Is PRKACA p.Leu206Arg (c.617T>G) pathogenic?

PRKACA p.Leu206Arg (c.617T>G) is classified Pathogenic/Likely pathogenic in PRKACA (ClinVar, No assertion criteria, 4 submitters; last evaluated 2014-06-01). AlphaMissense: likely pathogenic (0.9973); Absent from gnomAD v4.1; Associated with ACTH-independent adrenal Cushing syndrome, somatic.

What condition is associated with PRKACA p.Leu206Arg (c.617T>G)?

PRKACA p.Leu206Arg (c.617T>G) is associated with ACTH-independent adrenal Cushing syndrome, somatic, pigmented nodular adrenocortical disease, primary, 4 (ClinVar).

How common is PRKACA p.Leu206Arg (c.617T>G) in the general population?

PRKACA p.Leu206Arg (c.617T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PRKACA p.Leu206Arg (c.617T>G)?

AlphaMissense predicts likely pathogenic (score 0.9973) — an in-silico prediction, not a clinical call.

PRKACA p.Leu206Arg

c.617T>G · rs386352352 · VCV91945

Pathogenic/Likely pathogenic No assertion criteria

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9973 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ACTH-independent adrenal Cushing syndrome, somatic

Computational evidence

Protein change
AlphaMissense	0.9973	likely pathogenic ✓ concordant with ClinVar
REVEL	0.519	indeterminate
SaProt	LLR -14.18	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 11	phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 7,215 bp · p 3e-21 · regional, not allelic
Overall
CADD	31.0	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

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.Leu206Arg
Coding: c.617T>G
MANE Select: NM_002730
dbSNP: rs386352352
Type: single nucleotide variant
Location: chr19:14097604 (GRCh38)
Gene constraint: LOEUF 0.338 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 95.92 · 54 PDB
Residue 206: the protein kinase domain; a UniProt-annotated variant site (in ppnad4; somatic mutation; the mutation results in camp-independent basal protein kinase activity and constitutive activation of protein kinase a)

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

Disease context

ACTH-independent adrenal Cushing syndrome, somatic — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pigmented nodular adrenocortical disease, primary, 4

Similar variants

PRKACA p.Leu75= Uncertain significance ★ same condition
PRKACA p.Leu199_Cys200insTrp Pathogenic same condition
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

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-leu206arg (accessed [today's date]).

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