Is PIK3CD p.Pro65= (c.195C>G) pathogenic?

PIK3CD p.Pro65= (c.195C>G) is classified Likely benign in PIK3CD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-06). Very rare (popmax 0.000169%, nfe); Associated with immunodeficiency 14.

What condition is associated with PIK3CD p.Pro65= (c.195C>G)?

PIK3CD p.Pro65= (c.195C>G) is associated with immunodeficiency 14 (ClinVar).

How common is PIK3CD p.Pro65= (c.195C>G) in the general population?

PIK3CD p.Pro65= (c.195C>G) is very rare (popmax 0.000169%, 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.Pro65=

c.195C>G · rs752425885 · VCV1654429

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

immunodeficiency 14

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP -4.3	GERP -4.4
Overall
CADD	6.525	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,044 alleles

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

Overall 0.000124% 2/1,613,828 alleles · very rare exomes 2/1,461,448 · genomes 0/152,380 · 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: PIK3CD
Protein: p.Pro65=
Coding: c.195C>G
MANE Select: NM_005026
dbSNP: rs752425885
Type: single nucleotide variant
Location: chr1:9715594 (GRCh38)
Gene constraint: LOEUF 0.23 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.21 · 20 PDB
Residue 65: the pi3k-abd domain; an α-helix

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.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
PIK3CD p.Gly124Asp 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-pro65 (accessed [today's date]).

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