Is PRKAG2 p.Pro166Ser (c.496C>T) pathogenic?

PRKAG2 p.Pro166Ser (c.496C>T) is classified Uncertain significance in PRKAG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-17). AlphaMissense: likely benign (0.2225); Very rare (popmax 0.00266%, afr); Associated with lethal congenital glycogen storage disease of heart.

What condition is associated with PRKAG2 p.Pro166Ser (c.496C>T)?

PRKAG2 p.Pro166Ser (c.496C>T) is associated with lethal congenital glycogen storage disease of heart, cardiomyopathy (ClinVar).

How common is PRKAG2 p.Pro166Ser (c.496C>T) in the general population?

PRKAG2 p.Pro166Ser (c.496C>T) is very rare (popmax 0.00266%, afr) (gnomAD).

What do computational predictors say about PRKAG2 p.Pro166Ser (c.496C>T)?

AlphaMissense predicts likely benign (score 0.2225) — an in-silico prediction, not a clinical call.

PRKAG2 p.Pro166Ser

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.496C>T · rs1380074442 · VCV1803097

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2225 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

lethal congenital glycogen storage disease of heart

Computational evidence

Protein change
AlphaMissense	0.2225	likely benign
REVEL	0.363	indeterminate
SaProt	LLR -8.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 281 kb · p 0.8 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00266% African / African-American · 2/75,054 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,614,066 alleles · very rare exomes 2/1,461,742 · genomes 2/152,324 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00266%	37,527
European (non-Finnish)	0.00017%	589,946

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.Pro166Ser
Coding: c.496C>T
MANE Select: NM_016203
dbSNP: rs1380074442
Type: single nucleotide variant
Location: chr7:151675608 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI 0.20 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.24
Residue 166: 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: cardiomyopathy

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

Inheritance: Not applicable
Onset: Antenatal, Neonatal

Similar variants

PRKAG2 p.Pro166Leu Uncertain significance ★ ⚠ same residue
PRKAG2 p.Pro166= Likely benign ★ 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-pro166ser (accessed [today's date]).

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