Is PRKAR2A p.Pro27His (c.80C>A) pathogenic?

PRKAR2A p.Pro27His (c.80C>A) is classified Uncertain significance in PRKAR2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.1271); Ultra-rare (popmax 0.0286%, afr).

How common is PRKAR2A p.Pro27His (c.80C>A) in the general population?

PRKAR2A p.Pro27His (c.80C>A) is ultra-rare (popmax 0.0286%, afr) (gnomAD).

What do computational predictors say about PRKAR2A p.Pro27His (c.80C>A)?

AlphaMissense predicts likely benign (score 0.1271) — an in-silico prediction, not a clinical call.

PRKAR2A p.Pro27His

c.80C>A · VCV4144381

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1271 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0286%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1271	likely benign
REVEL	0.329	indeterminate
SaProt	LLR -8.78	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 96 kb · p 0.003 · regional, not allelic
Overall
CADD	24.8	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

Grpmax group 0.0286% African / African-American · 21/73,426 alleles

Filtering AF 0.0191% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00147% 23/1,560,148 alleles · ultra-rare exomes 13/1,407,918 · genomes 10/152,230 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0286%	3,496
Admixed American	0.00383%	26,101

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: PRKAR2A
Protein: p.Pro27His
Coding: c.80C>A
MANE Select: NM_004157
Type: single nucleotide variant
Location: chr3:48847517 (GRCh38)
Gene constraint: LOEUF 0.746 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.74 · 8 PDB
Residue 27: the 'dimerization and phosphorylation' region

Full PRKAR2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PRKAR2A p.Ala45Val Uncertain significance ★ ⚠ same type
PRKAR2A p.Ala47Val Uncertain significance ★ ⚠ same type
PRKAR2A p.Ala52Val Uncertain significance ★ ⚠ same type
PRKAR2A p.Ala74Ser Uncertain significance ★ ⚠ same type
PRKAR2A p.Arg158Lys Uncertain significance ★ ⚠ same type
PRKAR2A p.Arg195Cys Uncertain significance ★ ⚠ same type
PRKAR2A p.Arg195Gly Uncertain significance ★ same type
PRKAR2A p.Arg203Cys 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/prkar2a-p-pro27his (accessed [today's date]).

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