Is PRKAG2 p.Pro441Ser (c.1321C>T) pathogenic?

PRKAG2 p.Pro441Ser (c.1321C>T) is classified Uncertain significance in PRKAG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-22). AlphaMissense: ambiguous (0.3524); Very rare (popmax 0.00167%, amr); Associated with Cardiovascular phenotype.

What condition is associated with PRKAG2 p.Pro441Ser (c.1321C>T)?

PRKAG2 p.Pro441Ser (c.1321C>T) is associated with Cardiovascular phenotype, lethal congenital glycogen storage disease of heart (ClinVar).

How common is PRKAG2 p.Pro441Ser (c.1321C>T) in the general population?

PRKAG2 p.Pro441Ser (c.1321C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PRKAG2 p.Pro441Ser (c.1321C>T)?

AlphaMissense predicts ambiguous (score 0.3524) — an in-silico prediction, not a clinical call.

PRKAG2 p.Pro441Ser

c.1321C>T · rs2536296557 · VCV1769917

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3524 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3524	ambiguous
REVEL	0.569	indeterminate
SaProt	LLR -11.82	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 38 kb · p 8.3e-20 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,016 alleles

Overall 6.2e-05% 1/1,612,020 alleles · very rare exomes 1/1,459,730 · genomes 0/152,290 · 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.Pro441Ser
Coding: c.1321C>T
MANE Select: NM_016203
dbSNP: rs2536296557
Type: single nucleotide variant
Location: chr7:151565798 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI 0.20 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.24
Residue 441: the cbs 3 domain

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.Pro441= Likely benign ★★ same residue
PRKAG2 p.Pro441Thr 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

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-pro441ser (accessed [today's date]).

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