Is PRKAG2 p.Pro136Ser (c.406C>T) pathogenic?

PRKAG2 p.Pro136Ser (c.406C>T) is classified Uncertain significance in PRKAG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-26). AlphaMissense: likely benign (0.0631); Absent from gnomAD v4.1; Associated with hypertrophic cardiomyopathy.

What condition is associated with PRKAG2 p.Pro136Ser (c.406C>T)?

PRKAG2 p.Pro136Ser (c.406C>T) is associated with hypertrophic cardiomyopathy, lethal congenital glycogen storage disease of heart (ClinVar).

How common is PRKAG2 p.Pro136Ser (c.406C>T) in the general population?

PRKAG2 p.Pro136Ser (c.406C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PRKAG2 p.Pro136Ser (c.406C>T)?

AlphaMissense predicts likely benign (score 0.0631) — an in-silico prediction, not a clinical call.

PRKAG2 p.Pro136Ser

c.406C>T · rs1386603764 · VCV1046084

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0631 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.0631	likely benign
REVEL	0.301	indeterminate
SaProt	LLR -7.23	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 281 kb · p 0.8 · regional, not allelic
Overall
CADD	22.8	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

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.Pro136Ser
Coding: c.406C>T
MANE Select: NM_016203
dbSNP: rs1386603764
Type: single nucleotide variant
Location: chr7:151781212 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI 0.20 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.24
Residue 136: the 'disordered' region

Full PRKAG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypertrophic cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: lethal congenital glycogen storage disease of heart

Similar variants

PRKAG2 p.Pro136Ala 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.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

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-pro136ser (accessed [today's date]).

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