178,020

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.Ala575Val
Coding: c.1724C>T
MANE Select: NM_031431
Type: single nucleotide variant
Location: chr13:45511769 (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.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
COG3 p.Ala482Val 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-ala575val (accessed [today's date]).

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