Is PRKAG2 p.Phe127= (c.381C>T) pathogenic?

PRKAG2 p.Phe127= (c.381C>T) is classified Likely benign in PRKAG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-03). Very rare (popmax 0.000254%, nfe); Associated with lethal congenital glycogen storage disease of heart.

How common is PRKAG2 p.Phe127= (c.381C>T) in the general population?

PRKAG2 p.Phe127= (c.381C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

PRKAG2 p.Phe127=

Q: What condition is associated with PRKAG2 p.Phe127= (c.381C>T)?

PRKAG2 p.Phe127= (c.381C>T) is associated with lethal congenital glycogen storage disease of heart, hypertrophic cardiomyopathy (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.381C>T · rs778848729 · VCV2797498

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

lethal congenital glycogen storage disease of heart

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 1.7	GERP 1.7, phastCons 1
Overall
CADD	8.478	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,038 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,094 alleles · very rare exomes 3/1,461,766 · genomes 0/152,328 · joint denominator

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.Phe127=
Coding: c.381C>T
MANE Select: NM_016203
dbSNP: rs778848729
Type: single nucleotide variant
Location: chr7:151781237 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI 0.20 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.24
Residue 127: the 'disordered' region

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

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

Inheritance: Not applicable
Onset: Antenatal, Neonatal

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-phe127 (accessed [today's date]).

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