Is PRKACA p.Gly67Arg (c.199G>A) pathogenic?

PRKACA p.Gly67Arg (c.199G>A) is classified Uncertain significance in PRKACA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-27). AlphaMissense: ambiguous (0.3898); Very rare (popmax 0.00333%, amr).

How common is PRKACA p.Gly67Arg (c.199G>A) in the general population?

PRKACA p.Gly67Arg (c.199G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about PRKACA p.Gly67Arg (c.199G>A)?

AlphaMissense predicts ambiguous (score 0.3898) — an in-silico prediction, not a clinical call.

PRKACA p.Gly67Arg

c.199G>A · VCV3309934

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3898 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3898	ambiguous
REVEL	0.135	moderately benign-leaning
SaProt	LLR -12.70	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 17 kb · p 4.4e-06 · regional, not allelic
Overall
CADD	24.6	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 0.00333% Admixed American · 2/60,010 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00062% 10/1,614,076 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,005
South Asian	0.00329%	30,364
European (non-Finnish)	0.000424%	236,007

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: PRKACA
Protein: p.Gly67Arg
Coding: c.199G>A
MANE Select: NM_002730
Type: single nucleotide variant
Location: chr19:14106798 (GRCh38)
Gene constraint: LOEUF 0.338 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 95.92 · 54 PDB
Residue 67: the protein kinase domain

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

Similar variants

PRKACA p.Gly137Arg Pathogenic/Likely pathogenic ★★ same type
PRKACA p.Arg271Trp Uncertain significance ★★ ⚠ same type
PRKACA p.Asn341Ser Uncertain significance ★★ ⚠ same type
PRKACA c.109-6C>T Benign/Likely benign ★★ same type
PRKACA c.47-418C>T Benign/Likely benign ★★ same type
PRKACA p.Arg281= Benign ★★ same type
PRKACA p.Gly127= Benign ★★ same type
PRKACA p.Phe55= Likely benign ★★ 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/prkaca-p-gly67arg (accessed [today's date]).

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