Is PRKAR1A p.Arg74Pro (c.221G>C) pathogenic?

PRKAR1A p.Arg74Pro (c.221G>C) is classified Uncertain significance in PRKAR1A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-11). AlphaMissense: likely benign (0.1453); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with PRKAR1A p.Arg74Pro (c.221G>C)?

PRKAR1A p.Arg74Pro (c.221G>C) is associated with hereditary neoplastic syndrome, Carney complex, type 1 (ClinVar).

How common is PRKAR1A p.Arg74Pro (c.221G>C) in the general population?

PRKAR1A p.Arg74Pro (c.221G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PRKAR1A p.Arg74Pro (c.221G>C)?

AlphaMissense predicts likely benign (score 0.1453) — an in-silico prediction, not a clinical call.

PRKAR1A p.Arg74Pro

c.221G>C · rs200069356 · VCV648708

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1453 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1453	likely benign
REVEL	0.446	indeterminate
SaProt	LLR -6.03	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 6.4	GERP 2.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 7,453 bp · p 0.48 · regional, not allelic
Overall
CADD	20.3	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

Grpmax group 0.00223% East Asian · 1/44,878 alleles

Overall 0.000124% 2/1,614,122 alleles · very rare exomes 2/1,461,802 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,878
European (non-Finnish)	8.47e-05%	1,179,986

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: PRKAR1A
Protein: p.Arg74Pro
Coding: c.221G>C
MANE Select: NM_002734
dbSNP: rs200069356
Type: single nucleotide variant
Location: chr17:68522799 (GRCh38)
Gene constraint: LOEUF 0.158 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 87.95 · 3 PDB
Residue 74: the 'dimerization and phosphorylation' region; the 'disordered' region; a UniProt-annotated variant site (in cnc1; exhibits increased pka activity which is attributed to decreased binding to camp and/or the catalytic subunit)

Full PRKAR1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Carney complex, type 1

Similar variants

PRKAR1A p.Arg74Cys Uncertain significance ★★ ⚠ same residue
PRKAR1A p.Arg74= Likely benign ★★ same residue
PRKAR1A p.Arg74Gly Uncertain significance ★ ⚠ same residue
PRKAR1A p.Arg74His Conflicting classifications of pathogenicity ★ ⚠ same residue
PRKAR1A p.Arg74fs Pathogenic ★★ same residue
PRKAR1A p.Arg74_Pro84del Uncertain significance ★ same residue
PRKAR1A c.502+1G>A Pathogenic/Likely pathogenic ★★ same condition
PRKAR1A c.549+1G>A Pathogenic/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/prkar1a-p-arg74pro (accessed [today's date]).

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