Is PRKAG2 p.Ser548Pro (c.1642T>C) pathogenic?

PRKAG2 p.Ser548Pro (c.1642T>C) is classified Uncertain significance in PRKAG2 (ClinVar, Single submitter, 2 submitters; last evaluated 2019-12-19). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with lethal congenital glycogen storage disease of heart.

How common is PRKAG2 p.Ser548Pro (c.1642T>C) in the general population?

PRKAG2 p.Ser548Pro (c.1642T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PRKAG2 p.Ser548Pro (c.1642T>C)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

PRKAG2 p.Ser548Pro

Q: What condition is associated with PRKAG2 p.Ser548Pro (c.1642T>C)?

PRKAG2 p.Ser548Pro (c.1642T>C) is associated with lethal congenital glycogen storage disease of heart, hypertrophic cardiomyopathy 6 (ClinVar).

Q: How is Fatal congenital hypertrophic cardiomyopathy due to glycogen storage disease inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

c.1642T>C · rs267606979 · VCV6856

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lethal congenital glycogen storage disease of heart

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic · top 4% in PRKAG2
REVEL	0.984	strongly pathogenic-leaning
SaProt	LLR -13.21	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 2.6, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 38 kb · p 8.3e-20 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PRKAG2
Protein: p.Ser548Pro
Coding: c.1642T>C
MANE Select: NM_016203
dbSNP: rs267606979
Type: single nucleotide variant
Location: chr7:151560560 (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

lethal congenital glycogen storage disease of heart — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypertrophic cardiomyopathy 6

For Fatal congenital hypertrophic cardiomyopathy due to glycogen storage disease (Orphanet):

Inheritance: Not applicable
Onset: Antenatal, Neonatal

Similar variants

PRKAG2 p.Ser548= Benign/Likely benign ★★ same residue
PRKAG2 p.Ser548Ala Likely pathogenic ★ same residue
PRKAG2 p.Ser548Leu Conflicting classifications of pathogenicity ★ ⚠ 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-ser548pro (accessed [today's date]).

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