Is COG3 p.Phe630Leu (c.1888T>C) pathogenic?

COG3 p.Phe630Leu (c.1888T>C) is classified Uncertain significance in COG3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely pathogenic (0.993); Very rare (popmax 0.00224%, eas).

How common is COG3 p.Phe630Leu (c.1888T>C) in the general population?

COG3 p.Phe630Leu (c.1888T>C) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about COG3 p.Phe630Leu (c.1888T>C)?

AlphaMissense predicts likely pathogenic (score 0.993) — an in-silico prediction, not a clinical call.

COG3 p.Phe630Leu

c.1888T>C · VCV4231613

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.993 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.993	likely pathogenic · top 4% in COG3
REVEL	0.599	indeterminate
SaProt	LLR -10.48	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 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 43 kb · p 4.3e-11 · regional, not allelic
Overall
CADD	29.3	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 0.00224% East Asian · 1/44,654 alleles

Overall 0.000207% 3/1,447,780 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,654
Remaining individualsnot grpmax-eligible	0.00161%	61,966
South Asian	0.00114%	87,974

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.Phe630Leu
Coding: c.1888T>C
MANE Select: NM_031431
Type: single nucleotide variant
Location: chr13:45516221 (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-phe630leu (accessed [today's date]).

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