Is PRKACA p.Ala21Pro (c.61G>C) pathogenic?

PRKACA p.Ala21Pro (c.61G>C) is classified Uncertain significance in PRKACA (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-12). AlphaMissense: likely pathogenic (0.8935); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder.

What condition is associated with PRKACA p.Ala21Pro (c.61G>C)?

PRKACA p.Ala21Pro (c.61G>C) is associated with neurodevelopmental disorder (ClinVar).

How common is PRKACA p.Ala21Pro (c.61G>C) in the general population?

PRKACA p.Ala21Pro (c.61G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PRKACA p.Ala21Pro (c.61G>C)?

AlphaMissense predicts likely pathogenic (score 0.8935) — an in-silico prediction, not a clinical call.

PRKACA p.Ala21Pro

c.61G>C · rs1977645307 · VCV1321985

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8935 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.8935	likely pathogenic
REVEL	0.352	indeterminate
SaProt	LLR -13.57	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 17 kb · p 4.4e-06 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PRKACA
Protein: p.Ala21Pro
Coding: c.61G>C
MANE Select: NM_002730
dbSNP: rs1977645307
Type: single nucleotide variant
Location: chr19:14107395 (GRCh38)
Gene constraint: LOEUF 0.338 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 95.92 · 54 PDB
Residue 21: an α-helix

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

Disease context

neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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 p.Gly67Arg 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

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-ala21pro (accessed [today's date]).

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