Is COG6 p.Arg46Pro (c.137G>C) pathogenic?

COG6 p.Arg46Pro (c.137G>C) is classified Uncertain significance in COG6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-24). AlphaMissense: likely pathogenic (0.857); Very rare (popmax 0.00111%, sas).

How common is COG6 p.Arg46Pro (c.137G>C) in the general population?

COG6 p.Arg46Pro (c.137G>C) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about COG6 p.Arg46Pro (c.137G>C)?

AlphaMissense predicts likely pathogenic (score 0.857) — an in-silico prediction, not a clinical call.

COG6 p.Arg46Pro

c.137G>C · VCV4919907

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.857 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.857	likely pathogenic
REVEL	0.448	indeterminate
SaProt	LLR -8.55	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 95 kb · p 0.94 · regional, not allelic
Overall
CADD	26.8	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 0.00111% South Asian · 1/90,232 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000187% 3/1,607,314 alleles · very rare exomes 3/1,454,956 · genomes 0/152,358 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	90,232
European (non-Finnish)	0.00017%	588,959

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: COG6
Protein: p.Arg46Pro
Coding: c.137G>C
MANE Select: NM_020751
Type: single nucleotide variant
Location: chr13:39655863 (GRCh38)
Gene constraint: LOEUF 1.057 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.62

Full COG6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COG6 c.1166+1G>A Likely pathogenic ★★ same type
COG6 c.1167-24A>G Pathogenic/Likely pathogenic ★★ same type
COG6 p.Arg171Ter Pathogenic ★★ same type
COG6 p.Arg360Ter Pathogenic/Likely pathogenic ★★ same type
COG6 p.Leu512Ter Pathogenic/Likely pathogenic ★★ same type
COG6 c.*1532T>G Uncertain significance ★★ same type
COG6 c.*52G>A Uncertain significance ★★ same type
COG6 p.Ala13Thr 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/cog6-p-arg46pro (accessed [today's date]).

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