Is PRKAG2 p.Ser65= (c.195C>T) pathogenic?

PRKAG2 p.Ser65= (c.195C>T) is classified Likely benign in PRKAG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-27). Very rare (popmax 0.0034%, amr); Associated with Cardiovascular phenotype.

What condition is associated with PRKAG2 p.Ser65= (c.195C>T)?

PRKAG2 p.Ser65= (c.195C>T) is associated with Cardiovascular phenotype, lethal congenital glycogen storage disease of heart (ClinVar).

How common is PRKAG2 p.Ser65= (c.195C>T) in the general population?

PRKAG2 p.Ser65= (c.195C>T) is very rare (popmax 0.0034%, amr) (gnomAD).

PRKAG2 p.Ser65=

c.195C>T · VCV3425021

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0034%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.9	GERP 0.68, phastCons 1
Overall
CADD	7.261	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0034% Admixed American · 2/58,872 alleles

Filtering AF 0.000564% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000249% 4/1,606,300 alleles · very rare exomes 3/1,454,116 · genomes 1/152,184 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0034%	29,436
European (non-Finnish)	0.00017%	588,488

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.Ser65=
Coding: c.195C>T
MANE Select: NM_016203
Type: single nucleotide variant
Location: chr7:151781423 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI 0.20 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.24
Residue 65: a modified residue (phosphoserine); 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: lethal congenital glycogen storage disease of heart

Similar variants

PRKAG2 p.Ser65Ile Uncertain significance ★ 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
PRKAG2 c.1006-3C>T 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-ser65 (accessed [today's date]).

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