Is PRKACA p.Leu75= (c.225C>T) pathogenic?

PRKACA p.Leu75= (c.225C>T) is classified Uncertain significance in PRKACA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-17). Very rare (popmax 0.00167%, amr); Associated with cardioacrofacial dysplasia 1.

What condition is associated with PRKACA p.Leu75= (c.225C>T)?

PRKACA p.Leu75= (c.225C>T) is associated with cardioacrofacial dysplasia 1, pigmented nodular adrenocortical disease, primary, 4 (ClinVar).

How common is PRKACA p.Leu75= (c.225C>T) in the general population?

PRKACA p.Leu75= (c.225C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

PRKACA p.Leu75=

c.225C>T · VCV3583508

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

cardioacrofacial dysplasia 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.1
Overall
CADD	7.127	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,012 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00105% 17/1,614,082 alleles · very rare exomes 14/1,461,840 · genomes 3/152,242 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,012
European (non-Finnish)	0.00136%	73,752

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.Leu75=
Coding: c.225C>T
MANE Select: NM_002730
Type: single nucleotide variant
Location: chr19:14106772 (GRCh38)
Gene constraint: LOEUF 0.338 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 95.92 · 54 PDB
Residue 75: the protein kinase domain; a β-strand

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

Disease context

cardioacrofacial dysplasia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pigmented nodular adrenocortical disease, primary, 4

Similar variants

PRKACA p.Gly137Arg Pathogenic/Likely pathogenic ★★ same condition
PRKACA p.Asn341Ser Uncertain significance ★★ ⚠ same condition
PRKACA c.47-322G>A Uncertain significance ★ same condition
PRKACA c.47-404C>T Conflicting classifications of pathogenicity ★ same condition
PRKACA p.Glu108Ala Uncertain significance ★ ⚠ same condition
PRKACA p.Glu209Asp Uncertain significance ★ ⚠ same condition
PRKACA p.Gly201Ser Conflicting classifications of pathogenicity ★ ⚠ same condition
PRKACA p.Ile292Thr Uncertain significance ★ ⚠ same condition

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-leu75 (accessed [today's date]).

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