Is PRKCD p.Ser331Gly (c.991A>G) pathogenic?

PRKCD p.Ser331Gly (c.991A>G) is classified Uncertain significance in PRKCD (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-08). AlphaMissense: likely benign (0.062); Very rare (popmax 0.00271%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PRKCD p.Ser331Gly (c.991A>G)?

PRKCD p.Ser331Gly (c.991A>G) is associated with Inborn genetic diseases, autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD (ClinVar).

How common is PRKCD p.Ser331Gly (c.991A>G) in the general population?

PRKCD p.Ser331Gly (c.991A>G) is very rare (popmax 0.00271%, nfe) (gnomAD).

What do computational predictors say about PRKCD p.Ser331Gly (c.991A>G)?

AlphaMissense predicts likely benign (score 0.062) — an in-silico prediction, not a clinical call.

PRKCD p.Ser331Gly

c.991A>G · rs140359417 · VCV937453

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.062 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.062	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -6.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.56	acceptor loss, 2 bp away · raw score · deltas
Constraint at this position
Conservation	phyloP 3.3	GERP 1.1, phastCons 0.019
Regional constraint	o/e 1.12	unconstrained · MANE · 1,037 bp · p 0.31 · regional, not allelic
Overall
CADD	15.21	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00271% European (non-Finnish) · 32/1,180,016 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00198% 32/1,614,060 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: PRKCD
Protein: p.Ser331Gly
Coding: c.991A>G
MANE Select: NM_006254
dbSNP: rs140359417
Type: single nucleotide variant
Location: chr3:53185932 (GRCh38)
Gene constraint: LOEUF 0.344 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.29 · 2 PDB

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.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-ser331gly (accessed [today's date]).

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