Is PRKACA p.Ser264Pro (c.790T>C) pathogenic?

PRKACA p.Ser264Pro (c.790T>C) is classified Uncertain significance in PRKACA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-26). AlphaMissense: likely benign (0.1415); Very rare (popmax 0.00167%, amr).

How common is PRKACA p.Ser264Pro (c.790T>C) in the general population?

PRKACA p.Ser264Pro (c.790T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PRKACA p.Ser264Pro (c.790T>C)?

AlphaMissense predicts likely benign (score 0.1415) — an in-silico prediction, not a clinical call.

PRKACA p.Ser264Pro

c.790T>C · rs775116225 · VCV2541259

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1415 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1415	likely benign
REVEL	0.375	indeterminate
SaProt	LLR -10.14	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 7,215 bp · p 3e-21 · regional, not allelic
Overall
CADD	25.0	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 0.00167% Admixed American · 1/59,910 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,613,638 alleles · very rare exomes 6/1,461,344 · genomes 0/152,294 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,910
European (non-Finnish)	0.000424%	235,956

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.Ser264Pro
Coding: c.790T>C
MANE Select: NM_002730
dbSNP: rs775116225
Type: single nucleotide variant
Location: chr19:14093768 (GRCh38)
Gene constraint: LOEUF 0.338 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 95.92 · 54 PDB
Residue 264: the protein kinase domain; a UniProt-annotated variant site (in); an α-helix

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 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-ser264pro (accessed [today's date]).

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