Is COG2 p.Arg199Cys (c.595C>T) pathogenic?

COG2 p.Arg199Cys (c.595C>T) is classified Uncertain significance in COG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-18). AlphaMissense: ambiguous (0.4378); Very rare (popmax 0.00134%, afr).

How common is COG2 p.Arg199Cys (c.595C>T) in the general population?

COG2 p.Arg199Cys (c.595C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about COG2 p.Arg199Cys (c.595C>T)?

AlphaMissense predicts ambiguous (score 0.4378) — an in-silico prediction, not a clinical call.

COG2 p.Arg199Cys

c.595C>T · rs376181628 · VCV2539877

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4378 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Computational evidence

Protein change
AlphaMissense	0.4378	ambiguous
REVEL	0.53	indeterminate
SaProt	LLR -12.61	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 51 kb · p 0.037 · regional, not allelic
Overall
CADD	34.0	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 0.00134% African / African-American · 1/74,468 alleles

Filtering AF 0.000503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000368%

Overall 0.000998% 16/1,603,450 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0103%	9,739
African / African-Americangrpmax	0.00134%	74,468
South Asian	0.00111%	89,902
European (non-Finnish)	0.000937%	106,680

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: COG2
Protein: p.Arg199Cys
Coding: c.595C>T
MANE Select: NM_007357
dbSNP: rs376181628
Type: single nucleotide variant
Location: chr1:230669356 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.38

Full COG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COG2 p.Ala160Val Uncertain significance ★★ ⚠ same type
COG2 p.Ala339Pro Uncertain significance ★★ ⚠ same type
COG2 p.Arg138Gln Uncertain significance ★★ ⚠ same type
COG2 p.Arg241Gln Uncertain significance ★★ ⚠ same type
COG2 p.Arg356Gln Uncertain significance ★★ ⚠ same type
COG2 p.Arg356Trp Uncertain significance ★★ ⚠ same type
COG2 p.Arg39Gln Uncertain significance ★★ ⚠ same type
COG2 p.Arg39Trp 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/cog2-p-arg199cys (accessed [today's date]).

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