Is PRKAG2 p.Ser548= (c.1644G>A) pathogenic?

PRKAG2 p.Ser548= (c.1644G>A) is classified Benign/Likely benign in PRKAG2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-20). Ultra-rare (popmax 0.0267%, afr); Associated with Cardiovascular phenotype.

What condition is associated with PRKAG2 p.Ser548= (c.1644G>A)?

PRKAG2 p.Ser548= (c.1644G>A) is associated with Cardiovascular phenotype, cardiomyopathy, hypertrophic cardiomyopathy (ClinVar).

How common is PRKAG2 p.Ser548= (c.1644G>A) in the general population?

PRKAG2 p.Ser548= (c.1644G>A) is ultra-rare (popmax 0.0267%, afr) (gnomAD).

PRKAG2 p.Ser548=

c.1644G>A · rs376450705 · VCV45703

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, afr)

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 -11	GERP -5.1
Overall
CADD	0.385	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% African / African-American · 20/74,860 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00248% 40/1,613,842 alleles · ultra-rare exomes 26/1,461,768 · genomes 14/152,074 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0267%	3,743
Admixed American	0.00833%	12,000
South Asian	0.00549%	18,216
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)	0.000593%	168,559

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.Ser548=
Coding: c.1644G>A
MANE Select: NM_016203
dbSNP: rs376450705
Type: single nucleotide variant
Location: chr7:151560558 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI 0.20 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.24
Residue 548: the cbs 4 domain; a binding site

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 hypertrophic cardiomyopathy lethal congenital glycogen storage disease of heart

Similar variants

PRKAG2 p.Ser548Ala Likely pathogenic ★ same residue
PRKAG2 p.Ser548Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PRKAG2 p.Ser548Pro Uncertain significance ★ ⚠ same residue
PRKAG2 p.Ser548Thr 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.Glu506Gln Likely pathogenic ★★ 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-ser548 (accessed [today's date]).

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