Is PRKAG2 p.Phe76Ser (c.227T>C) pathogenic?

PRKAG2 p.Phe76Ser (c.227T>C) is classified Uncertain significance in PRKAG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: likely benign (0.1421); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with PRKAG2 p.Phe76Ser (c.227T>C)?

PRKAG2 p.Phe76Ser (c.227T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is PRKAG2 p.Phe76Ser (c.227T>C) in the general population?

PRKAG2 p.Phe76Ser (c.227T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PRKAG2 p.Phe76Ser (c.227T>C)?

AlphaMissense predicts likely benign (score 0.1421) — an in-silico prediction, not a clinical call.

PRKAG2 p.Phe76Ser

c.227T>C · VCV4614759

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1421 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1421	likely benign
REVEL	0.184	benign-leaning
SaProt	LLR -7.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 281 kb · p 0.8 · regional, not allelic
Overall
CADD	24.3	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.Phe76Ser
Coding: c.227T>C
MANE Select: NM_016203
Type: single nucleotide variant
Location: chr7:151781391 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI 0.20 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.24
Residue 76: the 'disordered' region

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

Similar variants

PRKAG2 p.Arg302Gln Pathogenic ★★ same condition
PRKAG2 p.His530Arg Pathogenic ★★ same condition
PRKAG2 c.467-2A>G Uncertain significance ★★ same condition
PRKAG2 c.684+1G>A Uncertain significance ★★ same condition
PRKAG2 c.755-1G>A Uncertain significance ★★ same condition
PRKAG2 p.Ala229Val Uncertain significance ★★ ⚠ same condition
PRKAG2 p.Ala304Gly Uncertain significance ★★ ⚠ same condition
PRKAG2 p.Ala368Ser 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-phe76ser (accessed [today's date]).

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