Is PRKAR2A p.Ser396Arg (c.1188C>A) pathogenic?

PRKAR2A p.Ser396Arg (c.1188C>A) is classified Uncertain significance in PRKAR2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: likely benign (0.2815); Very rare (popmax 0.005%, amr).

How common is PRKAR2A p.Ser396Arg (c.1188C>A) in the general population?

PRKAR2A p.Ser396Arg (c.1188C>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about PRKAR2A p.Ser396Arg (c.1188C>A)?

AlphaMissense predicts likely benign (score 0.2815) — an in-silico prediction, not a clinical call.

PRKAR2A p.Ser396Arg

c.1188C>A · VCV4144376

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2815 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2815	likely benign
REVEL	0.421	indeterminate
SaProt	LLR -8.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 96 kb · p 0.003 · regional, not allelic
Overall
CADD	22.1	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 0.005% Admixed American · 3/59,968 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00105% 17/1,613,152 alleles · very rare exomes 15/1,460,986 · genomes 2/152,166 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,989
African / African-American	0.00133%	74,918
European (non-Finnish)	0.0011%	90,742

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.Ser396Arg
Coding: c.1188C>A
MANE Select: NM_004157
Type: single nucleotide variant
Location: chr3:48751612 (GRCh38)
Gene constraint: LOEUF 0.746 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.74 · 8 PDB
Residue 396: a binding site

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

Similar variants

PRKAR2A p.Ser396Asn Uncertain significance ★ ⚠ same residue
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

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-ser396arg (accessed [today's date]).

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