Is APOL1 p.Ile245Val (c.733A>G) pathogenic?

APOL1 p.Ile245Val (c.733A>G) is classified Uncertain significance in APOL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-24). AlphaMissense: likely benign (0.1); Very rare (popmax 0.00173%, amr); Associated with focal segmental glomerulosclerosis 4, susceptibility to.

What condition is associated with APOL1 p.Ile245Val (c.733A>G)?

APOL1 p.Ile245Val (c.733A>G) is associated with focal segmental glomerulosclerosis 4, susceptibility to (ClinVar).

How common is APOL1 p.Ile245Val (c.733A>G) in the general population?

APOL1 p.Ile245Val (c.733A>G) is very rare (popmax 0.00173%, amr) (gnomAD).

What do computational predictors say about APOL1 p.Ile245Val (c.733A>G)?

AlphaMissense predicts likely benign (score 0.1) — an in-silico prediction, not a clinical call.

APOL1 p.Ile245Val

c.733A>G · VCV3587923

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00173%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

focal segmental glomerulosclerosis 4, susceptibility to

Computational evidence

Protein change
AlphaMissense	0.1	likely benign
REVEL	0.009	strongly benign-leaning
SaProt	LLR -5.58	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 -20	GERP -3.4
Regional constraint	o/e 1.08	unconstrained · MANE · 11 kb · p 0.093 · regional, not allelic
Overall
CADD	0.107	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 0.00173% Admixed American · 1/57,968 alleles

Filtering AF 0.000361% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000261%

Overall 0.000691% 10/1,448,020 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00173%	57,968
European (non-Finnish)	0.000767%	130,370

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: APOL1
Protein: p.Ile245Val
Coding: c.733A>G
MANE Select: NM_003661
Type: single nucleotide variant
Location: chr22:36265569 (GRCh38)
Gene constraint: LOEUF 1.68 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.94 · 5 PDB

Full APOL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

focal segmental glomerulosclerosis 4, susceptibility to — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

APOL1 p.Ala394Gly Uncertain significance ★★ ⚠ same condition
APOL1 p.Arg112Cys Uncertain significance ★★ ⚠ same condition
APOL1 p.Glu323Gln Uncertain significance ★★ ⚠ same condition
APOL1 p.Ile384Phe Uncertain significance ★★ ⚠ same condition
APOL1 p.Leu266Arg Uncertain significance ★★ ⚠ same condition
APOL1 p.Leu286Val Uncertain significance ★★ ⚠ same condition
APOL1 p.Tyr351His Uncertain significance ★★ ⚠ same condition
APOL1 c.188-14T>A Benign/Likely benign ★★ 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/apol1-p-ile245val (accessed [today's date]).

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