Is PRKAG2 p.Pro46= (c.138G>T) pathogenic?

PRKAG2 p.Pro46= (c.138G>T) is classified Benign/Likely benign in PRKAG2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-18). Very rare (popmax 0.0011%, sas); Associated with Cardiovascular phenotype.

What condition is associated with PRKAG2 p.Pro46= (c.138G>T)?

PRKAG2 p.Pro46= (c.138G>T) is associated with Cardiovascular phenotype, cardiomyopathy, lethal congenital glycogen storage disease of heart (ClinVar).

How common is PRKAG2 p.Pro46= (c.138G>T) in the general population?

PRKAG2 p.Pro46= (c.138G>T) is very rare (popmax 0.0011%, sas) (gnomAD).

PRKAG2 p.Pro46=

c.138G>T · rs767613486 · VCV1237822

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15	GERP -6.1
Overall
CADD	0.508	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,568 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,612,974 alleles · very rare exomes 6/1,460,614 · genomes 0/152,360 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,568
European (non-Finnish)	0.000424%	235,920

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: PRKAG2
Protein: p.Pro46=
Coding: c.138G>T
MANE Select: NM_016203
dbSNP: rs767613486
Type: single nucleotide variant
Location: chr7:151786518 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI 0.20 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.24
Residue 46: the 'disordered' region

Full PRKAG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy lethal congenital glycogen storage disease of heart

Similar variants

PRKAG2 p.Pro46Leu Uncertain significance ★★ same residue
PRKAG2 p.Pro46Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
PRKAG2 p.Arg302Gln Pathogenic ★★ same condition
PRKAG2 p.Arg302Pro Pathogenic/Likely pathogenic ★★ same condition
PRKAG2 p.Arg531Gln Pathogenic ★★ same condition
PRKAG2 p.His530Arg Pathogenic ★★ same condition
PRKAG2 p.Phe293Leu Pathogenic/Likely pathogenic ★★ same condition
PRKAG2 c.1005+6T>C Uncertain significance ★★ same condition

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/prkag2-p-pro46 (accessed [today's date]).

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