Is PRKCD p.Ala454= (c.1362C>T) pathogenic?

PRKCD p.Ala454= (c.1362C>T) is classified Likely benign in PRKCD (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-13). Ultra-rare (popmax 0.0774%, nfe); Associated with autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD.

What condition is associated with PRKCD p.Ala454= (c.1362C>T)?

PRKCD p.Ala454= (c.1362C>T) is associated with autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD (ClinVar).

How common is PRKCD p.Ala454= (c.1362C>T) in the general population?

PRKCD p.Ala454= (c.1362C>T) is ultra-rare (popmax 0.0774%, nfe) (gnomAD).

PRKCD p.Ala454=

Q: How is EBV-induced lymphoproliferative disease due to PRKCD deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1362C>T · rs41295962 · VCV541627

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0774%, nfe)

Conditions

autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD

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 -4	GERP -5.2
Overall
CADD	5.622	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0774% European (non-Finnish) · 913/1,180,028 alleles

Filtering AF 0.0732% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0715%

Overall 0.0618% 998/1,614,128 alleles · ultra-rare exomes 922/1,461,890 · genomes 76/152,238 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0774%	1,292
Remaining individualsnot grpmax-eligible	0.0576%	1,736
Middle Eastern	0.033%	3,031
Admixed American	0.03%	3,334
African / African-American	0.02%	5,001
East Asian	0.0156%	6,410
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804
South Asian	0.00439%	22,772
Finnishnot grpmax-eligible	0.00156%	64,030

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: PRKCD
Protein: p.Ala454=
Coding: c.1362C>T
MANE Select: NM_006254
dbSNP: rs41295962
Type: single nucleotide variant
Location: chr3:53187349 (GRCh38)
Gene constraint: LOEUF 0.344 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.29 · 2 PDB
Residue 454: the protein kinase domain

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

Disease context

autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For EBV-induced lymphoproliferative disease due to PRKCD deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

PRKCD p.Ala454Thr Uncertain significance ★★ same residue
PRKCD c.787+4C>T Uncertain significance ★★ same condition
PRKCD p.Ala195Val Uncertain significance ★★ ⚠ same condition
PRKCD p.Ala212Val Uncertain significance ★★ ⚠ same condition
PRKCD p.Ala404Gly Uncertain significance ★★ ⚠ same condition
PRKCD p.Arg273Trp Uncertain significance ★★ ⚠ same condition
PRKCD p.Arg40His Uncertain significance ★★ same condition
PRKCD p.Arg444Cys 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/prkcd-p-ala454 (accessed [today's date]).

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