Is PIK3CB p.Leu725Phe (c.2175A>T) pathogenic?

PIK3CB p.Leu725Phe (c.2175A>T) is classified Uncertain significance in PIK3CB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-17). AlphaMissense: likely benign (0.2043); Very rare (popmax 0.00267%, afr).

How common is PIK3CB p.Leu725Phe (c.2175A>T) in the general population?

PIK3CB p.Leu725Phe (c.2175A>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about PIK3CB p.Leu725Phe (c.2175A>T)?

AlphaMissense predicts likely benign (score 0.2043) — an in-silico prediction, not a clinical call.

PIK3CB p.Leu725Phe

c.2175A>T · VCV3306611

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2043 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2043	likely benign
REVEL	0.383	indeterminate
SaProt	LLR -5.93	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.7	GERP -4, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 27 kb · p 3.3e-14 · regional, not allelic
Overall
CADD	18.21	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 0.00267% African / African-American · 2/74,910 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00155% 25/1,613,766 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,455
European (non-Finnish)	0.00186%	53,630
Admixed American	0.00167%	59,954

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: PIK3CB
Protein: p.Leu725Phe
Coding: c.2175A>T
MANE Select: NM_006219
Type: single nucleotide variant
Location: chr3:138684765 (GRCh38)
Gene constraint: LOEUF 0.319 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.62

Full PIK3CB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PIK3CB c.1302+10T>C Benign ★★ same type
PIK3CB p.Arg1069= Benign ★★ same type
PIK3CB p.Arg811= Benign ★★ same type
PIK3CB p.Asn717Ser Likely benign ★★ same type
PIK3CB p.Gln644= Benign ★★ same type
PIK3CB p.Phe508= Likely benign ★★ same type
PIK3CB p.Tyr618= Benign ★★ same type
PIK3CB p.Ala490Val Uncertain significance ★ ⚠ same type

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/pik3cb-p-leu725phe (accessed [today's date]).

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