Is PRKAG2 p.Ser41= (c.123C>T) pathogenic?

PRKAG2 p.Ser41= (c.123C>T) is classified Conflicting classifications of pathogenicity in PRKAG2 (ClinVar, Conflicting submitters, 16 submitters; last evaluated 2026-05-01). Rare (popmax 0.529%, mid); Associated with Cardiovascular phenotype.

What condition is associated with PRKAG2 p.Ser41= (c.123C>T)?

PRKAG2 p.Ser41= (c.123C>T) is associated with Cardiovascular phenotype, cardiomyopathy, Wolff-Parkinson-White syndrome (ClinVar).

How common is PRKAG2 p.Ser41= (c.123C>T) in the general population?

PRKAG2 p.Ser41= (c.123C>T) is rare (popmax 0.529%, mid) (gnomAD).

PRKAG2 p.Ser41=

c.123C>T · rs397517263 · VCV45692

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 16 submitters

gnomAD v4.1

Rare

rare (popmax 0.529%, mid)

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 0.37	GERP -2.5, phastCons 0.93
Overall
CADD	5.434	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.529% Middle Eastern · 32/6,054 alleles

Filtering AF 0.385% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.336%

Overall 0.0155% 250/1,612,584 alleles · rare exomes 220/1,460,256 · genomes 30/152,328 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.529%	189
Ashkenazi Jewishnot grpmax-eligible	0.142%	704
Remaining individualsnot grpmax-eligible	0.064%	1,562
Admixed American	0.0318%	3,149
African / African-American	0.02%	5,002
South Asian	0.0144%	6,956
European (non-Finnish)	0.00755%	13,253

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.Ser41=
Coding: c.123C>T
MANE Select: NM_016203
dbSNP: rs397517263
Type: single nucleotide variant
Location: chr7:151786533 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI 0.20 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.24
Residue 41: 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 Wolff-Parkinson-White syndrome lethal congenital glycogen storage disease of heart hypertrophic cardiomyopathy 6

Similar variants

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
PRKAG2 p.His530Arg Pathogenic ★★ same condition
PRKAG2 p.Phe293Leu Pathogenic/Likely pathogenic ★★ same condition
PRKAG2 p.Thr400Asn 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-ser41 (accessed [today's date]).

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