Is PRKCH p.Ile445= (c.1335T>A) pathogenic?

PRKCH p.Ile445= (c.1335T>A) is classified Benign in PRKCH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). Common (popmax 6.95%, afr) — too common for a highly-penetrant pathogenic allele.

PRKCH p.Ile445=

Q: How common is PRKCH p.Ile445= (c.1335T>A) in the general population?

PRKCH p.Ile445= (c.1335T>A) is common (popmax 6.95%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1335T>A · rs2230502 · VCV768657

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 6.95%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.2	GERP -5.6, phastCons 0.56
Overall
CADD	7.511	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.95% African / African-American · 5,217/75,030 alleles

Filtering AF 6.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.73%

Overall 0.362% 5,838/1,614,178 alleles · common exomes 2,860/1,461,884 · genomes 2,978/152,294 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.95%	14
Admixed American	0.455%	220
Remaining individualsnot grpmax-eligible	0.387%	258
Middle Eastern	0.198%	505
South Asian	0.0154%	6,506
European (non-Finnish)	0.00678%	14,750

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: PRKCH
Protein: p.Ile445=
Coding: c.1335T>A
MANE Select: NM_006255
dbSNP: rs2230502
Type: single nucleotide variant
Location: chr14:61485558 (GRCh38)
Gene constraint: LOEUF 0.467 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.75 · 4 PDB
Residue 445: the protein kinase domain; an α-helix

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

Similar variants

PRKCH p.Ile445Val Uncertain significance ★ ⚠ same residue
PRKCH c.578+3A>G Uncertain significance ★ same type
PRKCH p.Ala114Val Uncertain significance ★ ⚠ same type
PRKCH p.Ala539Thr Uncertain significance ★ ⚠ same type
PRKCH p.Ala620Val Uncertain significance ★ ⚠ same type
PRKCH p.Arg110Cys Uncertain significance ★ ⚠ same type
PRKCH p.Arg149Trp Uncertain significance ★ ⚠ same type
PRKCH p.Arg26His 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/prkch-p-ile445 (accessed [today's date]).

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