Is PIK3CD p.Pro322= (c.966G>A) pathogenic?

PIK3CD p.Pro322= (c.966G>A) is classified Likely benign in PIK3CD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-22). Very rare (popmax 0.00661%, nfe); Associated with immunodeficiency 14.

What condition is associated with PIK3CD p.Pro322= (c.966G>A)?

PIK3CD p.Pro322= (c.966G>A) is associated with immunodeficiency 14 (ClinVar).

How common is PIK3CD p.Pro322= (c.966G>A) in the general population?

PIK3CD p.Pro322= (c.966G>A) is very rare (popmax 0.00661%, nfe) (gnomAD).

How is Activated PI3K-delta syndrome 1 inherited?

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

PIK3CD p.Pro322=

c.966G>A · rs769665281 · VCV1119362

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00661%, nfe)

Conditions

immunodeficiency 14

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 -9.2	GERP -3.8
Overall
CADD	2.178	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00661% European (non-Finnish) · 78/1,180,042 alleles

Filtering AF 0.00538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00498%

Overall 0.00527% 85/1,613,974 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00661%	15,129
South Asian	0.00329%	30,362
East Asian	0.00223%	44,900
Remaining individualsnot grpmax-eligible	0.0016%	62,484
Finnishnot grpmax-eligible	0.00156%	63,928
African / African-American	0.00133%	74,928

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: PIK3CD
Protein: p.Pro322=
Coding: c.966G>A
MANE Select: NM_005026
dbSNP: rs769665281
Type: single nucleotide variant
Location: chr1:9717572 (GRCh38)
Gene constraint: LOEUF 0.23 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.21 · 20 PDB
Residue 322: the c2 pi3k-type domain; a β-strand

Full PIK3CD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Activated PI3K-delta syndrome 1 (Orphanet):

Inheritance: Autosomal dominant

Similar variants

PIK3CD p.Pro322Leu Uncertain significance ★★★ ⚠ same residue
PIK3CD p.Asn334Lys Likely pathogenic ★★★ ⚠ same condition
PIK3CD p.Glu1021Lys Pathogenic ★★★ ⚠ same condition
PIK3CD p.Glu1025Gly Pathogenic ★★★ ⚠ same condition
PIK3CD p.Glu525Ala Likely pathogenic ★★★ ⚠ same condition
PIK3CD p.Glu525Gly Likely pathogenic ★★★ ⚠ same condition
PIK3CD p.Glu525Lys Pathogenic ★★★ ⚠ same condition
PIK3CD p.Glu81Lys Likely pathogenic ★★★ 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/pik3cd-p-pro322 (accessed [today's date]).

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