Is PRKCE p.Phe484Leu (c.1450T>C) pathogenic?

PRKCE p.Phe484Leu (c.1450T>C) is classified Uncertain significance in PRKCE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely pathogenic (0.9983); Very rare (popmax 0.00401%, afr).

How common is PRKCE p.Phe484Leu (c.1450T>C) in the general population?

PRKCE p.Phe484Leu (c.1450T>C) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about PRKCE p.Phe484Leu (c.1450T>C)?

AlphaMissense predicts likely pathogenic (score 0.9983) — an in-silico prediction, not a clinical call.

PRKCE p.Phe484Leu

c.1450T>C · VCV4144424

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9983 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9983	likely pathogenic
REVEL	0.452	indeterminate
SaProt	LLR -11.97	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 7.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 79 kb · p 1.6e-07 · regional, not allelic
Overall
CADD	29.2	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

Grpmax group 0.00401% African / African-American · 3/74,902 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000188% 3/1,599,462 alleles · very rare

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: PRKCE
Protein: p.Phe484Leu
Coding: c.1450T>C
MANE Select: NM_005400
Type: single nucleotide variant
Location: chr2:46086220 (GRCh38)
Gene constraint: LOEUF 0.278 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.45 · 2 PDB
Residue 484: the protein kinase domain

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

Similar variants

PRKCE p.Ala654Thr Benign ★★ same type
PRKCE p.Lys437= Benign ★★ same type
PRKCE p.Thr455= Benign ★★ same type
PRKCE p.Glu328Gln Likely pathogenic ★ ⚠ same type
PRKCE p.Glu599Lys Pathogenic ★ same type
PRKCE p.Arg150Cys Uncertain significance ★ ⚠ same type
PRKCE p.Arg150His Uncertain significance ★ same type
PRKCE p.Arg152Gln 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/prkce-p-phe484leu (accessed [today's date]).

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