Is PIK3CD p.Leu725Val (c.2173C>G) pathogenic?

PIK3CD p.Leu725Val (c.2173C>G) is classified Uncertain significance in PIK3CD (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-29). AlphaMissense: likely benign (0.0698); Very rare (popmax 0.004%, afr); Associated with immunodeficiency 14.

What condition is associated with PIK3CD p.Leu725Val (c.2173C>G)?

PIK3CD p.Leu725Val (c.2173C>G) is associated with immunodeficiency 14 (ClinVar).

How common is PIK3CD p.Leu725Val (c.2173C>G) in the general population?

PIK3CD p.Leu725Val (c.2173C>G) is very rare (popmax 0.004%, afr) (gnomAD).

How is Activated PI3K-delta syndrome 1 inherited?

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

What do computational predictors say about PIK3CD p.Leu725Val (c.2173C>G)?

AlphaMissense predicts likely benign (score 0.0698) — an in-silico prediction, not a clinical call.

PIK3CD p.Leu725Val

c.2173C>G · rs143471703 · VCV1479527

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0698 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 14

Computational evidence

Protein change
AlphaMissense	0.0698	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -3.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.71	GERP -0.088, phastCons 0.87
Regional constraint	o/e 0.67	unconstrained · MANE · 270 bp · p 0.0049 · regional, not allelic
Overall
CADD	16.89	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 0.004% African / African-American · 3/74,934 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,348 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: PIK3CD
Protein: p.Leu725Val
Coding: c.2173C>G
MANE Select: NM_005026
dbSNP: rs143471703
Type: single nucleotide variant
Location: chr1:9722092 (GRCh38)
Gene constraint: LOEUF 0.23 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.21 · 20 PDB
Residue 725: a UniProt-annotated variant site (in rochis; no protein can be detected by western blot in patient cells); 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-leu725val (accessed [today's date]).

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