Is PRKCD p.Arg40His (c.119G>A) pathogenic?

PRKCD p.Arg40His (c.119G>A) is classified Uncertain significance in PRKCD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-07). AlphaMissense: ambiguous (0.3713); Ultra-rare (popmax 0.0494%, sas); Associated with Inborn genetic diseases.

What condition is associated with PRKCD p.Arg40His (c.119G>A)?

PRKCD p.Arg40His (c.119G>A) is associated with Inborn genetic diseases, autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD (ClinVar).

How common is PRKCD p.Arg40His (c.119G>A) in the general population?

PRKCD p.Arg40His (c.119G>A) is ultra-rare (popmax 0.0494%, sas) (gnomAD).

What do computational predictors say about PRKCD p.Arg40His (c.119G>A)?

AlphaMissense predicts ambiguous (score 0.3713) — an in-silico prediction, not a clinical call.

PRKCD p.Arg40His

c.119G>A · rs376358631 · VCV2055331

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3713 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3713	ambiguous
REVEL	0.409	indeterminate
SaProt	LLR -5.88	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	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	26.1	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 0.0494% South Asian · 45/91,078 alleles

Filtering AF 0.0379% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0339%

Overall 0.00545% 88/1,614,070 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0494%	2,024
Middle Eastern	0.0493%	2,028
Ashkenazi Jewishnot grpmax-eligible	0.0439%	2,277
Remaining individualsnot grpmax-eligible	0.008%	12,497
African / African-American	0.004%	24,977
Finnishnot grpmax-eligible	0.00312%	32,018
European (non-Finnish)	0.00144%	69,414

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.Arg40His
Coding: c.119G>A
MANE Select: NM_006254
dbSNP: rs376358631
Type: single nucleotide variant
Location: chr3:53179580 (GRCh38)
Gene constraint: LOEUF 0.344 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.29 · 2 PDB
Residue 40: the c2 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD

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.Ala454Thr Uncertain significance ★★ same condition
PRKCD p.Arg273Trp Uncertain significance ★★ ⚠ same condition
PRKCD p.Arg444Cys Uncertain significance ★★ same condition
PRKCD p.Arg561His 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-arg40his (accessed [today's date]).

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