Is PRKCD p.Val90Met (c.268G>A) pathogenic?

PRKCD p.Val90Met (c.268G>A) is classified Uncertain significance in PRKCD (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-31). AlphaMissense: ambiguous (0.4297); Very rare (popmax 0.000171%, nfe); Associated with autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD.

What condition is associated with PRKCD p.Val90Met (c.268G>A)?

PRKCD p.Val90Met (c.268G>A) is associated with autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD (ClinVar).

How common is PRKCD p.Val90Met (c.268G>A) in the general population?

PRKCD p.Val90Met (c.268G>A) is very rare (popmax 0.000171%, nfe) (gnomAD).

What do computational predictors say about PRKCD p.Val90Met (c.268G>A)?

AlphaMissense predicts ambiguous (score 0.4297) — an in-silico prediction, not a clinical call.

PRKCD p.Val90Met

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.268G>A · rs1015113720 · VCV1016335

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4297 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000171%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD

Computational evidence

Protein change
AlphaMissense	0.4297	ambiguous
REVEL	0.253	benign-leaning
SaProt	LLR -7.63	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 3,131 bp · p 1.2e-05 · regional, not allelic
Overall
CADD	25.6	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

Grpmax group 0.000171% European (non-Finnish) · 2/1,171,112 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000125% 2/1,598,314 alleles · very rare exomes 0/1,446,104 · genomes 2/152,210 · joint denominator

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.Val90Met
Coding: c.268G>A
MANE Select: NM_006254
dbSNP: rs1015113720
Type: single nucleotide variant
Location: chr3:53179729 (GRCh38)
Gene constraint: LOEUF 0.344 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.29 · 2 PDB
Residue 90: the c2 domain; an α-helix

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 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
PRKCD p.Arg569His 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-val90met (accessed [today's date]).

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