Is PRKAG3 p.Pro339= (c.1017C>T) pathogenic?

PRKAG3 p.Pro339= (c.1017C>T) is classified Likely benign in PRKAG3 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-10-01). Ultra-rare (popmax 0.035%, nfe).

How common is PRKAG3 p.Pro339= (c.1017C>T) in the general population?

PRKAG3 p.Pro339= (c.1017C>T) is ultra-rare (popmax 0.035%, nfe) (gnomAD).

PRKAG3 p.Pro339=

c.1017C>T · rs747168458 · VCV2651899

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.067	moderately benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1	GERP -1.2, phastCons 1
Overall
CADD	8.036	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.035% European (non-Finnish) · 413/1,180,034 alleles

Filtering AF 0.0322% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0311%

Overall 0.0288% 465/1,613,182 alleles · ultra-rare exomes 432/1,460,974 · genomes 33/152,208 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0417%	2,400
European (non-Finnish)grpmax	0.035%	2,857
Finnishnot grpmax-eligible	0.0141%	7,116
South Asian	0.0121%	8,276
African / African-American	0.00534%	18,724
East Asian	0.00223%	44,898
Admixed American	0.00167%	60,014

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PRKAG3
Protein: p.Pro339=
Coding: c.1017C>T
MANE Select: NM_017431
dbSNP: rs747168458
Type: single nucleotide variant
Location: chr2:218827079 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.68
Residue 339: the cbs 2 domain

Full PRKAG3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PRKAG3 p.Phe206= Benign/Likely benign ★★ same type
PRKAG3 p.Pro3= Benign ★★ same type
PRKAG3 p.Pro313= Likely benign ★★ same type
PRKAG3 c.229+1G>T Uncertain significance ★ same type
PRKAG3 p.Ala100Pro Uncertain significance ★ ⚠ same type
PRKAG3 p.Ala102Asp Uncertain significance ★ ⚠ same type
PRKAG3 p.Ala123Thr Uncertain significance ★ ⚠ same type
PRKAG3 p.Ala158Pro Uncertain significance ★ ⚠ same type

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/prkag3-p-pro339 (accessed [today's date]).

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